|
The compound was tested for inhibitory activity against 5-Lipoxygenase in rat RBL-1
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : 5-lipoxygenase: properties, pharmacology, and the quinolinyl(bridged)aryl class of inhibitors.
Year : 1992
Volume : 35
Issue : 14
First Page : 2501
Last Page : 2524
Authors : Musser JH, Kreft AF.
Abstract : In conclusion, an effective modulator of the AA cascade for the treatment of asthma and other inflammatory diseases may require 5-LO inhibitory activity as well as LTD4 antagonism in order to limit the effects of LTB4, LTD4, and 5-HPETE. The unknown role of LTC4 with respect to bronchoconstriction and mucus production could mask the efficacy of a pure LTD4 antagonist in man, whereas the chemotactic property of LTB4 for eosinophils can contribute to lung inflammation. Indeed, it is observed that the blood of patients with bronchial asthma has increased numbers of hypodense eosinophils. In addition, the formation of lipid-derived peroxide radicals, such as 5-HPETE, are believed to be responsible for various types of cellular injuries associated with the inflammatory disease process. Because inhibition of the CO pathway is thought to explain the therapeutic effects of nonsteroidal antiinflammatory agents in rheumatic diseases, a 5-LO inhibitor with CO inhibitory activity may also be desirable profile for an antiasthma agent. The validation of the LT hypothesis of disease had to wait for the demonstration of a clinical effect by either a LTD4 receptor antagonist or a LT synthesis inhibitor (5-LO inhibitor). Only very recently has this evidence become available and it is now apparent that compounds that antagonize LTD4 receptors or inhibit LT synthesis have shown clinical efficacy in a wide range of diseases. Due to the breakthrough nature of this approach, certain of these compounds are being considered for expedited development. The absence of side effects seen in the clinical trials of selective 5-LO inhibitors is gratifying and argues that LTs are not important in homeostasis. Only time will tell whether 5-LO inhibitors will take their place in the therapeutic armamentarium; however, the recent demonstration of clinical efficacy by a number of these compounds is a significant step in this direction.
|
In vitro inhibitory activity against 5-lipoxygenase in a human whole blood assay
|
None
|
873.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-lipoxygenase inhibitors with histamine H(1) receptor antagonist activity.
Year : 2004
Volume : 14
Issue : 9
First Page : 2265
Last Page : 2268
Authors : Lewis TA, Bayless L, Eckman JB, Ellis JL, Grewal G, Libertine L, Marie Nicolas J, Scannell RT, Wels BF, Wenberg K, Wypij DM.
Abstract : A series of novel compounds with both 5-lipoxygenase (5-LO) inhibitory and histamine H(1) receptor antagonist activity were designed for the treatment of asthma. These dual-function compounds were made by connecting 5-LO and H(1) pharmacophores,N-hydroxyureas and benzhydryl piperazines, respectively. A range of in vitro activities was observed, with the furan analog 10 demonstrating both activities in an animal model. The activities observed were compared to single-function drugs.
|
Inhibitory activity against 5-lipoxygenase in Human whole blood (HWBL) stimulated with calcium ionophore (A23187) and LTB4 measured by enzyme immunoassay
|
Homo sapiens
|
760.0
nM
|
|
Journal : J. Med. Chem.
Title : Nonsteroidal anti-inflammatory drugs as scaffolds for the design of 5-lipoxygenase inhibitors.
Year : 1997
Volume : 40
Issue : 5
First Page : 819
Last Page : 824
Authors : Kolasa T, Brooks CD, Rodriques KE, Summers JB, Dellaria JF, Hulkower KI, Bouska J, Bell RL, Carter GW.
Abstract : Representative nonsteroidal anti-inflammatory drug (NSAID) cyclooxygenase inhibitors such as ibuprofen, naproxen, and indomethacin were used as orally bioavailable scaffolds to design selective 5-lipoxygenase (5-LO) inhibitors. Replacement of the NSAID carboxylic acid group with a N-hydroxyurea group provided congeners with selective 5-LO inhibitory activity.
|
Inhibition of 5-lipoxygenase mediated conversion of [14C]arachidonic acid to leukotrienes in RBL-2H3 cells
|
Rattus norvegicus
|
804.0
nM
|
|
Journal : J. Med. Chem.
Title : (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and platelet-activating factor receptor antagonist.
Year : 1998
Volume : 41
Issue : 11
First Page : 1970
Last Page : 1979
Authors : Cai X, Scannell RT, Yaeger D, Hussoin MS, Killian DB, Qian C, Eckman J, Hwang SB, Libertine-Garahan L, Yeh CG, Ip SH, Shen TY.
Abstract : By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid- and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl- N-h ydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.
|
Inhibition of 5-Lipoxygenase of rat basophilic leukemia cells
|
Rattus norvegicus
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Vinylogous hydroxamic acids: 5-lipoxygenase inhibitors
Year : 1992
Volume : 2
Issue : 9
First Page : 1079
Last Page : 1084
Authors : Wright SW, Pinto DJ, Sherk SR, Green AM, Magolda RL
|
Compound was tested for its inhibitory activity against 5-lipoxygenase in rat.
|
None
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Development of L-689,065 - the prototype of a new class of potent 5-lipoxygenase inhibitors
Year : 1992
Volume : 2
Issue : 12
First Page : 1699
Last Page : 1702
Authors : Hutchinson J, Prasit P, Choo L, Riendeau D, Charleson S, Evans J, Piechuta H, Ball R
|
In vitro inhibition of 5-lipoxygenase (5-HETE) derived from the 9000xg supernatant of RBL broken cell assay
|
None
|
370.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and 5-lipoxygenase inhibitory activities of some novel 2-substituted 5-benzofuran hydroxamic acids.
Year : 1994
Volume : 37
Issue : 21
First Page : 3663
Last Page : 3667
Authors : Ohemeng KA, Appollina MA, Nguyen VN, Schwender CF, Singer M, Steber M, Ansell J, Argentieri D, Hageman W.
Abstract : A series of 2-substituted benzofuran hydroxyamic acids were synthesized as rigid analogs of simple (benzyloxy)phenyl hydroxamates, evaluated for their in vitro and in vivo 5-lipoxygenase activity and found to be potent inhibitors of the enzyme. Substituents which enhanced lipophilicity near the 2-position of the benzofuran nucleus increased inhibitor potency but reduced oral activity. Incorporation of small polar substituents such as methoxymethylene, hydroxymethylene, and amino (urea) on the acyl group led to more consistent oral activity. The most potent inhibitors of this series in vitro were N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)-ethyl]furancarboxamide (12) and methyl 5-[N-hydroxy-N-[1-(2-(3,4,5-trimethoxyphenyl)-5-benzofuranyl]ethyl]-5- oxopentanoate (17), both with IC50 values of 40 nM, and in vivo the most potent compound was N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea, 20, with an ED50 = 10.3 mg/kg.
|
Inhibitory activity against 5-lipoxygenase catalysis (5-LO) in sonicated rat basophilic leukemia cell lysate
|
Rattus norvegicus
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Nonsteroidal anti-inflammatory drugs as scaffolds for the design of 5-lipoxygenase inhibitors.
Year : 1997
Volume : 40
Issue : 5
First Page : 819
Last Page : 824
Authors : Kolasa T, Brooks CD, Rodriques KE, Summers JB, Dellaria JF, Hulkower KI, Bouska J, Bell RL, Carter GW.
Abstract : Representative nonsteroidal anti-inflammatory drug (NSAID) cyclooxygenase inhibitors such as ibuprofen, naproxen, and indomethacin were used as orally bioavailable scaffolds to design selective 5-lipoxygenase (5-LO) inhibitors. Replacement of the NSAID carboxylic acid group with a N-hydroxyurea group provided congeners with selective 5-LO inhibitory activity.
|
Inhibitory concentration against human platelet 5-lipoxygenase in dog whole blood
|
Canis lupus familiaris
|
840.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituted chromenes as potent, orally active 5-lipoxygenase inhibitors.
Year : 1993
Volume : 36
Issue : 23
First Page : 3580
Last Page : 3594
Authors : Satoh Y, Stanton JL, Hutchison AJ, Libby AH, Kowalski TJ, Lee WH, White DH, Kimble EF.
Abstract : A series of chromene derivatives was synthesized and evaluated for their in vitro and ex vivo 5-lipoxygenase (5-LO) inhibitory activity. These compounds were prepared by condensation of appropriate salicyl aldehydes with alpha, beta-unsaturated carbonyl compounds, followed by transformation to the corresponding hydroxamic acids or N-hydroxyureas. Placement of phenoxy or p-fluorophenoxy substituents at the 6 position of the chromene ring led to a dramatic increase in the in vitro potency as demonstrated by the guinea pig PMN 5-LO assay. Chromene hydroxamic acids, in general, behaved poorly in the ex vivo dog model. On the other hand, replacement of the hydroxamic acid function with N-hydroxyurea yielded potent and long-lasting 5-LO inhibitors in the dog model. In most cases, the oral efficacy of the chromene N-hydroxyureas correlated very well with their in vitro activity. Compounds 43 (CGS 23885) and 55 (CGS 24891) are among the most potent inhibitors prepared, showing IC50 values of 48 and 51 nM, respectively. The values for the duration of action (DA) for compounds 43 and 55 are 21 and 20 h, respectively, following intravenous (i.v.) administration of 1.0 mg/kg. In the oral (po) experiments, 43 and 55 have DA's of 14 and 15 h, respectively, at a 1.0 mg/kg dose. In both iv and po experiments, 43 and 55 showed sustained maximal inhibition (> 95%) at earlier time points. The oral ED50 values of 43 and 55 in the ex vivo dog model are 0.23 and 0.23 mg/kg, respectively, at 6.0 h, and 2.37 and 1.63 mg/kg, respectively, at 24 h. Compound 43, which inhibits sheep seminal vesicle cyclooxygenase (CO) with an IC50 value of 36 microM, was shown to be a selective 5-lipoxygenase inhibitor in the ex vivo study. These compounds compare favorably with zileuton (A-64077) in all the parameters examined.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 0.08h, following intravenous administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
96.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 0.25h, following intravenous administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
94.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 0.5h, following intravenous administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
91.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 0.5h, following peroral administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
94.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 1.0h, following intravenous administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
87.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 1.0h, following peroral administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
91.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 24h, following intravenous administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
27.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 24h, following peroral administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
25.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 3.0h, following intravenous administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
81.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 3.0h, following peroral administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
87.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 6.0h, following intravenous administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
56.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 6.0h, following peroral administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
74.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 9.0h, following intravenous administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
47.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition of 5-lipoxygenase was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 9.0h, following peroral administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
49.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Ex vivo inhibition was determined by the measurement of A-23187-stimulated LTB4 production in dog blood at 0.25h, following peroral administration at the dose of 1.0 mg/kg
|
Canis lupus familiaris
|
89.0
%
|
|
Journal : J. Med. Chem.
Title : Derivatives of 2-[[N-(Aminocarbonyl)-N-hydroxyamino]methyl]-1,4- benzodioxan as orally active 5-lipoxygenase inhibitors.
Year : 1995
Volume : 38
Issue : 1
First Page : 68
Last Page : 75
Authors : Satoh Y, Powers C, Toledo LM, Kowalski TJ, Peters PA, Kimble EF.
Abstract : N-Hydroxyureas based on the 1,4-benzodioxan template were prepared from appropriately substituted 1,4-benzodioxan-2-methanols as the key intermediates and evaluated in the in vitro guinea pig polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay for their 5-LO inhibitory activity. Placement of a 7-phenoxy or 7-p-fluorophenoxy substituent resulted in a dramatic increase in in vitro potency. Selected compounds were subsequently assayed in an ex vivo dog model of LTB4 synthesis at a dose of 1.0 mg/kg. The 7-phenoxy derivatives 16 and 17 showed modest duration of action (DA) in this dog model. The 6-regioisomers 21 and 22 were less potent. Replacement of the 7-phenoxy group of 16 with the p-fluorophenoxy moiety enhanced the DA dramatically. Compound 18 (CGS 25667), which had an IC50 value of 100 nM in the in vitro guinea pig 5-LO assay, had a DA of 8.5 h (zileuton, DA = 8.5 h) at the oral dose of 1.0 mg/kg. Optical antipodes (24, 26) of 18 were independently synthesized in high (> 95%) enantiomeric purity from commercially available optically active glycidyl tosylates and evaluated. In the in vitro assay, the 2S-(-)-enantiomer (24, CGS 25997, IC50 = 85 nM) was found to be twice as active as the 2R-(+)-counterpart (26, CGS 25998, IC50 = 180 nM). In the ex vivo experiment, 24, which dose dependently inhibited plasma 5-LO activity, was shown to be significantly longer acting than 26, with a DA of 8.4 h when dosed orally at 1.0 mg/kg.
|
Inhibitory activity uM
|
Cavia porcellus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis, structure-activity relationships, and pharmacological evaluation of pyrrolo[3,2,1-ij]quinoline derivatives: potent histamine and platelet activating factor antagonism and 5-lipoxygenase inhibitory properties. Potential therapeutic application in asthma.
Year : 1995
Volume : 38
Issue : 4
First Page : 669
Last Page : 685
Authors : Paris D, Cottin M, Demonchaux P, Augert G, Dupassieux P, Lenoir P, Peck MJ, Jasserand D.
Abstract : A series of pyrrolo[3,2,1-ij]quinoline derivatives was synthesized and evaluated for their in vitro and in vivo activities against histamine, platelet activating factor (PAF), and leukotrienes which are recognized to be of importance in asthma. The structure-activity relationship studies have shown that the optimum moiety on the 1-position of the pyrroloquinoline nucleus is a 2-[4-(4-methyl-2-pyridinyl)-1-piperazinyl]ethyl chain in conjunction with a methyl group on the 2-position for potent antagonism of both histamine and PAF. The introduction of substituents on the 8- and 4-positions was also investigated in order to increase the potency of 5-lipoxygenase inhibition while retaining or improving the activities against histamine and PAF. This series is exemplified by 4-n-butyl-5,6-dihydro-8-hydroxy-2-methyl-1- [2-[4-(4-methyl-2-pyridinyl)-1-piperazinyl]ethyl]-4H-pyrrolo[3,2,1- ij]quinoline (24, KC 11404) which was found to be active against all three of the selected mediators. Compound 24 was found to be orally active in guinea pig models against the histaminic phase of antigen-induced bronchospasm and PAF-induced bronchoconstriction (ED50 = 1.9 and 2.1 mumol/kg, respectively). When tested against the leukotriene-dependent phase of the antigen-induced bronchoconstriction, compound 24 showed the same potency as zileuton.
|
5-lipoxygenase Inhibitory activity was measured by enzyme immunoassay using human whole blood stimulated with calcium ionophore (A23187) and LTB4 (leukotriene B4)
|
None
|
740.0
nM
|
|
Journal : J. Med. Chem.
Title : (R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl- 2-propynyl]-N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor.
Year : 1995
Volume : 38
Issue : 24
First Page : 4768
Last Page : 4775
Authors : Brooks CD, Stewart AO, Basha A, Bhatia P, Ratajczyk JD, Martin JG, Craig RA, Kolasa T, Bouska JB, Lanni C.
Abstract : Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5-lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N-hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N- hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2- thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene-mediated disorders.
|
Inhibitory activity against 5-lipoxygenase obtained from rat basophilic leukemia cells
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of conformationally constrained aci-reductone mimics of arachidonic acid.
Year : 1998
Volume : 41
Issue : 4
First Page : 420
Last Page : 427
Authors : Hopper AT, Witiak DT, Ziemniak J.
Abstract : An efficient and convergent synthesis has been developed for the production of 3,4-dihydroxy-5-[4-(2-((2Z)-hexenyl)phenyl)-3-(1Z)-but enyl]-2 (5H)-furanone (12d). This hydrophobic antioxidant is a stable conformationally constrained mimic of arachidonic acid (AA) (1) and its respective aci-reductone analogue (2). Pd(0)-catalyzed cross-coupling of 5-(3-butynyl)-3,4-dihydroxy-2(5H)-furanone (7) with 2-((2Z)-hexenyl)iodobenzene (8d) followed by Lindlar catalyzed hydrogenation produces 12d. Butynyl intermediate 7 is prepared from 2-(benzyloxy)-5-deoxyascorbic acid (15) by iodination (I2, PPh3, Imd), iodo substitution with lithium acetylide ethylenediamine complex (LiAEDA, HMPA, -5 degrees C), and benzyl group cleavage (Ac2O, Pyr, BCl3). The utility of this synthetic method was demonstrated by the synthesis of analogues 10e-k. Biological testing revealed that certain of these antioxidants inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) with comparable efficacy as reported for aspirin and zileuton, respectively. The antioxidant activity of these aci-reductones, measured as a function of their inhibitory effect on CCl4-induced lipid peroxidation of hepatic microsomes, exceeds that produced by alpha-tocopherol. Synthetic routes and initial structure-activity relationships (SAR) for these novel mixed functioning antioxidants are presented.
|
The compound was tested for its inhibitory activity against arachidonic acid in rat 5-lipoxygenase
|
None
|
320.0
nM
|
|
Journal : J. Med. Chem.
Title : Development of 2,3-dihydro-6-(3-phenoxypropyl)-2-(2-phenylethyl)-5-benzofuranol (L-670,630) as a potent and orally active inhibitor of 5-lipoxygenase.
Year : 1992
Volume : 35
Issue : 7
First Page : 1299
Last Page : 1318
Authors : Lau CK, Bélanger PC, Dufresne C, Scheigetz J, Therien M, Fitzsimmons B, Young RN, Ford-Hutchinson AW, Riendeau D, Denis D.
Abstract : Leukotrienes are potent biological mediators of allergic and inflammatory diseases and are derived from arachidonic acid through the action of the 5-lipoxygenase. In this study, the syntheses and comparative biological activities of three series of 2,3-dihydro-2,6-disubstituted-5-benzofuranols with various substituents on position 3 are described. Compounds from each series were evaluated for their ability to inhibit the production of leukotriene B4 (LTB4) in human peripheral blood polymorphonuclear (PMN) leukocytes and the 5-lipoxygenase reaction in cell-free preparations from rat PMN leukocytes. The structure-activity relationships of each series in vitro and in vivo are presented. The bioavailability, metabolism, and toxicity profile of each series are discussed. The series with no substituent at position 3 was the most potent and among the compounds in that series 2,3-dihydro-6-(3-phenoxypropyl)-2-(2-phenylethyl)-5-benzofuranol (46, L-670,630) was chosen for further development.
|
In vitro inhibition of 5-lipoxygenase (5-lo) from the 20000 g supernatant of RBI-1 cells
|
None
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-hydroxythiazole inhibitors of 5-lipoxygenase.
Year : 1991
Volume : 34
Issue : 7
First Page : 2158
Last Page : 2165
Authors : Kerdesky FA, Holms JH, Moore JL, Bell RL, Dyer RD, Carter GW, Brooks DW.
Abstract : 4-Hydroxythiazoles have been identified as potent inhibitors of 5-lipoxygenase in vitro exhibiting IC50's of less than 1 microM. An investigation of structure-activity relationships showed that the most potent inhibitors of this series are the 5-phenyl derivatives. The corresponding thiazolidin-4-one analogues were found to be relatively inactive. The 4-hydroxythiazoles were active inhibitors against 5-lipoxygenase in both intact rat polymorphonuclear leukocytes and human whole blood. The compounds were also selective inhibitors of 5-lipoxygenase, displaying only weak activity against other related enzymes, cyclooxygenase and 12- and 15-lipoxygenase.
|
Inhibition of 5-lipoxygenase on rat basophil leukemia cell line lysate (RBL-1 2H3 subline) by measuring 5-HETE production
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of N-hydroxyurea 5-lipoxygenase inhibitors.
Year : 1997
Volume : 40
Issue : 13
First Page : 1955
Last Page : 1968
Authors : Stewart AO, Bhatia PA, Martin JG, Summers JB, Rodriques KE, Martin MB, Holms JH, Moore JL, Craig RA, Kolasa T, Ratajczyk JD, Mazdiyasni H, Kerdesky FA, DeNinno SL, Maki RG, Bouska JB, Young PR, Lanni C, Bell RL, Carter GW, Brooks CD.
Abstract : The discovery of second generation N-hydroxyurea 5-lipoxygenase inhibitors was accomplished through the development of a broad structure-activity relationship (SAR) study. This study identified requirements for improving potency and also extending duration by limiting metabolism. Potency could be maintained by the incorporation of heterocyclic templates substituted with selected lipophilic substituents. Duration of inhibition after oral administration was optimized by identification of structural features in the proximity of the N-hydroxyurea which correlated to low in vitro glucuronidation rates. Furthermore, the rate of in vitro glucuronidation was shown to be stereoselective for certain analogs. (R)-N-[3-[5-(4-Fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N-hydroxyure a (17c) was identified and selected for clinical development.
|
Inhibitory activity against LTB4 production upon intravenous administration at a dose of 1.0 mg/Kg (0.08-0.5 hour) in dog ex vivo model
|
Canis lupus familiaris
|
90.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzoxepin and benzothiepin derivatives as potent, orally active inhibitors of 5-lipoxygenase
Year : 1994
Volume : 4
Issue : 4
First Page : 549
Last Page : 552
Authors : Satoh Y, Libby AH, Powers C, Kowalski TJ, White D, Kimble EF
|
Inhibitory activity against LTB4 production upon oral administration at a dose of 1.0 mg/Kg (0.5-1 hour) in dog ex vivo model
|
Canis lupus familiaris
|
90.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzoxepin and benzothiepin derivatives as potent, orally active inhibitors of 5-lipoxygenase
Year : 1994
Volume : 4
Issue : 4
First Page : 549
Last Page : 552
Authors : Satoh Y, Libby AH, Powers C, Kowalski TJ, White D, Kimble EF
|
In vitro binding affinity towards histamine H1 receptor at 5 mg/kg
|
Cavia porcellus
|
82.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-lipoxygenase inhibitors with histamine H(1) receptor antagonist activity.
Year : 2004
Volume : 14
Issue : 9
First Page : 2265
Last Page : 2268
Authors : Lewis TA, Bayless L, Eckman JB, Ellis JL, Grewal G, Libertine L, Marie Nicolas J, Scannell RT, Wels BF, Wenberg K, Wypij DM.
Abstract : A series of novel compounds with both 5-lipoxygenase (5-LO) inhibitory and histamine H(1) receptor antagonist activity were designed for the treatment of asthma. These dual-function compounds were made by connecting 5-LO and H(1) pharmacophores,N-hydroxyureas and benzhydryl piperazines, respectively. A range of in vitro activities was observed, with the furan analog 10 demonstrating both activities in an animal model. The activities observed were compared to single-function drugs.
|
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophil assay
|
None
|
320.0
nM
|
|
Journal : J. Med. Chem.
Title : Heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids as leukotriene biosynthesis inhibitors.
Year : 2000
Volume : 43
Issue : 4
First Page : 690
Last Page : 705
Authors : Kolasa T, Gunn DE, Bhatia P, Woods KW, Gane T, Stewart AO, Bouska JB, Harris RR, Hulkower KI, Malo PE, Bell RL, Carter GW, Brooks CD.
Abstract : A novel series of heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as leukotriene biosynthesis inhibitors. A hypothesis of structure-activity optimization by insertion of an oxime moiety was investigated using REV-5901 as a starting point. A systematic structure-activity optimization showed that the spatial arrangement and stereochemistry of the oxime insertion unit proved to be important for inhibitory activity. The promising lead, S-(E)-11, inhibited LTB(4) biosynthesis in the intact human neutrophil with IC(50) of 8 nM and had superior oral activity in vivo, in a rat pleurisy model (ED(50) = 0.14 mg/kg) and rat anaphylaxis model (ED(50) = 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked LTE(4) biosynthesis (ED(50) of 0.1 mg/kg) and eosinophil influx (ED(50) of 0.2 mg/kg). S-(E)-11 (A-93178) was selected for further preclinical evaluation.
|
Compound was tested for in vitro inhibition on human whole blood.
|
Homo sapiens
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Modulators of leukotriene biosynthesis and receptor activation.
Year : 1996
Volume : 39
Issue : 14
First Page : 2629
Last Page : 2654
Authors : Brooks CD, Summers JB.
|
Effect on production of LTB4 in human whole blood
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Thiopyrano[2,3,4-cd]indoles as 5-lipoxygenase inhibitors: synthesis, biological profile, and resolution of 2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5 -dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]butanoic acid.
Year : 1994
Volume : 37
Issue : 8
First Page : 1153
Last Page : 1164
Authors : Hutchinson JH, Riendeau D, Brideau C, Chan C, Falgueyret JP, Guay J, Jones TR, Lépine C, Macdonald D, McFarlane CS.
Abstract : Leukotriene biosynthesis inhibitors have potential as new therapies for asthma and inflammatory diseases. The recently disclosed thiopyrano[2,3,4-cd]indole class of 5-lipoxygenase (5-LO) inhibitors has been investigated with particular emphasis on the side chain bearing the acidic functionality. The SAR studies have shown that the inclusion of a heteroatom (O or S) in conjunction with an alpha-ethyl substituted acid leads to inhibitors of improved potency. The most potent inhibitor prepared contains a 2-ethoxybutanoic acid side chain. This compound, 14d (2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methox y]- 4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]-butanoic acid, L-699,333), inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50s of 22 nM, 7 nM and 3.8 microM, respectively). The racemic acid 14d has been shown to be functionally active in a rat pleurisy model (inhibition of LTB4, ED50 = 0.65 mg/kg, 6 h pretreatment) and in the hyperreactive rat model of antigen-induced dyspnea (50% inhibition at 2 and 4 h pretreatment; 0.5 mg/kg po). In addition, 14d shows excellent functional activity against antigen-induced bronchoconstriction in the conscious squirrel monkey [89% inhibition of the increase in RL and 68% inhibition in the decrease in Cdyn (0.1 mg/kg, n = 3)] and in the conscious sheep models of asthma (iv infusion at 2.5 micrograms/kg/min). Acid 14d is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of human 15-LO, porcine 12-LO and ram seminal vesicle cyclooxygenase (IC50 > 5 microM) or competition in a FLAP binding assay (IC50 > 10 microM). Resolution of 14d affords 14g, the most potent diastereomer, which inhibits the 5-HPETE production of human 5-LO and LTB4 biosynthesis of human PMN leukocytes and human whole blood with IC50s of 8 nM, 4 nM, and 1 microM respectively. The in vitro and in vivo profile of 14d is comparable to that of MK-0591, which has showed biochemical efficacy in inhibiting ex vivo LTB4 biosynthesis and urinary LTE4 excretion in clinical trials.
|
Inhibition of 5-lipoxygenase (5-LO) measured as LTB4 production in human whole blood stimulated with calcium ionophore (A23187).
|
None
|
740.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of N-hydroxyurea 5-lipoxygenase inhibitors.
Year : 1997
Volume : 40
Issue : 13
First Page : 1955
Last Page : 1968
Authors : Stewart AO, Bhatia PA, Martin JG, Summers JB, Rodriques KE, Martin MB, Holms JH, Moore JL, Craig RA, Kolasa T, Ratajczyk JD, Mazdiyasni H, Kerdesky FA, DeNinno SL, Maki RG, Bouska JB, Young PR, Lanni C, Bell RL, Carter GW, Brooks CD.
Abstract : The discovery of second generation N-hydroxyurea 5-lipoxygenase inhibitors was accomplished through the development of a broad structure-activity relationship (SAR) study. This study identified requirements for improving potency and also extending duration by limiting metabolism. Potency could be maintained by the incorporation of heterocyclic templates substituted with selected lipophilic substituents. Duration of inhibition after oral administration was optimized by identification of structural features in the proximity of the N-hydroxyurea which correlated to low in vitro glucuronidation rates. Furthermore, the rate of in vitro glucuronidation was shown to be stereoselective for certain analogs. (R)-N-[3-[5-(4-Fluorophenoxy)-2-furyl]-1-methyl-2-propynyl]-N-hydroxyure a (17c) was identified and selected for clinical development.
|
Compound was evaluated for inhibiting production of LTB4 in calcium Ionophore (A23187) activated human whole blood.
|
Homo sapiens
|
1.0
%
|
|
Journal : J. Med. Chem.
Title : (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and platelet-activating factor receptor antagonist.
Year : 1998
Volume : 41
Issue : 11
First Page : 1970
Last Page : 1979
Authors : Cai X, Scannell RT, Yaeger D, Hussoin MS, Killian DB, Qian C, Eckman J, Hwang SB, Libertine-Garahan L, Yeh CG, Ip SH, Shen TY.
Abstract : By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid- and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl- N-h ydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.
|
Inhibition of human whole blood (HWB) LTB4 production in A-23,187-activated human whole blood by the enzyme immunoassay at a dose of 3 uM
|
Homo sapiens
|
75.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cmi-206: A potent dual platelet activating factor antagonist and 5-lipoxygenase inhibitor
Year : 1995
Volume : 5
Issue : 6
First Page : 643
Last Page : 648
Authors : Sajjat Hussoin M, Cai X, Scannell RT, Yaeger D, Killian DB, Eckman J, Hwang S, Libertine-Garahan L, Qian C, Grace Yen C, Ip S
|
In vitro inhibition of ionophore stimulated LTB4 release from human peripheral blood leukocytes.
|
None
|
470.0
nM
|
|
Journal : J. Med. Chem.
Title : Benzothiazole hydroxy ureas as inhibitors of 5-lipoxygenase: use of the hydroxyurea moiety as a replacement for hydroxamic acid.
Year : 1992
Volume : 35
Issue : 17
First Page : 3180
Last Page : 3183
Authors : Greco MN, Hageman WE, Powell ET, Tighe JJ, Persico FJ.
Abstract : A novel series of N-[(2-benzothiazolylthio)alkyl]-N'-hydroxyurea derivatives (9-25) was synthesized and evaluated for biological activity as inhibitors of 5-lipoxygenase both in vivo (mouse zymosan peritonitis assay) and in vitro (Ca2+ ionophore-stimulated human peripheral blood leukocyte model). The compounds of this series were based on the corresponding hydroxamic acid derivatives (1, 3, 4, and 5) which were moderately active in vitro but inactive in vivo. A number of compounds in the hydroxyurea series exhibited oral activity for 5-lipoxygenase inhibition. Results of studies relating structure to in vivo and in vitro 5-lipoxygenase activity are reported.
|
Ex vivo inhibition of LTB-4 determined by measurement of A-23187-stimulated LTB-4 production in dog blood at 1 mg/kg iv
|
Canis lupus familiaris
|
95.0
%
|
|
Journal : J. Med. Chem.
Title : Substituted chromenes as potent, orally active 5-lipoxygenase inhibitors.
Year : 1993
Volume : 36
Issue : 23
First Page : 3580
Last Page : 3594
Authors : Satoh Y, Stanton JL, Hutchison AJ, Libby AH, Kowalski TJ, Lee WH, White DH, Kimble EF.
Abstract : A series of chromene derivatives was synthesized and evaluated for their in vitro and ex vivo 5-lipoxygenase (5-LO) inhibitory activity. These compounds were prepared by condensation of appropriate salicyl aldehydes with alpha, beta-unsaturated carbonyl compounds, followed by transformation to the corresponding hydroxamic acids or N-hydroxyureas. Placement of phenoxy or p-fluorophenoxy substituents at the 6 position of the chromene ring led to a dramatic increase in the in vitro potency as demonstrated by the guinea pig PMN 5-LO assay. Chromene hydroxamic acids, in general, behaved poorly in the ex vivo dog model. On the other hand, replacement of the hydroxamic acid function with N-hydroxyurea yielded potent and long-lasting 5-LO inhibitors in the dog model. In most cases, the oral efficacy of the chromene N-hydroxyureas correlated very well with their in vitro activity. Compounds 43 (CGS 23885) and 55 (CGS 24891) are among the most potent inhibitors prepared, showing IC50 values of 48 and 51 nM, respectively. The values for the duration of action (DA) for compounds 43 and 55 are 21 and 20 h, respectively, following intravenous (i.v.) administration of 1.0 mg/kg. In the oral (po) experiments, 43 and 55 have DA's of 14 and 15 h, respectively, at a 1.0 mg/kg dose. In both iv and po experiments, 43 and 55 showed sustained maximal inhibition (> 95%) at earlier time points. The oral ED50 values of 43 and 55 in the ex vivo dog model are 0.23 and 0.23 mg/kg, respectively, at 6.0 h, and 2.37 and 1.63 mg/kg, respectively, at 24 h. Compound 43, which inhibits sheep seminal vesicle cyclooxygenase (CO) with an IC50 value of 36 microM, was shown to be a selective 5-lipoxygenase inhibitor in the ex vivo study. These compounds compare favorably with zileuton (A-64077) in all the parameters examined.
|
Ex vivo inhibition of LTB-4 determined by measurement of A-23187-stimulated LTB-4 production in dog blood at 1 mg/kg po
|
Canis lupus familiaris
|
95.0
%
|
|
Journal : J. Med. Chem.
Title : Substituted chromenes as potent, orally active 5-lipoxygenase inhibitors.
Year : 1993
Volume : 36
Issue : 23
First Page : 3580
Last Page : 3594
Authors : Satoh Y, Stanton JL, Hutchison AJ, Libby AH, Kowalski TJ, Lee WH, White DH, Kimble EF.
Abstract : A series of chromene derivatives was synthesized and evaluated for their in vitro and ex vivo 5-lipoxygenase (5-LO) inhibitory activity. These compounds were prepared by condensation of appropriate salicyl aldehydes with alpha, beta-unsaturated carbonyl compounds, followed by transformation to the corresponding hydroxamic acids or N-hydroxyureas. Placement of phenoxy or p-fluorophenoxy substituents at the 6 position of the chromene ring led to a dramatic increase in the in vitro potency as demonstrated by the guinea pig PMN 5-LO assay. Chromene hydroxamic acids, in general, behaved poorly in the ex vivo dog model. On the other hand, replacement of the hydroxamic acid function with N-hydroxyurea yielded potent and long-lasting 5-LO inhibitors in the dog model. In most cases, the oral efficacy of the chromene N-hydroxyureas correlated very well with their in vitro activity. Compounds 43 (CGS 23885) and 55 (CGS 24891) are among the most potent inhibitors prepared, showing IC50 values of 48 and 51 nM, respectively. The values for the duration of action (DA) for compounds 43 and 55 are 21 and 20 h, respectively, following intravenous (i.v.) administration of 1.0 mg/kg. In the oral (po) experiments, 43 and 55 have DA's of 14 and 15 h, respectively, at a 1.0 mg/kg dose. In both iv and po experiments, 43 and 55 showed sustained maximal inhibition (> 95%) at earlier time points. The oral ED50 values of 43 and 55 in the ex vivo dog model are 0.23 and 0.23 mg/kg, respectively, at 6.0 h, and 2.37 and 1.63 mg/kg, respectively, at 24 h. Compound 43, which inhibits sheep seminal vesicle cyclooxygenase (CO) with an IC50 value of 36 microM, was shown to be a selective 5-lipoxygenase inhibitor in the ex vivo study. These compounds compare favorably with zileuton (A-64077) in all the parameters examined.
|
In vitro activities of Leukotriene B4 receptor (LTB4) in human neutrophils
|
Homo sapiens
|
420.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationships of (E)-3-(1,4-benzoquinonyl)-2-[(3-pyridyl)-alkyl]-2-propenoic acid derivatives that inhibit both 5-lipoxygenase and thromboxane A2 synthetase.
Year : 1996
Volume : 39
Issue : 16
First Page : 3148
Last Page : 3157
Authors : Hibi S, Okamoto Y, Tagami K, Numata H, Kobayashi N, Shinoda M, Kawahara T, Harada K, Miyamoto K, Yamatsu I.
Abstract : As part of our research for the development of novel antiinflammatory drug candidates, we have designed and synthesized a series of (E)-3-(1,4-benzoquinonyl)-2-[(3-pyridyl)alkyl]-2-propenoic acid derivatives as dual inhibitors of 5-lipoxygenase (5-LO) and thromboxane (TX) A2 synthetase. In order to increase the absorption after oral administration, we introduced a carboxylic acid moiety into the 1,4-benzoquinone skeleton, which has 5-LO-inhibitory character. Introduction of a 3-pyridylalkyl group at the double bond of the 1,4-benzoquinonyl propenoic acid moiety afforded good to moderate inhibitory activities against the production of leukotriene (LT) B4 and TXA2 while not significantly inhibiting that of prostaglandin E2 by glycogen-induced peritoneal cells of rat (in vitro). The length of the methylene chain of the 3-pyridylalkyl group influenced the inhibition of LTB4 and TXB2 production. An increase of lipophilicity by introducing a more lipophilic alkoxy group did not markedly increase the inhibitory activity on LTB4 production. The position of alkoxy group on the 1,4-benzoquinone skeleton played an important role in TXA2 synthetase inhibition. Compounds such as 20c (E6700) with an appropriate alkoxy group and proper length of methylene side chain, together with a polar substituent (carboxylic acid), showed good inhibition of both 5-LO and TXA2 synthetase and possess a variety of pharmacologically beneficial effects.
|
Percent inhibition was determined at a dose of 10 mg/Kg in mouse ex vivo assay
|
None
|
95.0
%
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase.
Year : 2000
Volume : 43
Issue : 4
First Page : 721
Last Page : 735
Authors : Penning TD, Chandrakumar NS, Chen BB, Chen HY, Desai BN, Djuric SW, Docter SH, Gasiecki AF, Haack RA, Miyashiro JM, Russell MA, Yu SS, Corley DG, Durley RC, Kilpatrick BF, Parnas BL, Askonas LJ, Gierse JK, Harding EI, Highkin MK, Kachur JF, Kim SH, Krivi GG, Villani-Price D, Pyla EY, Smith WG.
Abstract : Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.
|
Percentage inhibition of LTB4 after 6 hr at dose 2 mg/kg in mouse
|
Mus musculus
|
40.0
%
|
|
Journal : J. Med. Chem.
Title : Bicyclic N-hydroxyurea inhibitors of 5-lipoxygenase: pharmacodynamic, pharmacokinetic, and in vitro metabolic studies characterizing N-hydroxy-N-(2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl)urea.
Year : 1996
Volume : 39
Issue : 26
First Page : 5035
Last Page : 5046
Authors : Adams JL, Garigipati RS, Sorenson M, Schmidt SJ, Brian WR, Newton JF, Tyrrell KA, Garver E, Yodis LA, Chabot-Fletcher M, Tzimas M, Webb EF, Breton JJ, Griswold DE.
Abstract : A series of N-hydroxyurea derivatives have been prepared and examined as inhibitors of 5-lipoxygenase. Oral activity was established by examining the inhibition of LTB4 biosynthesis in an ex vivo assay in the mouse. The pharmacodynamic performance in the mouse of selected compounds was assessed using an ex vivo LTB4 assay and an adoptive peritoneal anaphylaxis assay at extended pretreat times. Compounds with an extended duration of action were re-examined as the individual enantiomers in the ex vivo assay, and the (S) enantiomer of N-hydroxy-N-[2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl]urea, (+)-1a (SB 202235), was selected as the compound with the best overall profile. Higher plasma concentrations and longer plasma half-lives were found for (+)-1a relative to its enantiomer in the mouse, monkey, and dog. In vitro metabolic studies in mouse liver microsomes established enantiospecific glucuronidation as a likely mechanism for the observed differences between the enantiomers of 1a. Enantioselective glucuronidation favoring (-)-1a was also found in human liver microsomes.
|
Inhibition activity against recombinant human Prostaglandin G/H synthase 2
|
None
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Nonsteroidal anti-inflammatory drugs as scaffolds for the design of 5-lipoxygenase inhibitors.
Year : 1997
Volume : 40
Issue : 5
First Page : 819
Last Page : 824
Authors : Kolasa T, Brooks CD, Rodriques KE, Summers JB, Dellaria JF, Hulkower KI, Bouska J, Bell RL, Carter GW.
Abstract : Representative nonsteroidal anti-inflammatory drug (NSAID) cyclooxygenase inhibitors such as ibuprofen, naproxen, and indomethacin were used as orally bioavailable scaffolds to design selective 5-lipoxygenase (5-LO) inhibitors. Replacement of the NSAID carboxylic acid group with a N-hydroxyurea group provided congeners with selective 5-LO inhibitory activity.
|
Compound was tested for in vitro inhibition on human PMNL.
|
Homo sapiens
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Modulators of leukotriene biosynthesis and receptor activation.
Year : 1996
Volume : 39
Issue : 14
First Page : 2629
Last Page : 2654
Authors : Brooks CD, Summers JB.
|
Inhibition activity against recombinant human Prostaglandin G/H synthase 1
|
None
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Nonsteroidal anti-inflammatory drugs as scaffolds for the design of 5-lipoxygenase inhibitors.
Year : 1997
Volume : 40
Issue : 5
First Page : 819
Last Page : 824
Authors : Kolasa T, Brooks CD, Rodriques KE, Summers JB, Dellaria JF, Hulkower KI, Bouska J, Bell RL, Carter GW.
Abstract : Representative nonsteroidal anti-inflammatory drug (NSAID) cyclooxygenase inhibitors such as ibuprofen, naproxen, and indomethacin were used as orally bioavailable scaffolds to design selective 5-lipoxygenase (5-LO) inhibitors. Replacement of the NSAID carboxylic acid group with a N-hydroxyurea group provided congeners with selective 5-LO inhibitory activity.
|
Compound was tested for in vitro inhibition on broken RBL-1.
|
Rattus norvegicus
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Modulators of leukotriene biosynthesis and receptor activation.
Year : 1996
Volume : 39
Issue : 14
First Page : 2629
Last Page : 2654
Authors : Brooks CD, Summers JB.
|
Concentration required for the inhibition of LTB4 production in human whole blood
|
Homo sapiens
|
640.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A congener study of zileuton reveals interesting effects on glucuronidation rates
Year : 1994
Volume : 4
Issue : 12
First Page : 1437
Last Page : 1442
Authors : Galeazzi E, Guzman A, Kluge A, Morgans D, Muchowski J, Jamil-Panah S, Saavedra P, Salazar MA, Talamas FX, Teitelbaum P, Young J, Yamamoto D
|
Inhibitory activity was determined for LTB4 production in human whole blood.
|
None
|
850.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase.
Year : 2000
Volume : 43
Issue : 4
First Page : 721
Last Page : 735
Authors : Penning TD, Chandrakumar NS, Chen BB, Chen HY, Desai BN, Djuric SW, Docter SH, Gasiecki AF, Haack RA, Miyashiro JM, Russell MA, Yu SS, Corley DG, Durley RC, Kilpatrick BF, Parnas BL, Askonas LJ, Gierse JK, Harding EI, Highkin MK, Kachur JF, Kim SH, Krivi GG, Villani-Price D, Pyla EY, Smith WG.
Abstract : Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.
|
Inhibition of 5-lipoxygenase activity in human whole blood assay
|
Homo sapiens
|
873.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cetirizine and loratadine-based antihistamines with 5-lipoxygenase inhibitory activity.
Year : 2004
Volume : 14
Issue : 22
First Page : 5591
Last Page : 5594
Authors : Lewis TA, Young MA, Arrington MP, Bayless L, Cai X, Collart P, Eckman JB, Ellis JL, Ene DG, Libertine L, Nicolas JM, Scannell RT, Wels BF, Wenberg K, Wypij DM.
Abstract : A series of compounds possessing both H(1) histamine receptor antagonist and 5-lipoxygenase (5-LO) inhibitory activities was synthesized. The H(1)-binding scaffolds of cetirizine, efletirizine, and loratadine were linked to a lipophilic N-hydroxyurea, the 5-LO inhibiting moiety of zileuton. Both activities were observed in vivo, as was increased CYP3A4 inhibition compared to their respective single-function drugs. Selected analogs in the series were shown to be orally active in guinea pig models.
|
Inhibitory concentration against human 5-lipoxygenase
|
Homo sapiens
|
518.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-Lipoxygenase inhibition by N-hydroxycarbamates in dual-function compounds.
Year : 2005
Volume : 15
Issue : 4
First Page : 1083
Last Page : 1085
Authors : Lewis TA, Bayless L, DiPesa AJ, Eckman JB, Gillard M, Libertine L, Scannell RT, Wypij DM, Young MA.
Abstract : A series of N-hydroxycarbamates containing a histaminergic H(1) receptor antagonist pharmacophore was synthesized. In vitro assays determined the compounds had both histaminergic binding and 5-lipoxygenase inhibiting activities comparable to the corresponding N-hydroxyurea analog. Animal models demonstrated antihistaminergic and the 5-lipopxygenase inhibitory activity, with the N-hydroxyurea analog having a better overall profile.
|
Inhibitory concentration against 5-lipoxygenase in human whole blood
|
Homo sapiens
|
873.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-Lipoxygenase inhibition by N-hydroxycarbamates in dual-function compounds.
Year : 2005
Volume : 15
Issue : 4
First Page : 1083
Last Page : 1085
Authors : Lewis TA, Bayless L, DiPesa AJ, Eckman JB, Gillard M, Libertine L, Scannell RT, Wypij DM, Young MA.
Abstract : A series of N-hydroxycarbamates containing a histaminergic H(1) receptor antagonist pharmacophore was synthesized. In vitro assays determined the compounds had both histaminergic binding and 5-lipoxygenase inhibiting activities comparable to the corresponding N-hydroxyurea analog. Animal models demonstrated antihistaminergic and the 5-lipopxygenase inhibitory activity, with the N-hydroxyurea analog having a better overall profile.
|
Inhibition of 5-LOX in rat peritoneal leukocytes at 5 uM
|
Rattus norvegicus
|
86.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Indole derivatives as potent inhibitors of 5-lipoxygenase: design, synthesis, biological evaluation, and molecular modeling.
Year : 2007
Volume : 17
Issue : 9
First Page : 2414
Last Page : 2420
Authors : Zheng M, Zheng M, Ye D, Deng Y, Qiu S, Luo X, Chen K, Liu H, Jiang H.
Abstract : A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial screening hit 1a (IC(50)=74 microM). Selected compounds for concentration-response studies showed prominent inhibitory activities with IC(50) values ranging from 0.74 microM to 3.17 microM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activity compared to that of the reference drug (Zileuton), with IC(50) values less than 1 microM. Molecular modeling studies for compounds 1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treatment of LT-related diseases.
|
Inhibition of 5-LOX in rat peritoneal leukocytes
|
Rattus norvegicus
|
830.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Indole derivatives as potent inhibitors of 5-lipoxygenase: design, synthesis, biological evaluation, and molecular modeling.
Year : 2007
Volume : 17
Issue : 9
First Page : 2414
Last Page : 2420
Authors : Zheng M, Zheng M, Ye D, Deng Y, Qiu S, Luo X, Chen K, Liu H, Jiang H.
Abstract : A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial screening hit 1a (IC(50)=74 microM). Selected compounds for concentration-response studies showed prominent inhibitory activities with IC(50) values ranging from 0.74 microM to 3.17 microM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activity compared to that of the reference drug (Zileuton), with IC(50) values less than 1 microM. Molecular modeling studies for compounds 1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treatment of LT-related diseases.
|
Antileukotrienic activity in rat polymorphonuclear cells assessed as inhibition of LTB4 biosynthesis
|
Rattus norvegicus
|
10.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Antileukotrienic N-arylethyl-2-arylacetamides in the treatment of ulcerative colitis.
Year : 2007
Volume : 42
Issue : 8
First Page : 1084
Last Page : 1094
Authors : Junek R, Brůnová B, Kverka M, Panajotová V, Jandera A, Kuchar M.
Abstract : A series of arylacetic acid derivatives bearing methyl(arylethyl)amino groups were prepared and their antileukotrienic activities involving LTB(4) were evaluated. Regression analysis has shown a strong dependence of these activities on lipophilicity for both LTB(4) receptor binding and inhibition of LTB(4) biosynthesis; parabolic relationships were derived. The values of slopes of the ascending linear parts of these dependences indicate various types of hydrophobic binding at the site of ligand interaction with relevant biomacromolecules. The anti-inflammatory effect of the compounds under study was also evaluated in three animal models of inflammation and their possible utilization in the treatment of ulcerative colitis (UC) was followed. The importance of antileukotrienic activities for the anti-inflammatory effect, especially in the model of UC was discussed, but further experiments are necessary to confirm the respective relations.
|
Antiinflammatory activity in rat assessed as inhibition of carrageenan-induced oedema at 100 mg/kg by Winter method
|
Rattus norvegicus
|
46.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Antileukotrienic N-arylethyl-2-arylacetamides in the treatment of ulcerative colitis.
Year : 2007
Volume : 42
Issue : 8
First Page : 1084
Last Page : 1094
Authors : Junek R, Brůnová B, Kverka M, Panajotová V, Jandera A, Kuchar M.
Abstract : A series of arylacetic acid derivatives bearing methyl(arylethyl)amino groups were prepared and their antileukotrienic activities involving LTB(4) were evaluated. Regression analysis has shown a strong dependence of these activities on lipophilicity for both LTB(4) receptor binding and inhibition of LTB(4) biosynthesis; parabolic relationships were derived. The values of slopes of the ascending linear parts of these dependences indicate various types of hydrophobic binding at the site of ligand interaction with relevant biomacromolecules. The anti-inflammatory effect of the compounds under study was also evaluated in three animal models of inflammation and their possible utilization in the treatment of ulcerative colitis (UC) was followed. The importance of antileukotrienic activities for the anti-inflammatory effect, especially in the model of UC was discussed, but further experiments are necessary to confirm the respective relations.
|
Antiinflammatory activity in mouse assessed as inhibition of arachidonic acid-induced hyperaemia at 200 mg/kg, po
|
Mus musculus
|
13.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Antileukotrienic N-arylethyl-2-arylacetamides in the treatment of ulcerative colitis.
Year : 2007
Volume : 42
Issue : 8
First Page : 1084
Last Page : 1094
Authors : Junek R, Brůnová B, Kverka M, Panajotová V, Jandera A, Kuchar M.
Abstract : A series of arylacetic acid derivatives bearing methyl(arylethyl)amino groups were prepared and their antileukotrienic activities involving LTB(4) were evaluated. Regression analysis has shown a strong dependence of these activities on lipophilicity for both LTB(4) receptor binding and inhibition of LTB(4) biosynthesis; parabolic relationships were derived. The values of slopes of the ascending linear parts of these dependences indicate various types of hydrophobic binding at the site of ligand interaction with relevant biomacromolecules. The anti-inflammatory effect of the compounds under study was also evaluated in three animal models of inflammation and their possible utilization in the treatment of ulcerative colitis (UC) was followed. The importance of antileukotrienic activities for the anti-inflammatory effect, especially in the model of UC was discussed, but further experiments are necessary to confirm the respective relations.
|
Inhibition of IgE-specific antigen-induced LBT4 release in rat MC9 cells at 0.55 uM
|
Rattus norvegicus
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Reactions of functionalized sulfonamides: application to lowering the lipophilicity of cytosolic phospholipase A2alpha inhibitors.
Year : 2009
Volume : 52
Issue : 4
First Page : 1156
Last Page : 1171
Authors : Chen L, Wang W, Lee KL, Shen MW, Murphy EA, Zhang W, Xu X, Tam S, Nickerson-Nutter C, Goodwin DG, Clark JD, McKew JC.
Abstract : The cPLA(2)alpha inhibitors we reported earlier were potent in both isolated enzyme and rat whole blood assays but have high plogD(7.4). To address these issues, reactions of electrophilic sulfonamides 9-12 were employed to incorporate various heterocyclic or heteroatom-based reagents into cPLA(2)alpha inhibitors. For example, reactions of 9 with sulfur nucleophiles such as thiophenol allowed rapid assembly of thioether analogues that were converted into the corresponding sulfoxides to afford less lipophilic derivatives. Reactions of 10 and 11 with various nitrogen nucleophiles, including aromatic heterocycles and aliphatic amines, provided an efficient way to introduce polarity into cPLA(2)alpha inhibitors. Finally, we report the first application of (2-formylphenyl)methanesulfonyl chloride, 13. Reductive amination of 2-formylphenylmethane sulfonamides allowed the introduction of various nitrogen nucleophiles. Several inhibitors obtained herein have plogD(7.4) values 3-4 units lower than previously synthesized compounds and yet maintain in vitro potency.
|
Inhibition of 5LOX in human whole blood assessed as inhibition of calcium ionophore A-stimulated 5-HETE production at 0.7 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological activities of a series of 4,5-diaryl-3-hydroxy-2(5H)-furanones.
Year : 2008
Volume : 43
Issue : 6
First Page : 1222
Last Page : 1229
Authors : Bailly F, Queffélec C, Mbemba G, Mouscadet JF, Pommery N, Pommery J, Hénichart JP, Cotelle P.
Abstract : A series of thirteen 4,5-diaryl-3-hydroxy-2(5H)-furanones were synthesized. They were evaluated for their antioxidant potencies and inhibitory properties of 5-lipoxygenase, cyclooxygenases, HIV-1 integrase and PC3 cell proliferation. New hits were discovered either in the anti-proliferation test or in the HIV anti-integrase test.
|
Inhibition of 5-lipoxygenase in A-23817-challenged human neutrophils assessed as 5LO product formation by intact cell based assay in presence of exogenous arachidonic acid
|
Homo sapiens
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural optimization and biological evaluation of 2-substituted 5-hydroxyindole-3-carboxylates as potent inhibitors of human 5-lipoxygenase.
Year : 2009
Volume : 52
Issue : 11
First Page : 3474
Last Page : 3483
Authors : Karg EM, Luderer S, Pergola C, Bühring U, Rossi A, Northoff H, Sautebin L, Troschütz R, Werz O.
Abstract : Pharmacological suppression of leukotriene biosynthesis by inhibitors of 5-lipoxygenase (5-LO) is a strategy to intervene with inflammatory and allergic disorders. We recently presented 2-amino-5-hydroxy-1H-indoles as efficient 5-LO inhibitors in cell-based and cell-free assays. Structural optimization led to novel benzo[g]indole-3-carboxylates exemplified by ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 11a), which inhibits 5-LO activity in human neutrophils and recombinant human 5-LO with IC(50) values of 0.23 and 0.086 microM, respectively. Notably, 11a efficiently blocks 5-LO product formation in human whole blood assays (IC(50) = 0.83-1.6 microM) and significantly prevented leukotriene B(4) production in pleural exudates of carrageenan-treated rats, associated with reduced severity of pleurisy. Together, on the basis of their high potency against 5-LO and the marked efficacy in biological systems, these novel and straightforward benzo[g]indole-3-carboxylates may have potential as anti-inflammatory therapeutics.
|
Inhibition of human recombinant 5-lipoxygenase expressed in Escherichia coli assessed as 5LO product formation by cell free assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Structural optimization and biological evaluation of 2-substituted 5-hydroxyindole-3-carboxylates as potent inhibitors of human 5-lipoxygenase.
Year : 2009
Volume : 52
Issue : 11
First Page : 3474
Last Page : 3483
Authors : Karg EM, Luderer S, Pergola C, Bühring U, Rossi A, Northoff H, Sautebin L, Troschütz R, Werz O.
Abstract : Pharmacological suppression of leukotriene biosynthesis by inhibitors of 5-lipoxygenase (5-LO) is a strategy to intervene with inflammatory and allergic disorders. We recently presented 2-amino-5-hydroxy-1H-indoles as efficient 5-LO inhibitors in cell-based and cell-free assays. Structural optimization led to novel benzo[g]indole-3-carboxylates exemplified by ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 11a), which inhibits 5-LO activity in human neutrophils and recombinant human 5-LO with IC(50) values of 0.23 and 0.086 microM, respectively. Notably, 11a efficiently blocks 5-LO product formation in human whole blood assays (IC(50) = 0.83-1.6 microM) and significantly prevented leukotriene B(4) production in pleural exudates of carrageenan-treated rats, associated with reduced severity of pleurisy. Together, on the basis of their high potency against 5-LO and the marked efficacy in biological systems, these novel and straightforward benzo[g]indole-3-carboxylates may have potential as anti-inflammatory therapeutics.
|
Inhibition of LTB4 production in mouse MC9 cells
|
Mus musculus
|
550.0
nM
|
|
Journal : J. Med. Chem.
Title : Indole cytosolic phospholipase A2 alpha inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid, efipladib.
Year : 2008
Volume : 51
Issue : 12
First Page : 3388
Last Page : 3413
Authors : McKew JC, Lee KL, Shen MW, Thakker P, Foley MA, Behnke ML, Hu B, Sum FW, Tam S, Hu Y, Chen L, Kirincich SJ, Michalak R, Thomason J, Ipek M, Wu K, Wooder L, Ramarao MK, Murphy EA, Goodwin DG, Albert L, Xu X, Donahue F, Ku MS, Keith J, Nickerson-Nutter CL, Abraham WM, Williams C, Hegen M, Clark JD.
Abstract : The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.
|
Inhibition of human recombinant 5-LO expressed in Escherichia coli by cell-free assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : J. Med. Chem.
Title : Pirinixic acid derivatives as novel dual inhibitors of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase.
Year : 2008
Volume : 51
Issue : 24
First Page : 8068
Last Page : 8076
Authors : Koeberle A, Zettl H, Greiner C, Wurglics M, Schubert-Zsilavecz M, Werz O.
Abstract : Dual inhibition of the prostaglandin (PG) and leukotriene (LT) biosynthetic pathway is supposed to be superior over single interference, both in terms of efficacy and side effects. Here, we present a novel class of dual microsomal PGE(2) synthase-1/5-lipoxygenase (5-LO) inhibitors based on the structure of pirinixic acid [PA, 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)acetic acid, compound 1]. Target-oriented structural modification of 1, particularly alpha substitution with extended n-alkyl or bulky aryl substituents and concomitant replacement of the 2,3-dimethylaniline by a biphenyl-4-yl-methane-amino residue, resulted in potent suppression of mPGES-1 and 5-LO activity, exemplified by 2-(4-(biphenyl-4-ylmethylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (7b, IC(50) = 1.3 and 1 microM, respectively). Select compounds also potently reduced PGE(2) and 5-LO product formation in intact cells. Importantly, inhibition of cyclooxygenases-1/2 was significantly less pronounced. Taken together, these pirinixic acid derivatives constitute a novel class of dual mPGES-1/5-LO inhibitors with a promising pharmacological profile and a potential for therapeutic use.
|
Antiallergic activity in Ca(2+)-stimulated differentiated human HeLa cells assessed as inhibition of cys-leukotriene release after 6 days by ELISA
|
Homo sapiens
|
0.04
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Inhibitory activity of Brazilian green propolis components and their derivatives on the release of cys-leukotrienes.
Year : 2010
Volume : 18
Issue : 1
First Page : 151
Last Page : 157
Authors : Tani H, Hasumi K, Tatefuji T, Hashimoto K, Koshino H, Takahashi S.
Abstract : The effects of Brazilian green propolis ethanol extract on Cry j1-induced cys-leukotrienes and histamine release from peripheral leukocytes of patients with allergic rhinitis were investigated. One of the key mechanisms for the anti-allergic properties of the extract was revealed to be the suppression of cys-LTs release. Furthermore, a series of propolis components and their phenethyl esters were synthesized and evaluated as inhibitors of cys-LTs release. Artepillin C, baccharin, and kaempferide were the major active components of the ethanol extract. The inhibitory activity of artepillin C phenethyl ester was comparable to that of existing LT synthesis inhibitors.
|
Inhibition of 5-LOX at 100 uM after 5 mins
|
None
|
83.05
%
|
|
Journal : J. Nat. Prod.
Title : Monoterpenoid indole alkaloids from Alstonia yunnanensis.
Year : 2009
Volume : 72
Issue : 10
First Page : 1836
Last Page : 1841
Authors : Feng T, Li Y, Cai XH, Gong X, Liu YP, Zhang RT, Zhang XY, Tan QG, Luo XD.
Abstract : Eight new monoterpenoid indole alkaloids, alstoyunines A-H (1-8), along with 17 known analogues, were isolated from Alstonia yunnanensis. The structures of the new alkaloids were established by means of extensive spectroscopic methods. Alstoyunines C (3), E (5), and F (6) showed selective inhibition of Cox-2 (>75%). Alstoyunine F (6) showed weak cytotoxicity against the human myeloid leukemia HL-60 (IC50 = 3.89 microM) and hepatocellular carcinoma SMMC-7721 (IC50 = 21.73 microM) cell lines.
|
Inhibition of 5-lipoxygenase in human whole blood
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological activity of N-aroyl-tetrahydro-gamma-carbolines.
Year : 2010
Volume : 18
Issue : 11
First Page : 3910
Last Page : 3924
Authors : Bridoux A, Millet R, Pommery J, Pommery N, Henichart JP.
Abstract : Research on dual inhibitors of both 5-LOX and COXs gained interest due to the overexpressions of these enzymes during the malignant state of the evolution of prostate cancer. In order to take part in this research, new N-aroyl-tetrahydro-gamma-carbolines issued from the modification of Indomethacin have been synthesised. As for the NSAIDs, the compounds have been tested for their activity against COX(1), COX(2) plus against 5-LOX and against the proliferation of malignant prostate cancer. Interesting cytotoxic activities and selectivities of some tetrahydro-gamma-carboline derivatives have been obtained.
|
Inhibition of 5-lipoxygenase in human whole blood assessed as inhibition of LTB4 production by HPLC method
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological activity of N-aroyl-tetrahydro-gamma-carbolines.
Year : 2010
Volume : 18
Issue : 11
First Page : 3910
Last Page : 3924
Authors : Bridoux A, Millet R, Pommery J, Pommery N, Henichart JP.
Abstract : Research on dual inhibitors of both 5-LOX and COXs gained interest due to the overexpressions of these enzymes during the malignant state of the evolution of prostate cancer. In order to take part in this research, new N-aroyl-tetrahydro-gamma-carbolines issued from the modification of Indomethacin have been synthesised. As for the NSAIDs, the compounds have been tested for their activity against COX(1), COX(2) plus against 5-LOX and against the proliferation of malignant prostate cancer. Interesting cytotoxic activities and selectivities of some tetrahydro-gamma-carboline derivatives have been obtained.
|
Inhibition of 5-lipoxygenase in human whole blood assessed as inhibition of 5-hydroxyeicosatetraenoic acid production by HPLC method
|
Homo sapiens
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological activity of N-aroyl-tetrahydro-gamma-carbolines.
Year : 2010
Volume : 18
Issue : 11
First Page : 3910
Last Page : 3924
Authors : Bridoux A, Millet R, Pommery J, Pommery N, Henichart JP.
Abstract : Research on dual inhibitors of both 5-LOX and COXs gained interest due to the overexpressions of these enzymes during the malignant state of the evolution of prostate cancer. In order to take part in this research, new N-aroyl-tetrahydro-gamma-carbolines issued from the modification of Indomethacin have been synthesised. As for the NSAIDs, the compounds have been tested for their activity against COX(1), COX(2) plus against 5-LOX and against the proliferation of malignant prostate cancer. Interesting cytotoxic activities and selectivities of some tetrahydro-gamma-carboline derivatives have been obtained.
|
Inhibition of 5-Lipoxygenase in arachidonic acid-stimulated human neutrophils after 15 mins by HPLC analysis in presence of A23187
|
Homo sapiens
|
800.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Pyrazol-3-propanoic acid derivatives as novel inhibitors of leukotriene biosynthesis in human neutrophils.
Year : 2011
Volume : 46
Issue : 10
First Page : 5021
Last Page : 5033
Authors : Calışkan B, Luderer S, Özkan Y, Werz O, Banoglu E.
Abstract : We recently presented that compounds 4a-b moderately inhibited leukotriene (LT) formation in human neutrophils. For structural derivatization of 4a-b, novel thirty-six title compounds were synthesized and led to more potent inhibition of LT biosynthesis in activated human neutrophils exemplified by compounds 15, 27-30, 32-37, 41, 42 with IC(50) values in the range of 1.6-3.5 μM. Moreover, compounds 32, 35, 42, 43 and 44 showed a substantial inhibition of platelet COX-1 activity with IC(50) of 2.5, 0.041, 0.3, 0.9 and 0.014 μM, respectively, leading up to dual acting inhibitors. On the basis of their high potency in cellular environment, these straightforward pyrazole-3-propanoic acid derivatives may possess potential in the design of more potent compounds for intervention with inflammatory and allergic diseases.
|
Inhibition of 5-lipoxygenase
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : SAR-study on a new class of imidazo[1,2-a]pyridine-based inhibitors of 5-lipoxygenase.
Year : 2012
Volume : 22
Issue : 5
First Page : 1969
Last Page : 1975
Authors : Hieke M, Rödl CB, Wisniewska JM, la Buscató E, Stark H, Schubert-Zsilavecz M, Steinhilber D, Hofmann B, Proschak E.
Abstract : A novel class of 5-lipoxygenase (5-LO) inhibitors characterized by a central imidazo[1,2-a]pyridine scaffold, a cyclohexyl moiety and an aromatic system, is presented. This scaffold was identified in a virtual screening study and exhibits promising inhibitory potential on the 5-LO. Here, we investigate the structure-activity relationships of this compound class. With N-cyclohexyl-6-methyl-2-(4-morpholinophenyl)imidazo[1,2-a]pyridine-3-amine (14), we identified a potent 5-LO inhibitor (IC(50)=0.16μM (intact cells) and 0.1μM (cell-free)), which may possess potential as an effective lead compound intervening with inflammatory diseases and certain types of cancer.
|
Inhibition of 5-lipoxygenase in human polynuclear leukocytes assessed as inhibition of A23187-stimulated 5-LO product formation preincubated for 15 mins measured after 10 mins by HPLC analysis
|
Homo sapiens
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of a class of 5-benzylidene-2-phenyl-thiazolinones as potent 5-lipoxygenase inhibitors.
Year : 2012
Volume : 20
Issue : 11
First Page : 3575
Last Page : 3583
Authors : Barzen S, Rödl CB, Lill A, Steinhilber D, Stark H, Hofmann B.
Abstract : A class of 5-lipoxygenase (5-LO) inhibitors characterized by a central 5-benzylidene-2-phenyl-thiazolinone scaffold was synthesized as a new series of molecular modifications and extensions of a previously reported series. Compounds were tested in a cell-based and a cell-free assay and furthermore evaluated for their influence on cell viability. The presented substituted thiazolinone scaffold turned out to be essential for both the 5-LO inhibitory activity and the non-cytotoxic profile. With (Z)-5-(4-methoxybenzylidene)-2-(naphthalen-2-yl)-5H-thiazol-4-one (2k, ST1237), a potent, direct, non-cytotoxic 5-LO inhibitor with IC(50) of 0.08 μM and 0.12 μM (cell-free assay and intact cells), we present a promising lead optimization and development for further investigations as novel anti-inflammatory drug.
|
Inhibition of 5-lipoxygenase in cell free S100 freshly isolated human PMNL cells assessed as inhibition of A23187-stimulated 5-LO product formation preincubated for 15 mins measured after 10 mins by HPLC analysis
|
Homo sapiens
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of a class of 5-benzylidene-2-phenyl-thiazolinones as potent 5-lipoxygenase inhibitors.
Year : 2012
Volume : 20
Issue : 11
First Page : 3575
Last Page : 3583
Authors : Barzen S, Rödl CB, Lill A, Steinhilber D, Stark H, Hofmann B.
Abstract : A class of 5-lipoxygenase (5-LO) inhibitors characterized by a central 5-benzylidene-2-phenyl-thiazolinone scaffold was synthesized as a new series of molecular modifications and extensions of a previously reported series. Compounds were tested in a cell-based and a cell-free assay and furthermore evaluated for their influence on cell viability. The presented substituted thiazolinone scaffold turned out to be essential for both the 5-LO inhibitory activity and the non-cytotoxic profile. With (Z)-5-(4-methoxybenzylidene)-2-(naphthalen-2-yl)-5H-thiazol-4-one (2k, ST1237), a potent, direct, non-cytotoxic 5-LO inhibitor with IC(50) of 0.08 μM and 0.12 μM (cell-free assay and intact cells), we present a promising lead optimization and development for further investigations as novel anti-inflammatory drug.
|
Inhibition of 5-LOX in stimulated leukocytes
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Dynamic modeling of human 5-lipoxygenase-inhibitor interactions helps to discover novel inhibitors.
Year : 2012
Volume : 55
Issue : 6
First Page : 2597
Last Page : 2605
Authors : Wu Y, He C, Gao Y, He S, Liu Y, Lai L.
Abstract : Human 5-lipoxygenase (5-LOX) is one of the key anti-inflammatory drug targets due to its key role in leukotrienes biosynthesis. We have built a model for the active conformation of human 5-LOX using comparative modeling, docking of known inhibitors, and molecular dynamics simulation. Using this model, novel 5-LOX inhibitors were identified by virtual screen. Of the 105 compounds tested in a cell-free assay, 30 have IC(50) values less than 100 μM and 11 less than 10 μM with the strongest inhibition of 620 nM. Compounds 4, 7, and 11 showed strong inhibition activity in the human whole blood (HWB) assay with IC(50) values of 8.6, 9.7, 8.1 μM, respectively. Moreover, compounds 4 and 7 were also found to inhibit microsomal prostaglandin E synthase (mPGES)-1 with micromolar IC(50) values, similar to licofelone, a dual functional inhibitor of 5-LOX/mPGES-1. The compounds reported here provide new scaffolds for anti-inflammatory drug design.
|
Inhibition of 5-LOX
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Anacardic acid derived salicylates are inhibitors or activators of lipoxygenases.
Year : 2012
Volume : 20
Issue : 16
First Page : 5027
Last Page : 5032
Authors : Wisastra R, Ghizzoni M, Boltjes A, Haisma HJ, Dekker FJ.
Abstract : Lipoxygenases catalyze the oxidation of unsaturated fatty acids, such as linoleic acid, which play a crucial role in inflammatory responses. Selective inhibitors may provide a new therapeutic approach for inflammatory diseases. In this study, we describe the identification of a novel soybean lipoxygenase-1 (SLO-1) inhibitor and a potato 5-lipoxygenase (5-LOX) activator from a screening of a focused compound collection around the natural product anacardic acid. The natural product anacardic acid inhibits SLO-1 with an IC(50) of 52 μM, whereas the inhibitory potency of the novel mixed type inhibitor 23 is fivefold enhanced. In addition, another derivative (21) caused non-essential activation of potato 5-LOX. This suggests the presence of an allosteric binding site that regulates the lipoxygenase activity.
|
Inhibition of mouse Ido2 transfected in HEK293T cells using L-tryptophan as substrate assessed as kynurenine formation at 20 uM after 45 mins by spectrophotometric analysis relative to control
|
Mus musculus
|
55.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.
Year : 2012
Volume : 22
Issue : 24
First Page : 7641
Last Page : 7646
Authors : Bakmiwewa SM, Fatokun AA, Tran A, Payne RJ, Hunt NH, Ball HJ.
Abstract : The kynurenine pathway is responsible for the breakdown of the majority of the essential amino acid, tryptophan (Trp). The first and rate-limiting step of the kynurenine pathway can be independently catalysed by tryptophan 2,3-dioxygenase (Tdo2), indoleamine 2,3-dioxygenase 1 (Ido1) or indoleamine 2,3-dioxygenase 2 (Ido2). Tdo2 or Ido1 enzymatic activity has been implicated in a number of actions of the kynurenine pathway, including immune evasion by tumors. IDO2 is expressed in several human pancreatic cancer cell lines, suggesting it also may play a role in tumorigenesis. Although Ido2 was originally suggested to be a target of the chemotherapeutic agent dextro-1-methyl-tryptophan, subsequent studies suggest this compound does not inhibit Ido2 activity. The development of selective Ido2 inhibitors could provide valuable tools for investigating its activity in tumor development and normal physiology. In this study, a library of Food and Drug Administration-approved drugs was screened for inhibition of mouse Ido2 enzymatic activity. A number of candidates were identified and IC(50) values of each compound for Ido1 and Ido2 were estimated. The Ido2 inhibitors were also tested for inhibition of Tdo2 activity. Our results showed that compounds from a class of drugs used to inhibit proton pumps were the most potent and selective Ido2 inhibitors identified in the library screen. These included tenatoprazole, which exhibited an IC(50) value of 1.8μM for Ido2 with no inhibition of Ido1 or Tdo2 activity detected at a concentration of 100μM tenatoprazole. These highly-selective Ido2 inhibitors will be useful for defining the distinct biological roles of the three Trp-catabolizing enzymes.
|
Inhibition of 5-LOX (unknown origin) at 10 uM by cell-free assay
|
Homo sapiens
|
95.9
%
|
|
Journal : J. Med. Chem.
Title : Discovery of highly potent microsomal prostaglandin e2 synthase 1 inhibitors using the active conformation structural model and virtual screen.
Year : 2013
Volume : 56
Issue : 8
First Page : 3296
Last Page : 3309
Authors : He S, Li C, Liu Y, Lai L.
Abstract : Microsomal prostaglandin E2 synthase 1 (mPGES-1) has been identified as a promising drug target due to its key role in prostaglandin biosynthesis. However, the lack of a well-characterized structure constitutes a great challenge for the development of inhibitors. Recently, we have built a model for the active conformation of mPGES-1. In the present study, the model was used for structure-based virtual screen of novel mPGES-1 inhibitors. Of the 142 compounds tested in the cell-free assay, 10 molecules are highly potent with IC50 values of single digit nanomolar and the strongest inhibition of 1.1 nM. Moreover, nine compounds showed strong activity in the human whole blood (HWB) assay with IC50 values of less than 10 μM. The lead compounds 1 and 2 showed HWB IC50 values of 0.3 and 0.7 μM which are among the most potent mPGES-1 inhibitors reported. These compounds represent new scaffolds for future development of drugs against mPGES-1.
|
Inhibition of 5-LOX-mediated LTB4 formation in human whole blood at 10 uM incubated for 20 mins prior to substrate addition measured after 0.5 hrs by EIA in presence of calcium ionophore A23187
|
Homo sapiens
|
80.6
%
|
|
Journal : J. Med. Chem.
Title : Discovery of highly potent microsomal prostaglandin e2 synthase 1 inhibitors using the active conformation structural model and virtual screen.
Year : 2013
Volume : 56
Issue : 8
First Page : 3296
Last Page : 3309
Authors : He S, Li C, Liu Y, Lai L.
Abstract : Microsomal prostaglandin E2 synthase 1 (mPGES-1) has been identified as a promising drug target due to its key role in prostaglandin biosynthesis. However, the lack of a well-characterized structure constitutes a great challenge for the development of inhibitors. Recently, we have built a model for the active conformation of mPGES-1. In the present study, the model was used for structure-based virtual screen of novel mPGES-1 inhibitors. Of the 142 compounds tested in the cell-free assay, 10 molecules are highly potent with IC50 values of single digit nanomolar and the strongest inhibition of 1.1 nM. Moreover, nine compounds showed strong activity in the human whole blood (HWB) assay with IC50 values of less than 10 μM. The lead compounds 1 and 2 showed HWB IC50 values of 0.3 and 0.7 μM which are among the most potent mPGES-1 inhibitors reported. These compounds represent new scaffolds for future development of drugs against mPGES-1.
|
Inhibition of human recombinant soluble epoxide hydrolase expressed in Escherichia coli using 3-phenyl-cyano(6-methoxy-2-naphthalenyl)methylester-2-oxiraneacetic acid as substrate after 30 mins by fluorescence-based assay
|
Homo sapiens
|
591.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship studies of novel dual inhibitors of soluble epoxide hydrolase and 5-lipoxygenase.
Year : 2013
Volume : 56
Issue : 4
First Page : 1777
Last Page : 1781
Authors : Meirer K, Rödl CB, Wisniewska JM, George S, Häfner AK, Buscató EL, Klingler FM, Hahn S, Berressem D, Wittmann SK, Steinhilber D, Hofmann B, Proschak E.
Abstract : Current research leads to the assumption that drugs affecting more than one target could result in a more efficient treatment of diseases and fewer safety concerns. Administration of drugs inhibiting only one branch of the arachidonic acid cascade is usually accompanied by side effects. We therefore designed and synthesized a library of hybrid molecules incorporating an imidazo[1,2-a]pyridine and an urea moiety as novel soluble epoxide hydrolase (sEH)/5-lipoxygenase (5-LO) dual inhibitors. Evaluation of the compounds was accomplished by in vitro testing using recombinant enzyme assays.
|
Inhibition of N-terminal His6-tagged human prostate epithelial 15-LOX2 pseudoperoxidase activity assessed as reduction of active ferric ion to inactive ferrous state measured decomposition of 13-(S)-HPODE at 40 uM after 30 mins by iron-xylenol orange staining assay
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases.
Year : 2013
Volume : 21
Issue : 13
First Page : 3894
Last Page : 3899
Authors : Hoobler EK, Holz C, Holman TR.
Abstract : Understanding the mode of action for lipoxygenase (LOX) inhibitors is critical to determining their efficacy in the cell. The pseudoperoxidase assay is an important tool for establishing if a LOX inhibitor is reductive in nature, however, there have been difficulties identifying the proper conditions for each of the many human LOX isozymes. In the current paper, both the 234 nM decomposition (UV) and iron-xylenol orange (XO) assays are shown to be effective methods of detecting pseudoperoxidase activity for 5-LOX, 12-LOX, 15-LOX-1 and 15-LOX-2, but only if 13-(S)-HPODE is used as the hydroperoxide substrate. The AA products, 12-(S)-HPETE and 15-(S)-HPETE, are not consistent hydroperoxide substrates since they undergo a competing transformation to the di-HETE products. Utilizing the above conditions, the selective 12-LOX and 15-LOX-1 inhibitors, probes for diabetes, stroke and asthma, are characterized for their inhibitory nature. Interestingly, ascorbic acid also supports the pseudoperoxidase assay, suggesting that it may have a role in maintaining the inactive ferrous form of LOX in the cell. In addition, it is observed that nordihydroguaiaretic acid (NDGA), a known reductive LOX inhibitor, appears to generate radical species during the pseudoperoxidase assay, which are potent inhibitors against the human LOX isozymes, producing a negative pseudoperoxidase result. Therefore, inhibitors that do not support the pseudoperoxidase assay with the human LOX isozymes, should also be investigated for rapid inactivation, to clarify the negative pseudoperoxidase result.
|
Inhibition of N-terminal His6-tagged human reticulocyte 15-LOX1 pseudoperoxidase activity assessed as reduction of active ferric ion to inactive ferrous state measured decomposition of 13-(S)-HPODE at 40 uM after 30 mins by iron-xylenol orange staining assay
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases.
Year : 2013
Volume : 21
Issue : 13
First Page : 3894
Last Page : 3899
Authors : Hoobler EK, Holz C, Holman TR.
Abstract : Understanding the mode of action for lipoxygenase (LOX) inhibitors is critical to determining their efficacy in the cell. The pseudoperoxidase assay is an important tool for establishing if a LOX inhibitor is reductive in nature, however, there have been difficulties identifying the proper conditions for each of the many human LOX isozymes. In the current paper, both the 234 nM decomposition (UV) and iron-xylenol orange (XO) assays are shown to be effective methods of detecting pseudoperoxidase activity for 5-LOX, 12-LOX, 15-LOX-1 and 15-LOX-2, but only if 13-(S)-HPODE is used as the hydroperoxide substrate. The AA products, 12-(S)-HPETE and 15-(S)-HPETE, are not consistent hydroperoxide substrates since they undergo a competing transformation to the di-HETE products. Utilizing the above conditions, the selective 12-LOX and 15-LOX-1 inhibitors, probes for diabetes, stroke and asthma, are characterized for their inhibitory nature. Interestingly, ascorbic acid also supports the pseudoperoxidase assay, suggesting that it may have a role in maintaining the inactive ferrous form of LOX in the cell. In addition, it is observed that nordihydroguaiaretic acid (NDGA), a known reductive LOX inhibitor, appears to generate radical species during the pseudoperoxidase assay, which are potent inhibitors against the human LOX isozymes, producing a negative pseudoperoxidase result. Therefore, inhibitors that do not support the pseudoperoxidase assay with the human LOX isozymes, should also be investigated for rapid inactivation, to clarify the negative pseudoperoxidase result.
|
Inhibition of N-terminal His6-tagged human platelet 12-LOX pseudoperoxidase activity assessed as reduction of active ferric ion to inactive ferrous state measured decomposition of 13-(S)-HPODE at 40 uM after 30 mins by iron-xylenol orange staining assay
|
Homo sapiens
|
50.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases.
Year : 2013
Volume : 21
Issue : 13
First Page : 3894
Last Page : 3899
Authors : Hoobler EK, Holz C, Holman TR.
Abstract : Understanding the mode of action for lipoxygenase (LOX) inhibitors is critical to determining their efficacy in the cell. The pseudoperoxidase assay is an important tool for establishing if a LOX inhibitor is reductive in nature, however, there have been difficulties identifying the proper conditions for each of the many human LOX isozymes. In the current paper, both the 234 nM decomposition (UV) and iron-xylenol orange (XO) assays are shown to be effective methods of detecting pseudoperoxidase activity for 5-LOX, 12-LOX, 15-LOX-1 and 15-LOX-2, but only if 13-(S)-HPODE is used as the hydroperoxide substrate. The AA products, 12-(S)-HPETE and 15-(S)-HPETE, are not consistent hydroperoxide substrates since they undergo a competing transformation to the di-HETE products. Utilizing the above conditions, the selective 12-LOX and 15-LOX-1 inhibitors, probes for diabetes, stroke and asthma, are characterized for their inhibitory nature. Interestingly, ascorbic acid also supports the pseudoperoxidase assay, suggesting that it may have a role in maintaining the inactive ferrous form of LOX in the cell. In addition, it is observed that nordihydroguaiaretic acid (NDGA), a known reductive LOX inhibitor, appears to generate radical species during the pseudoperoxidase assay, which are potent inhibitors against the human LOX isozymes, producing a negative pseudoperoxidase result. Therefore, inhibitors that do not support the pseudoperoxidase assay with the human LOX isozymes, should also be investigated for rapid inactivation, to clarify the negative pseudoperoxidase result.
|
Inhibition of human leukocyte 5-LOX pseudoperoxidase activity assessed as reduction of active ferric ion to inactive ferrous state measured decomposition of 13-(S)-HPODE at 40 uM after 30 mins by iron-xylenol orange staining assay
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases.
Year : 2013
Volume : 21
Issue : 13
First Page : 3894
Last Page : 3899
Authors : Hoobler EK, Holz C, Holman TR.
Abstract : Understanding the mode of action for lipoxygenase (LOX) inhibitors is critical to determining their efficacy in the cell. The pseudoperoxidase assay is an important tool for establishing if a LOX inhibitor is reductive in nature, however, there have been difficulties identifying the proper conditions for each of the many human LOX isozymes. In the current paper, both the 234 nM decomposition (UV) and iron-xylenol orange (XO) assays are shown to be effective methods of detecting pseudoperoxidase activity for 5-LOX, 12-LOX, 15-LOX-1 and 15-LOX-2, but only if 13-(S)-HPODE is used as the hydroperoxide substrate. The AA products, 12-(S)-HPETE and 15-(S)-HPETE, are not consistent hydroperoxide substrates since they undergo a competing transformation to the di-HETE products. Utilizing the above conditions, the selective 12-LOX and 15-LOX-1 inhibitors, probes for diabetes, stroke and asthma, are characterized for their inhibitory nature. Interestingly, ascorbic acid also supports the pseudoperoxidase assay, suggesting that it may have a role in maintaining the inactive ferrous form of LOX in the cell. In addition, it is observed that nordihydroguaiaretic acid (NDGA), a known reductive LOX inhibitor, appears to generate radical species during the pseudoperoxidase assay, which are potent inhibitors against the human LOX isozymes, producing a negative pseudoperoxidase result. Therefore, inhibitors that do not support the pseudoperoxidase assay with the human LOX isozymes, should also be investigated for rapid inactivation, to clarify the negative pseudoperoxidase result.
|
Inhibition of 5-LOX (unknown origin)-mediated leukotriene (LT)B4 biosynthesis
|
Homo sapiens
|
410.0
nM
|
|
Journal : J. Med. Chem.
Title : Investigating the selectivity of metalloenzyme inhibitors.
Year : 2013
Volume : 56
Issue : 20
First Page : 7997
Last Page : 8007
Authors : Day JA, Cohen SM.
Abstract : The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY), was selected based on their clinical importance for a range of pathologies. In addition, each inhibitor was evaluated for its ability to remove Fe(3+) from holo-transferrin to gauge the ability of the inhibitors to access Fe(3+) from a primary transport protein. The results show that the metalloenzyme inhibitors are quite selective for their intended targets, suggesting that despite their ability to bind metal ions, metalloprotein inhibitors are not prone to widespread off-target enzyme inhibition activity.
|
Inhibition of human recombinant 5-lipoxygenase expressed in Escherichia coli BL21 using arachidonic acid as substrate incubated 5 to 10 mins prior to substrate addition measured after 10 mins by HPLC analysis
|
Homo sapiens
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Aminothiazole-featured pirinixic acid derivatives as dual 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 inhibitors with improved potency and efficiency in vivo.
Year : 2013
Volume : 56
Issue : 22
First Page : 9031
Last Page : 9044
Authors : Hanke T, Dehm F, Liening S, Popella SD, Maczewsky J, Pillong M, Kunze J, Weinigel C, Barz D, Kaiser A, Wurglics M, Lämmerhofer M, Schneider G, Sautebin L, Schubert-Zsilavecz M, Werz O.
Abstract : Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2-aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.4 μM, respectively) and bioactivity in vivo. Computational analysis presumes binding sites of 16 at the tip of the 5-LO catalytic domain and within a subpocket of the mPGES-1 active site. Compound 16 (10 μM) hardly suppressed cyclooxygenase (COX)-1/2 activities, failed to inhibit 12/15-LOs, and is devoid of radical scavenger properties. Finally, compound 16 reduced vascular permeability and inflammatory cell infiltration in a zymosan-induced mouse peritonitis model accompanied by impaired levels of cysteinyl-leukotrienes and prostaglandin E2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs.
|
Inhibition of 5-lipoxygenase in A23187-stimulated human polymorphonuclear leukocytes using arachidonic acid as substrate incubated 15 mins prior to substrate addition measured after 10 mins by HPLC analysis
|
Homo sapiens
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Aminothiazole-featured pirinixic acid derivatives as dual 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 inhibitors with improved potency and efficiency in vivo.
Year : 2013
Volume : 56
Issue : 22
First Page : 9031
Last Page : 9044
Authors : Hanke T, Dehm F, Liening S, Popella SD, Maczewsky J, Pillong M, Kunze J, Weinigel C, Barz D, Kaiser A, Wurglics M, Lämmerhofer M, Schneider G, Sautebin L, Schubert-Zsilavecz M, Werz O.
Abstract : Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2-aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.4 μM, respectively) and bioactivity in vivo. Computational analysis presumes binding sites of 16 at the tip of the 5-LO catalytic domain and within a subpocket of the mPGES-1 active site. Compound 16 (10 μM) hardly suppressed cyclooxygenase (COX)-1/2 activities, failed to inhibit 12/15-LOs, and is devoid of radical scavenger properties. Finally, compound 16 reduced vascular permeability and inflammatory cell infiltration in a zymosan-induced mouse peritonitis model accompanied by impaired levels of cysteinyl-leukotrienes and prostaglandin E2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs.
|
Inhibition of 5-LO (unknown origin)
|
Homo sapiens
|
560.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery and biological evaluation of novel 1,4-benzoquinone and related resorcinol derivatives that inhibit 5-lipoxygenase.
Year : 2013
Volume : 67
First Page : 269
Last Page : 279
Authors : Filosa R, Peduto A, Aparoy P, Schaible AM, Luderer S, Krauth V, Petronzi C, Massa A, de Rosa M, Reddanna P, Werz O.
Abstract : 5-Lipoxygenase (5-LO), an enzyme that catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes, is an attractive drug target for the pharmacotherapy of inflammatory and allergic diseases. Here, we present the discovery and biological evaluation of novel series of 1,4-benzoquinones and respective resorcinol derivatives that efficiently inhibit human 5-LO, with little effects on other human lipoxygenases. SAR analysis revealed that the potency of the compounds strongly depends on structural features of the lipophilic residues, where bulky naphthyl or dibenzofuran moieties favor 5-LO inhibition. Among the 1,4-benzoquinones, compound Ig 5-[(2-naphthyl)methyl]-2-hydroxy-2,5-cyclohexadiene-1,4-dione potently blocked 5-LO activity in cell-free assays with IC50 = 0.78 μM, and suppressed 5-LO product synthesis in polymorphonuclear leukocytes with IC50 = 2.3 μM. Molecular docking studies suggest a concrete binding site for Ig in 5-LO where select π-π interactions along with hydrogen bond interactions accomplish binding to the active site of the enzyme. Together, our study reveals novel valuable 5-LO inhibitors with potential for further preclinical assessment as anti-inflammatory compounds.
|
Inhibition of human recombinant 5-LO expressed in Escherichia coli BL21 using arachidonic acid as substrate after 10 mins
|
Homo sapiens
|
560.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery and biological evaluation of novel 1,4-benzoquinone and related resorcinol derivatives that inhibit 5-lipoxygenase.
Year : 2013
Volume : 67
First Page : 269
Last Page : 279
Authors : Filosa R, Peduto A, Aparoy P, Schaible AM, Luderer S, Krauth V, Petronzi C, Massa A, de Rosa M, Reddanna P, Werz O.
Abstract : 5-Lipoxygenase (5-LO), an enzyme that catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes, is an attractive drug target for the pharmacotherapy of inflammatory and allergic diseases. Here, we present the discovery and biological evaluation of novel series of 1,4-benzoquinones and respective resorcinol derivatives that efficiently inhibit human 5-LO, with little effects on other human lipoxygenases. SAR analysis revealed that the potency of the compounds strongly depends on structural features of the lipophilic residues, where bulky naphthyl or dibenzofuran moieties favor 5-LO inhibition. Among the 1,4-benzoquinones, compound Ig 5-[(2-naphthyl)methyl]-2-hydroxy-2,5-cyclohexadiene-1,4-dione potently blocked 5-LO activity in cell-free assays with IC50 = 0.78 μM, and suppressed 5-LO product synthesis in polymorphonuclear leukocytes with IC50 = 2.3 μM. Molecular docking studies suggest a concrete binding site for Ig in 5-LO where select π-π interactions along with hydrogen bond interactions accomplish binding to the active site of the enzyme. Together, our study reveals novel valuable 5-LO inhibitors with potential for further preclinical assessment as anti-inflammatory compounds.
|
Inhibition of 5-LOX (unknown origin) using arachidonic acid as substrate after 5 mins by EIA
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Lead modification: amino acid appended indoles as highly effective 5-LOX inhibitors.
Year : 2014
Volume : 22
Issue : 5
First Page : 1642
Last Page : 1648
Authors : Prasher P, Pooja, Singh P.
Abstract : N-1 tosyl indoles carrying amino acid as a part of C-3 substituent are identified with considerable 5-LOX inhibitory activities. On the basis of enzyme inhibitory activities and logP, it is found that these compounds are more suitable to use as ester prodrugs. In addition to the significant Ka and Ki for 5-LOX, advantageously the compounds under present investigation do not affect the viability of the cell. The experimental results were also supported by molecular docking of compounds in the active site of 5-LOX.
|
Inhibition of 5-LO in human polymorphonuclear leukocytes assessed as inhibition of LTB4 production from arachidonic acid preincubated for 15 mins by HPLC analysis
|
Homo sapiens
|
700.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Further studies on ethyl 5-hydroxy-indole-3-carboxylate scaffold: design, synthesis and evaluation of 2-phenylthiomethyl-indole derivatives as efficient inhibitors of human 5-lipoxygenase.
Year : 2014
Volume : 81
First Page : 492
Last Page : 498
Authors : Peduto A, Bruno F, Dehm F, Krauth V, de Caprariis P, Weinigel C, Barz D, Massa A, De Rosa M, Werz O, Filosa R.
Abstract : 5-Lipoxygenase (5-LO), an enzyme that catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes, is an attractive drug target for the pharmacotherapy of inflammatory and allergic diseases. Here, we present the design, synthesis and biological evaluation of novel series of ethyl 5-hydroxyindole-3-carboxylate derivatives that efficiently inhibit human 5-LO. SAR analysis revealed that the potency of compounds is closely related to the positioning of the substituents at the phenylthiomethyl ring. The introduction of methyl or chlorine groups in ortho- and ortho/para-position of thiophenol represent the most favorable modifications. Among all tested compounds, ethyl 5-hydroxy-2-(mesitylthiomethyl)-1-methyl-1H-indole-3-carboxylate (19) is the most potent derivative which blocks 5-LO activity in cell-free assays with IC50 = 0.7 μM, and suppressed 5-LO product synthesis in polymorphonuclear leukocytes with IC50 = 0.23 μM.
|
Inhibition of human recombinant 5-LO expressed in Escherichia coli BL21 using arachidonic acid as substrate preincubated for 5 to 10 mins by HPLC analysis
|
Homo sapiens
|
600.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Further studies on ethyl 5-hydroxy-indole-3-carboxylate scaffold: design, synthesis and evaluation of 2-phenylthiomethyl-indole derivatives as efficient inhibitors of human 5-lipoxygenase.
Year : 2014
Volume : 81
First Page : 492
Last Page : 498
Authors : Peduto A, Bruno F, Dehm F, Krauth V, de Caprariis P, Weinigel C, Barz D, Massa A, De Rosa M, Werz O, Filosa R.
Abstract : 5-Lipoxygenase (5-LO), an enzyme that catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes, is an attractive drug target for the pharmacotherapy of inflammatory and allergic diseases. Here, we present the design, synthesis and biological evaluation of novel series of ethyl 5-hydroxyindole-3-carboxylate derivatives that efficiently inhibit human 5-LO. SAR analysis revealed that the potency of compounds is closely related to the positioning of the substituents at the phenylthiomethyl ring. The introduction of methyl or chlorine groups in ortho- and ortho/para-position of thiophenol represent the most favorable modifications. Among all tested compounds, ethyl 5-hydroxy-2-(mesitylthiomethyl)-1-methyl-1H-indole-3-carboxylate (19) is the most potent derivative which blocks 5-LO activity in cell-free assays with IC50 = 0.7 μM, and suppressed 5-LO product synthesis in polymorphonuclear leukocytes with IC50 = 0.23 μM.
|
Inhibition of human recombinant 5-LO assessed as product formation at 3 uM by cell-free assay relative to control
|
Homo sapiens
|
28.1
%
|
|
Journal : J. Med. Chem.
Title : Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase.
Year : 2014
Volume : 57
Issue : 9
First Page : 3715
Last Page : 3723
Authors : Pergola C, Gaboriaud-Kolar N, Jestädt N, König S, Kritsanida M, Schaible AM, Li H, Garscha U, Weinigel C, Barz D, Albring KF, Huber O, Skaltsounis AL, Werz O.
Abstract : The enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase (GSK)-3 represent promising drug targets in inflammation. We made use of the bisindole core of indirubin, present in GSK-3 inhibitors, to innovatively target 5-LO at the ATP-binding site for the design of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin derivatives led to the identification of (3Z)-6-bromo-3-[(3E)-3-hydroxyiminoindolin-2-ylidene]indolin-2-one (15) as a potent, direct, and reversible 5-LO inhibitor (IC50 = 1.5 μM), with comparable cellular effectiveness on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes for the development of 5-LO inhibitors, the interference with the ATP-binding site as a novel strategy for 5-LO targeting, and dual 5-LO/GSK-3 inhibition as an unconventional and promising concept for anti-inflammatory intervention.
|
Inhibition of 5-LO in human neutrophils assessed as product formation at 3 uM by cell-intact assay relative to control in presence of 2.5 uM A23187 ionophore
|
Homo sapiens
|
37.9
%
|
|
Journal : J. Med. Chem.
Title : Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase.
Year : 2014
Volume : 57
Issue : 9
First Page : 3715
Last Page : 3723
Authors : Pergola C, Gaboriaud-Kolar N, Jestädt N, König S, Kritsanida M, Schaible AM, Li H, Garscha U, Weinigel C, Barz D, Albring KF, Huber O, Skaltsounis AL, Werz O.
Abstract : The enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase (GSK)-3 represent promising drug targets in inflammation. We made use of the bisindole core of indirubin, present in GSK-3 inhibitors, to innovatively target 5-LO at the ATP-binding site for the design of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin derivatives led to the identification of (3Z)-6-bromo-3-[(3E)-3-hydroxyiminoindolin-2-ylidene]indolin-2-one (15) as a potent, direct, and reversible 5-LO inhibitor (IC50 = 1.5 μM), with comparable cellular effectiveness on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes for the development of 5-LO inhibitors, the interference with the ATP-binding site as a novel strategy for 5-LO targeting, and dual 5-LO/GSK-3 inhibition as an unconventional and promising concept for anti-inflammatory intervention.
|
Inhibition of human recombinant 5-LO assessed as product formation by cell-free assay relative to control
|
Homo sapiens
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase.
Year : 2014
Volume : 57
Issue : 9
First Page : 3715
Last Page : 3723
Authors : Pergola C, Gaboriaud-Kolar N, Jestädt N, König S, Kritsanida M, Schaible AM, Li H, Garscha U, Weinigel C, Barz D, Albring KF, Huber O, Skaltsounis AL, Werz O.
Abstract : The enzymes 5-lipoxygenase (5-LO) and glycogen synthase kinase (GSK)-3 represent promising drug targets in inflammation. We made use of the bisindole core of indirubin, present in GSK-3 inhibitors, to innovatively target 5-LO at the ATP-binding site for the design of dual 5-LO/GSK-3 inhibitors. Evaluation of substituted indirubin derivatives led to the identification of (3Z)-6-bromo-3-[(3E)-3-hydroxyiminoindolin-2-ylidene]indolin-2-one (15) as a potent, direct, and reversible 5-LO inhibitor (IC50 = 1.5 μM), with comparable cellular effectiveness on 5-LO and GSK-3. Together, we present indirubins as novel chemotypes for the development of 5-LO inhibitors, the interference with the ATP-binding site as a novel strategy for 5-LO targeting, and dual 5-LO/GSK-3 inhibition as an unconventional and promising concept for anti-inflammatory intervention.
|
Inhibition of human recombinant 5-LOX expressed in Escherichia coli BL21 incubated for 10 mins in presence of arachidonic acid by RP-HPLC based cell-free assay
|
Homo sapiens
|
590.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel series of benzoquinones with high potency against 5-lipoxygenase in human polymorphonuclear leukocytes.
Year : 2015
Volume : 94
First Page : 132
Last Page : 139
Authors : Filosa R, Peduto A, Schaible AM, Krauth V, Weinigel C, Barz D, Petronzi C, Bruno F, Roviezzo F, Spaziano G, D'Agostino B, De Rosa M, Werz O.
Abstract : 5-Lipoxygenase (5-LO) is a potential target for pharmacological intervention with various inflammatory and allergic diseases. Starting from the natural dual 5-LO/microsomal prostaglandin E2 synthase (mPGES)-1 inhibitor embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone, 2) that suppresses 5-LO activity in human primary leukocytes with IC50 = 0.8-2 μM, we synthesized 48 systematically modified derivatives of 2. We modified the 1,4-quinone to 1,2-quinone, mono- or bimethylated the hydroxyl groups, and varied the C11-n-alkyl residue (C4- to C16-n-alkyl or prenyl) of 2. Biological evaluation yields potent analogues being superior over 2 and obvious structure-activity relationships (SAR) for inhibition of 5-LO. Interestingly, conversion to 1,2-benzoquinone and bimethylation of the hydroxyl moieties strongly improves 5-LO inhibition in polymorphonuclear leukocytes versus 2 up to 60-fold, exemplified by the C12-n-alkyl derivative 22c (4,5-dimethoxy-3-dodecyl-1,2-benzoquinone) with IC50 = 29 nM. Regarding inhibition of mPGES-1, none of the novel benzoquinones could outperform the parental compound 2 (IC50 = 0.21 μM), and only modest suppressive effects on 12- and 15-LOs were evident. Together, our detailed SAR study reveals 22c as highly potent 5-LO-selective lead compound in intact cells that warrants further preclinical evaluation as anti-inflammatory agent.
|
Inhibition of 5-LOX in A23187-stimulated human blood PMNL assessed as reduction in lipoxygenase products formation pre-incubated for 15 mins followed by stimulation with A23187 for 10 mins by RP-HPLC based cell based assay
|
Homo sapiens
|
900.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel series of benzoquinones with high potency against 5-lipoxygenase in human polymorphonuclear leukocytes.
Year : 2015
Volume : 94
First Page : 132
Last Page : 139
Authors : Filosa R, Peduto A, Schaible AM, Krauth V, Weinigel C, Barz D, Petronzi C, Bruno F, Roviezzo F, Spaziano G, D'Agostino B, De Rosa M, Werz O.
Abstract : 5-Lipoxygenase (5-LO) is a potential target for pharmacological intervention with various inflammatory and allergic diseases. Starting from the natural dual 5-LO/microsomal prostaglandin E2 synthase (mPGES)-1 inhibitor embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone, 2) that suppresses 5-LO activity in human primary leukocytes with IC50 = 0.8-2 μM, we synthesized 48 systematically modified derivatives of 2. We modified the 1,4-quinone to 1,2-quinone, mono- or bimethylated the hydroxyl groups, and varied the C11-n-alkyl residue (C4- to C16-n-alkyl or prenyl) of 2. Biological evaluation yields potent analogues being superior over 2 and obvious structure-activity relationships (SAR) for inhibition of 5-LO. Interestingly, conversion to 1,2-benzoquinone and bimethylation of the hydroxyl moieties strongly improves 5-LO inhibition in polymorphonuclear leukocytes versus 2 up to 60-fold, exemplified by the C12-n-alkyl derivative 22c (4,5-dimethoxy-3-dodecyl-1,2-benzoquinone) with IC50 = 29 nM. Regarding inhibition of mPGES-1, none of the novel benzoquinones could outperform the parental compound 2 (IC50 = 0.21 μM), and only modest suppressive effects on 12- and 15-LOs were evident. Together, our detailed SAR study reveals 22c as highly potent 5-LO-selective lead compound in intact cells that warrants further preclinical evaluation as anti-inflammatory agent.
|
Inhibition of soyabean 5-LOX using arachidonic acid as substrate by microplate scanning spectrophotometer analysis
|
Glycine max
|
300.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Indole based peptidomimetics as anti-inflammatory and anti-hyperalgesic agents: Dual inhibition of 5-LOX and COX-2 enzymes.
Year : 2015
Volume : 97
First Page : 104
Last Page : 123
Authors : Singh P, Prasher P, Dhillon P, Bhatti R.
Abstract : The indoles bearing a tosyl group at N-1 and a dipeptide substituent at C-3 were screened for anti-inflammatory and anti-hyperalgesic activities. Some of the compounds made significant reduction in the dextran induced swelling and capsaicin induced pain in the albino mice. About 95% reversal in capsaicin induced pain occurred in the presence of 5 mg kg(-1) of compound 7b, 7d and 7h while diclofenac showed 90% reversal when its 10 mg kg(-1) dose was used. In order to examine the mode of action of these compounds; COX-1, COX-2 and 5-LOX enzyme immunoassays were performed. The IC50 of compound 7b for COX-2 and 5-LOX were in the nM range: 5-LOX, IC50 = 2.0 nM; COX-2, IC50 = 6.3 nM, selectivity for COX-2 over COX-1 was 351. The interactions of the compounds with COX-2 and 5-LOX were supported by the physical parameters including Ki, Ka and ΔG. The most potent compounds 7b, 7d and 7h showed no toxicity to the animals and were identified as the promising leads for anti-inflammatory drugs.
|
Anti-inflammatory activity in rat assessed as inhibition of arachidonic acid-induced paw edema at 10 mg/kg, po dosed 30 mins before arachidonic acid injection and measured 1 hr after arachidonic acid injection
|
Rattus norvegicus
|
67.42
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6-diphenyl-1,2,4-triazin-3(2H)-one derivatives bearing 5-substituted 1,3,4-oxadiazole as potential anti-inflammatory and analgesic agents.
Year : 2015
Volume : 101
First Page : 81
Last Page : 95
Authors : Banerjee AG, Das N, Shengule SA, Srivastava RS, Shrivastava SK.
Abstract : A series of triazin-3(2H)-one derivatives bearing 1,3,4-oxadiazole (4a-4o) were synthesized, characterized and evaluated for anti-inflammatory and analgesic activities. Preliminary in vitro anti-inflammatory activity was assessed using an albumin denaturation assay. The promising compounds were further evaluated in acute, sub-chronic and chronic animal models of inflammation. Derivatives 4d, 4e, 4g, 4j and 4l exhibited significant anti-inflammatory activity with reduced ulcerogenic, hepatotoxic and renotoxic liabilities compared to standard indomethacin. These potential derivatives were also evaluated for in vivo analgesic activity using a writhing model and the formalin-induced paw licking response in mice. Compounds 4d, 4e and 4g exhibited comparable analgesic activity, whereas 4j and 4l yielded moderate effects. The specificity of compounds 4d, 4e, 4g, 4j, and 4l to inhibit (cyclooxygenase-1) COX-1 and (cyclooxygenase-2) COX-2 isozymes and their kinetics were also determined via an in vitro COX inhibition assay. In silico docking studies were performed using a molecular dynamics simulation of the most active compound 4d (COX-2 IC50: 3.07 μM) at the COX-2 active site. The outcome of this exercise helped to verify the consensual interaction of these compounds with the enzyme.
|
Inhibition of 5-LOX in human neutrophils assessed as reduction in LTB4 and 5-H(P)ETE) formation pre-incubated for 15 mins before A23187 and arachidonic acid substrate addition by RP-HPLC method
|
Homo sapiens
|
540.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and evaluation of semi-synthetic triazole-containing caffeic acid analogues as 5-lipoxygenase inhibitors.
Year : 2015
Volume : 101
First Page : 573
Last Page : 583
Authors : De Lucia D, Lucio OM, Musio B, Bender A, Listing M, Dennhardt S, Koeberle A, Garscha U, Rizzo R, Manfredini S, Werz O, Ley SV.
Abstract : In this work the synthesis, structure-activity relationship (SAR) and biological evaluation of a novel series of triazole-containing 5-lipoxygenase (5-LO) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent 5-LO inhibition with IC50 of 0.2 and 3.2 μm in cell-based and cell-free assays, respectively. Optimization of binding and functional potencies resulted in the identification of compound 13d, which showed an enhanced activity compared to the parent bioactive compound caffeic acid 5 and the clinically approved zileuton 3. Compounds 15 and 16 were identified as lead compounds in inhibiting 5-LO products formation in neutrophils. Their interference with other targets on the arachidonic acid pathway was also assessed. Cytotoxicity tests were performed to exclude a relationship between cytotoxicity and the increased activity observed after structure optimization.
|
Inhibition of 5-LO in mouse BMM cells assessed as formation of LTC4 after 30 mins by enzyme immunoassay
|
Mus musculus
|
190.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 5-Lipoxygenase inhibitors suppress RANKL-induced osteoclast formation via NFATc1 expression.
Year : 2015
Volume : 23
Issue : 21
First Page : 7069
Last Page : 7078
Authors : Kang JH, Ting Z, Moon MR, Sim JS, Lee JM, Doh KE, Hong S, Cui M, Choi S, Chang HW, Park Choo HY, Yim M.
Abstract : 5-Lipoxygenase synthesizes leukotrienes from arachidonic acid. We developed three novel 5-LO inhibitors having a benzoxazole scaffold as a potential anti-osteoclastogenics. They significantly suppressed RANKL-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, one compound, K7, inhibited the bone resorptive activity of osteoclasts. The anti-osteoclastogenic effect of K7 was mainly attributable to reduction in the expression of NFATc1, an essential transcription factor for osteoclast differentiation. K7 inhibited osteoclast formation via ERK and p38 MAPK, as well as NF-κB signaling pathways. K7 reduced lipopolysaccharide (LPS)-induced osteoclast formation in vivo, corroborating the in vitro data. Thus, K7 exerted an inhibitory effect on osteoclast formation in vitro and in vivo, properties that make it a potential candidate for the treatment of bone diseases associated with excessive bone resorption.
|
Inhibition of 5-LOX in Sprague-Dawley rat leukocytes assessed as A23187 stimulated LTB4 production pretreated for 30 mins followed by addition of A23187 for 30 mins by EIA
|
Rattus norvegicus
|
800.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of novel hybrids of diaryl-1,2,4-triazoles and caffeic acid as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase for cancer therapy.
Year : 2016
Volume : 108
First Page : 89
Last Page : 103
Authors : Cai H, Huang X, Xu S, Shen H, Zhang P, Huang Y, Jiang J, Sun Y, Jiang B, Wu X, Yao H, Xu J.
Abstract : Inflammation plays a key role in cancer initiation and propagation. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), two important enzymes in inflammatory responses are up-regulated in various tumor types. Dual inhibition of COX-2 and 5-LOX constitutes a rational concept for the design of more efficacious anti-tumor agents with an improved safety profile. We have previously reported a series of diaryl-1,2,4-triazole derivatives as selective COX-2 inhibitors. Herein, we hybridized the diaryl-1,2,4-triazoles with caffeic acid (CA) which was reported to display 5-LOX inhibitory and anti-tumor activities, affording a novel class of COX-2/5-LOX dual inhibitors as anti-tumor drug candidates. Most of these compounds exhibited potent COX-2/5-LOX inhibitory and antiproliferative activities in vitro. And the most potent compound 22b could significantly inhibit tumor growth in vivo. Furthermore, mechanistic investigation showed that the representative compound 15c blocked cell cycle in G2 phase and induced apoptosis in human non-small cell lung cancer A549 cells in a dose-dependent manner. Our preliminary investigation results would provide new clues for the cancer theatment with COX-2/5-LOX dual inhibitors.
|
Inhibition of FLAP in Ca+2 ionophore A23187 stimulated human neutrophils assessed as 5-LO product formation preincubated for 15 mins measured after 10 mins by RP-HPLC analysis
|
Homo sapiens
|
580.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP).
Year : 2016
Volume : 113
First Page : 1
Last Page : 10
Authors : Banoglu E, Çelikoğlu E, Völker S, Olgaç A, Gerstmeier J, Garscha U, Çalışkan B, Schubert US, Carotti A, Macchiarulo A, Werz O.
Abstract : In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 μM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 ≥ 8 μM). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis.
|
Inhibition of recombinant human 5-LO expressed in Escherichia coli BL21 assessed as 5-LO product formation preincubated for 15 mins followed by addition of arachidonic acid as substrate measured after 10 mins by RP-HPLC analysis
|
Homo sapiens
|
910.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP).
Year : 2016
Volume : 113
First Page : 1
Last Page : 10
Authors : Banoglu E, Çelikoğlu E, Völker S, Olgaç A, Gerstmeier J, Garscha U, Çalışkan B, Schubert US, Carotti A, Macchiarulo A, Werz O.
Abstract : In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 μM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 ≥ 8 μM). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis.
|
Inhibition of recombinant human 5-LO expressed in Escherichia coli BL21 at 3 uM using arachidonic acid as substrate preincubated for 15 mins followed by substrate addition measured after 10 mins by RP-HPLC analysis relative to control
|
Homo sapiens
|
80.0
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of C(5)-substituted derivatives of leukotriene biosynthesis inhibitor BRP-7.
Year : 2016
Volume : 122
First Page : 510
Last Page : 519
Authors : Levent S, Gerstmeier J, Olgaç A, Nikels F, Garscha U, Carotti A, Macchiarulo A, Werz O, Banoglu E, Çalışkan B.
Abstract : Pharmacological intervention with 5-lipoxygenase (5-LO) pathway leading to suppression of leukotriene (LT) biosynthesis is a clinically validated strategy for treatment of respiratory and cardiovascular diseases such as asthma and atherosclerosis. Here we describe the synthesis of a series of C(5)-substituted analogues of the previously described 5-LO-activating protein (FLAP) inhibitor BRP-7 (IC50 = 0.31 μM) to explore the effects of substitution at the C(5)-benzimidazole (BI) ring as a strategy to increase the potency against FLAP-mediated 5-LO product formation. Incorporation of polar substituents on the C(5) position of the BI core, exemplified by compound 11 with a C(5)-nitrile substituent, significantly enhances the potency for suppression of 5-LO product synthesis in human neutrophils (IC50 = 0.07 μM) and monocytes (IC50 = 0.026 μM).
|
Inhibition of human recombinant 5-LOX expressed in Escherichia coli BL21 assessed as decrease in 5-HPETE production at 50 uM preincubated with enzyme followed by arachidonic acid substrate addition by UV-vis spectrophotometry
|
Homo sapiens
|
97.0
%
|
|
Journal : Eur J Med Chem
Title : Inhibition of the enzymes in the leukotriene and prostaglandin pathways in inflammation by 3-aryl isocoumarins.
Year : 2016
Volume : 124
First Page : 428
Last Page : 434
Authors : Ramanan M, Sinha S, Sudarshan K, Aidhen IS, Doble M.
Abstract : The biosynthesis of leukotrienes in one of the arachidonic acid pathways and PGE2 in the other by 5-LOX and mPGES1 respectively, play pivotal roles in augmenting inflammatory responses. PGE2 is known to participate in cancer pathological processes as well. Isocoumarins are natural compounds with a wide range of biological activities. In this study, 3-aryl isocoumarin derivatives are synthesized and tested against 5-LOX enzyme in vitro and PGE2 production in HeLa cells. Most of the compounds show high activity, and 1c is identified as a dual inhibitor with an IC50 of 4.6 ± 0.26 μM and 6.3 ± 0.13 μM against 5-LOX and PGE2 production respectively. Another compound 7f, exhibits an IC50 of 12.4 ± 0.14 μM against 5-LOX. Further investigations reveal that the mechanism of action of 1c and 7f against 5-LOX is mixed and competitive modes of action respectively. Thunberginol A (7c) exhibits IC50 of 15.8 ± 0.03 μM against PGE2 production. 1c and 7c inhibit the mRNA expression of mPGES1 and COX-2. The study has identified a novel scaffold, 1c with a dual inhibitory activity which can be further optimized to compete against Licofelone which is under clinical trials (with IC50 of 6.0 μM for mPGES1 & 0.2 μM for 5-LOX). To conclude, 3-aryl isocoumarin derivatives appears as promising tools to fight against inflammatory diseases as well as cancer.
|
Inhibition of mPGES1 in human HeLa cells assessed as reduction in TNF-alpha induced PGE2 production at 50 uM preincubated for 2 hrs followed by TNF-alpha addition for 24 hrs by ELISA
|
Homo sapiens
|
50.0
%
|
|
Journal : Eur J Med Chem
Title : Inhibition of the enzymes in the leukotriene and prostaglandin pathways in inflammation by 3-aryl isocoumarins.
Year : 2016
Volume : 124
First Page : 428
Last Page : 434
Authors : Ramanan M, Sinha S, Sudarshan K, Aidhen IS, Doble M.
Abstract : The biosynthesis of leukotrienes in one of the arachidonic acid pathways and PGE2 in the other by 5-LOX and mPGES1 respectively, play pivotal roles in augmenting inflammatory responses. PGE2 is known to participate in cancer pathological processes as well. Isocoumarins are natural compounds with a wide range of biological activities. In this study, 3-aryl isocoumarin derivatives are synthesized and tested against 5-LOX enzyme in vitro and PGE2 production in HeLa cells. Most of the compounds show high activity, and 1c is identified as a dual inhibitor with an IC50 of 4.6 ± 0.26 μM and 6.3 ± 0.13 μM against 5-LOX and PGE2 production respectively. Another compound 7f, exhibits an IC50 of 12.4 ± 0.14 μM against 5-LOX. Further investigations reveal that the mechanism of action of 1c and 7f against 5-LOX is mixed and competitive modes of action respectively. Thunberginol A (7c) exhibits IC50 of 15.8 ± 0.03 μM against PGE2 production. 1c and 7c inhibit the mRNA expression of mPGES1 and COX-2. The study has identified a novel scaffold, 1c with a dual inhibitory activity which can be further optimized to compete against Licofelone which is under clinical trials (with IC50 of 6.0 μM for mPGES1 & 0.2 μM for 5-LOX). To conclude, 3-aryl isocoumarin derivatives appears as promising tools to fight against inflammatory diseases as well as cancer.
|
Inhibition of 15-LOX in human primary polymorphonuclear leukocytes
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Easy and rapid preparation of benzoylhydrazides and their diazene derivatives as inhibitors of 15-lipoxygenase.
Year : 2017
Volume : 27
Issue : 8
First Page : 1649
Last Page : 1653
Authors : Tirapegui C, Acevedo-Fuentes W, Dahech P, Torrent C, Barrias P, Rojas-Poblete M, Mascayano C.
Abstract : Two series of diaza derivatives were prepared by solvent-free condensation of benzoic acid and 4-substituted phenylhydrazines in order to obtain phenylhydrazides (HYD series) and, by oxidation of these compounds, the corresponding benzoyldiazenes (DIA series). Both sets were evaluated as inhibitors of soybean 15-lipoxygenase activity and antioxidant capability in the FRAP and CUPRAC assays. The most potent inhibitors of both series exhibited IC50 values in the low micromolar range. Kinetic studies showed that at least the more active compounds were competitive inhibitors. Docking results indicated that the most potent inhibitor interacts strongly with Ile-839 and iron in the active site.
|
Inhibition of human recombinant 5-lipoxygenase expressed in Escherichia coli MV1190 pre-incubated for 10 mins before arachidonic acid substrate addition and measured after 10 mins by RP-HPLC method
|
Homo sapiens
|
800.0
nM
|
|
Journal : J Nat Prod
Title : The Bibenzyl Canniprene Inhibits the Production of Pro-Inflammatory Eicosanoids and Selectively Accumulates in Some Cannabis sativa Strains.
Year : 2017
Volume : 80
Issue : 3
First Page : 731
Last Page : 734
Authors : Allegrone G, Pollastro F, Magagnini G, Taglialatela-Scafati O, Seegers J, Koeberle A, Werz O, Appendino G.
Abstract : Canniprene (1), an isoprenylated bibenzyl unique to Cannabis sativa, can be vaporized and therefore potentially inhaled from marijuana. Canniprene (1) potently inhibited the production of inflammatory eicosanoids via the 5-lipoxygenase pathway (IC50 0.4 μM) and also affected the generation of prostaglandins via the cyclooxygenase/microsomal prostaglandin E2 synthase pathway (IC50 10 μM), while the related spiranoid bibenzyls cannabispiranol (2) and cannabispirenone (3) were almost inactive in these bioassays. The concentration of canniprene (1) was investigated in the leaves of 160 strains of C. sativa, showing wide variations, from traces to >0.2%, but no correlation was found between its accumulation and a specific phytocannabinoid profile.
|
Anti inflammatory activity in arachidonic acid-induced Wistar rat paw edema model assessed as inhibition of right hind paw edema thickness at 10 mg/kg, po pretreated for 30 mins followed by arachidonic acid challenge measured after 1 hr (Rvb = 0%)
|
Rattus norvegicus
|
72.3
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and biological evaluation of some novel indolizine derivatives as dual cyclooxygenase and lipoxygenase inhibitor for anti-inflammatory activity.
Year : 2017
Volume : 25
Issue : 16
First Page : 4424
Last Page : 4432
Authors : Shrivastava SK, Srivastava P, Bandresh R, Tripathi PN, Tripathi A.
Abstract : Some novel indolizine derivatives were synthesized by bioisosteric modification of imidazo[1,2-a]pyridine for anti-inflammatory activity. The physicochemical characterization and structure of compounds were elucidated by state of the art spectroscopic technique. Induced fit docking was performed for initial screening to elucidate the interactions with corresponding amino acids of cyclooxygenase (COX-1, COX-2) and lipoxygenase (LOX) enzymes. The target compounds 53-60 were then evaluated against in vivo carrageenan and arachidonic acid induced rat paw edema models for anti-inflammatory activity. Amongst all the synthesized derivatives, compound 56 showed the significant anti-inflammatory activity in both rat paw edema models with very less ulcerogenic liability in comparison to standard diclofenac, celecoxib, and zileuton. The compounds 56 was further assessed to observe in vitro enzyme inhibition assay on both cyclooxygenase and lipoxygenase enzyme where it showed a preferential and selective non-competitive enzyme inhibition towards the COX-2 (IC50=14.91μM, Ki=0.72µM) over COX-1 (IC50>50μM) and a significant non-competitive inhibition of soybean lipoxygenase enzyme (IC50=13.09μM, Ki=0.92µM). Thus, in silico, in vivo, and in vitro findings suggested that the synthesized indolizine compound 56 has a dual COX-2 and LOX inhibition characteristic and parallel in vivo anti-inflammatory activity in comparison to the standard drugs.
|
Inhibition of human recombinant 5-LO at 3 mM using arachidonic acid as substrate in presence of Ca2+ stimulating cofactor
|
Homo sapiens
|
79.0
%
|
|
Journal : Bioorg Med Chem
Title : Recent synthetic and medicinal perspectives of tryptanthrin.
Year : 2017
Volume : 25
Issue : 17
First Page : 4533
Last Page : 4552
Authors : Kaur R, Manjal SK, Rawal RK, Kumar K.
Abstract : Tryptanthrin is a natural alkaloidal compound having basic indoloquinazoline moiety. It is obtained from various natural plant sources as well as different cell cultures including yeast etc. Trptanthrin is considered as biogenetic precursor for phaitanthrin A-C, pyrroloindoloquinazoline, (±)-cruciferane. Different synthetic approaches for the synthesis of tryptanthrin have been very well reported. It has broad spectrum of biological activities including anticancer activity, anti-inflammatory, antiprotozoal, antiallergic, antioxidant, and antimicrobial. In this review, our focus will be, on the various approaches for the synthesis of tryptanthrins and its derivatives along with the biological activities.
|
Inhibition of human recombinant 5-LO expressed in Escherichia coli MV1190 using arachidonic acid as substrate preincubated for 10 mins followed by substrate addition measured after 10 mins by RP-HPLC analysis
|
Homo sapiens
|
800.0
nM
|
|
Journal : J Nat Prod
Title : Evaluation of Dual 5-Lipoxygenase/Microsomal Prostaglandin E2 Synthase-1 Inhibitory Effect of Natural and Synthetic Acronychia-Type Isoprenylated Acetophenones.
Year : 2017
Volume : 80
Issue : 3
First Page : 699
Last Page : 706
Authors : Svouraki A, Garscha U, Kouloura E, Pace S, Pergola C, Krauth V, Rossi A, Sautebin L, Halabalaki M, Werz O, Gaboriaud-Kolar N, Skaltsounis AL.
Abstract : Among the pathways responsible for the development of inflammatory responses, the cyclooxygenase and lipoxygenase pathways are among the most important ones. Two key enzymes, namely, 5-LO and mPGES-1, are involved in the biosynthesis of leukotrienes and prostaglandins, respectively, which are considered attractive therapeutic targets, so their dual inhibition might be an effective strategy to control inflammatory deregulation. Several natural products have been identified as 5-LO inhibitors, with some also being dual 5-LO/mPGES-1 inhibitors. Here, some prenylated acetophenone dimers from Acronychia pedunculata have been identified for their dual inhibitory potency toward 5-LO and mPGES-1. To gain insight into the SAR of this family of natural products, the synthesis and biological evaluation of analogues are presented. The results show the ability of the natural and synthetic molecules to potently inhibit 5-LO and mPEGS-1 in vitro. The potency of the most active compound (10) has been evaluated in vivo in an acute inflammatory mouse model and displayed potent anti-inflammatory activity comparable in potency to the drug zileuton used as a positive control.
|
Inhibition of rat 5-LOX expressed in Sf21 insect cells preincubated for 4 mins followed by AA substrate addition and measured after 4 mins by FOX assay
|
Rattus norvegicus
|
180.0
nM
|
|
Journal : MedChemComm
Title : Recent development of lipoxygenase inhibitors as anti-inflammatory agents.
Year : 2018
Volume : 9
Issue : 2
First Page : 212
Last Page : 225
Authors : Hu C, Ma S.
Abstract : Inflammation is favorable in most cases, because it is a kind of body defensive response to external stimuli; sometimes, inflammation is also harmful, such as attacks on the body's own tissues. It could be that inflammation is a unified process of injury and resistance to injury. Inflammation brings extreme pain to patients, showing symptoms of rubor, swelling, fever, pain and dysfunction. As the specific mechanism is not clear yet, the current anti-inflammatory agents are given priority for relieving suffering of patients. Thus it is emergent to find new anti-inflammatory agents with rapid effect. Lipoxygenase (LOX) is a kind of rate-limiting enzyme in the process of arachidonic acid metabolism into leukotriene (LT) which mediates the occurrence of inflammation. The inhibition of LOX can reduce LT, thereby producing an anti-inflammatory effect. In this review, the LOX inhibitors reported in recent years are summarized, and, in particular, their activities, structure-activity relationships and molecular docking studies are emphasized, which will provide new ideas to design novel LOX inhibitors.
|
Inhibition of recombinant human 5-LOX expressed in Escherichia coli BL21 at 10 uM using arachidonic acid as substrate by UV-vis spectrophotometric method relative to control
|
Homo sapiens
|
86.9
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and identification of novel substituted 2-amino thiazole analogues as potential anti-inflammatory agents targeting 5-lipoxygenase.
Year : 2018
Volume : 158
First Page : 34
Last Page : 50
Authors : Sinha S, Doble M, Manju SL.
Abstract : Human 5-Lipoxygenase (5-LOX) is a key enzyme targeted for asthma and inflammation. Zileuton, the only drug against 5-LOX, was withdrawn from the market due to several problems. In the present study, the performance of rationally designed conjugates of thiazole (2) and thiourea (3) scaffolds from our previously reported 2-amino-4-aryl thiazole (1) is reported. They are synthesized (total 31 derivatives), characterized, and tested against the 5-LOX enzyme in vitro and the mode of action of the most active ones are determined. Compound 2m exhibited an IC50 of 0.9 ± 0.1 μM acting through competitive (non-redox) mechanism, unlike Zileuton, and found to be devoid of radical scavenging properties. Computational studies are in good agreement with the experimental data supporting its mechanism of action. Another lead molecule from the thiourea series (3), 3f, exhibited an IC50 of 1.4 ± 0.1 μM against 5-LOX whose mode of action is redox type (non-competitive). It is promising to note that the activities displayed by both the lead inhibitors, 2m and 3f, are better than the commercial drug, Zileuton (IC50 = 1.5 ± 0.3 μM). These inhibitors could be further developed as drugs against inflammation.
|
Inhibition of human recombinant 5-LOX assessed as reduction in leukotriene B4 production pre-incubated for 10 mins before arachidonic acid addition and measured after 10 mins by ELISA
|
Homo sapiens
|
350.0
nM
|
|
Journal : J Nat Prod
Title : Anti-inflammatory Activity of Natural Geranylated Flavonoids: Cyclooxygenase and Lipoxygenase Inhibitory Properties and Proteomic Analysis.
Year : 2017
Volume : 80
Issue : 4
First Page : 999
Last Page : 1006
Authors : Hanáková Z, Hošek J, Kutil Z, Temml V, Landa P, Vaněk T, Schuster D, Dall'Acqua S, Cvačka J, Polanský O, Šmejkal K.
Abstract : Geranyl flavones have been studied as compounds that potentially can be developed as anti-inflammatory agents. A series of natural geranylated flavanones was isolated from Paulownia tomentosa fruits, and these compounds were studied for their anti-inflammatory activity and possible mechanism of action. Two new compounds were characterized [paulownione C (17) and tomentodiplacone O (20)], and all of the isolated derivatives were assayed for their ability to inhibit cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX). The compounds tested showed variable degrees of activity, with several of them showing activity comparable to or greater than the standards used in COX-1, COX-2, and 5-LOX assays. However, only the compound tomentodiplacone O (20) showed more selectivity against COX-2 versus COX-1 when compared with ibuprofen. The ability of the test compounds to interact with the above-mentioned enzymes was supported by docking studies, which revealed the possible incorporation of selected test substances into the active sites of these enzymes. Furthermore, one of the COX/LOX dual inhibitors, diplacone (14) (a major geranylated flavanone of P. tomentosa), was studied in vitro to obtain a proteomic overview of its effect on inflammation in LPS-treated THP-1 macrophages, supporting its previously observed anti-inflammatory activity and revealing the mechanism of its anti-inflammatory effect.
|
Inhibition of human 5-lipoxygenase using arachidonic acid as substrate pretreated for 10 mins followed by substrate and ATP addition and measured after 20 mins by H2DCFDA probe based fluorescence assay
|
Homo sapiens
|
150.0
nM
|
|
Journal : Eur J Med Chem
Title : Neurogenic and neuroprotective donepezil-flavonoid hybrids with sigma-1 affinity and inhibition of key enzymes in Alzheimer's disease.
Year : 2018
Volume : 156
First Page : 534
Last Page : 553
Authors : Estrada Valencia M, Herrera-Arozamena C, de Andrés L, Pérez C, Morales-García JA, Pérez-Castillo A, Ramos E, Romero A, Viña D, Yáñez M, Laurini E, Pricl S, Rodríguez-Franco MI.
Abstract : In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (σ1R) and inhibition of key enzymes in Alzheimer's disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N-(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4H-chromene-2-carboxamide (18) is highlighted due to its interesting biological profile in σ1R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and σ1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs.
|
Inhibition of mPGES-1 isolated from microsomes of interleukin-1 beta-stimulated human A549 cells using PGH2 as substrate preincubated for 15 mins followed by substrate addition measured after 1 min by RP-HPLC analysis
|
Homo sapiens
|
600.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of a benzenesulfonamide-based dual inhibitor of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase that favorably modulates lipid mediator biosynthesis in inflammation.
Year : 2018
Volume : 156
First Page : 815
Last Page : 830
Authors : Cheung SY, Werner M, Esposito L, Troisi F, Cantone V, Liening S, König S, Gerstmeier J, Koeberle A, Bilancia R, Rizza R, Rossi A, Roviezzo F, Temml V, Schuster D, Stuppner H, Schubert-Zsilavecz M, Werz O, Hanke T, Pace S.
Abstract : Leukotrienes (LTs) and prostaglandin (PG)E2, produced by 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), respectively, are key players in inflammation, and pharmacological suppression of these lipid mediators (LM) represents a strategy to intervene with inflammatory disorders. Previous studies revealed that the benzenesulfonamide scaffold displays efficient 5-LO-inhibitory properties. Here, we structurally optimized benzenesulfonamides which led to an N-phenylbenzenesulfonamide derivative (compound 47) with potent inhibitory activities (IC50 = 2.3 and 0.4 μM for isolated 5-LO and 5-LO in intact cells, respectively). Compound 47 prevented the interaction of 5-LO with its activating protein (FLAP) at the nuclear envelope in transfected HEK293 cells as shown by in situ proximity ligation assay. Comprehensive assessment of the LM profile produced by human macrophages revealed the ability of 47 to selectively down-regulate pro-inflammatory LMs (i.e. LTs and PGE2) in M1 but to enhance the formation of pro-resolving LMs (i.e. resolvins and maresins) in M2 macrophages. Moreover, 47 strongly inhibited LT formation and cell infiltration in two in vivo models of acute inflammation (i.e., peritonitis and air pouch sterile inflammation in mice). Together, 47 represents a novel LT biosynthesis inhibitor with an attractive pharmacological profile as anti-inflammatory drug that also promotes the biosynthesis of pro-resolving LM.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
-21.42
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
6.17
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
4.07
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
6.91
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
10.68
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
5.22
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
2.66
%
|
|
|
Inhibition of human recombinant 5-LOX expressed in Escherichia coli BL21 assessed as conversion of arachidonic acid to 5-HPETE at 10 uM using arachidonic acid as substrate in presence of ATP by UV-vis spectrophotometry analysis relative to control
|
Homo sapiens
|
86.6
%
|
|
Journal : ACS Med Chem Lett
Title : Chalcone-Thiazole Hybrids: Rational Design, Synthesis, and Lead Identification against 5-Lipoxygenase.
Year : 2019
Volume : 10
Issue : 10
First Page : 1415
Last Page : 1422
Authors : Sinha S, Manju SL, Doble M.
Abstract : A hybrid pharmacophore approach is used to design and synthesize novel chalcone-thiazole hybrid molecules. Herein, thiazole has been hybridized with chalcone to obtain a new class of 5-LOX inhibitors. In vitro biological evaluation showed that most of the compounds were better 5-LOX inhibitors than the positive control, Zileuton (IC50 = 1.05 ± 0.03 μM). The best compounds in the series, namely, 4k, 4n, and 4v (4k: IC50 = 0.07 ± 0.02 μM, 4n: IC50 = 0.08 ± 0.05 μM, 4v: 0.12 ± 0.04 μM) are found to be 10 times more active than previously reported 2-amino thiazole (2m: IC50 = 0.9 ± 0.1 μM) by us. Further, 4k has redox (noncompetitive) while 4n and 4v act through a competitive inhibition mechanism. SAR indicated that the presence of methoxy/methyl either in the vicinity of chalcone or both thiazole and chalcone contributed to the synergistic inhibitory effect.
|
Inhibition of human recombinant 5-LOX assessed as reduction in leukotriene B4 synthesis using arachidonic acid substrate by ELISA
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Nat Prod
Title : Prenylated Stilbenoids Affect Inflammation by Inhibiting the NF-κB/AP-1 Signaling Pathway and Cyclooxygenases and Lipoxygenase.
Year : 2019
Volume : 82
Issue : 7
First Page : 1839
Last Page : 1848
Authors : Hošek J, Leláková V, Bobál P, Pížová H, Gazdová M, Malaník M, Jakubczyk K, Veselý O, Landa P, Temml V, Schuster D, Prachyawarakorn V, Pailee P, Ren G, Zpurný F, Oravec M, Šmejkal K.
Abstract : Stilbenoids are important components of foods (e.g., peanuts, grapes, various edible berries), beverages (wine, white tea), and medicinal plants. Many publications have described the anti-inflammatory potential of stilbenoids, including the widely known trans-resveratrol and its analogues. However, comparatively little information is available regarding the activity of their prenylated derivatives. One new prenylated stilbenoid (2) was isolated from Artocarpus altilis and characterized structurally based on 1D and 2D NMR analysis and HRMS. Three other prenylated stilbenoids were prepared synthetically (9-11). Their antiphlogistic potential was determined by testing them together with known natural prenylated stilbenoids from Macaranga siamensis and Artocarpus heterophyllus in both cell-free and cell assays. The inhibition of 5-lipoxygenase (5-LOX) was also shown by simulated molecular docking for the most active stilbenoids in order to elucidate the mode of interaction between these compounds and the enzyme. Their effects on the pro-inflammatory nuclear factor-κB (NF-κB) and the activator protein 1 (AP-1) signaling pathway were also analyzed. The THP1-XBlue-MD2-CD14 cell line was used as a model for determining their anti-inflammatory potential, and lipopolysaccharide (LPS) stimulation of Toll-like receptor 4 induced a signaling cascade leading to the activation of NF-κB/AP-1. The ability of prenylated stilbenoids to attenuate the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was further evaluated using LPS-stimulated THP-1 macrophages.
|
Inhibition of Sprague-Dawley rat 5-LOX assessed as calcium ionophore A23187-stimulated LTB4 production preincubated for 30 mins followed by calcium ionophore A23187 addition and measured after 30 mins by ELISA
|
Rattus norvegicus
|
830.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual COX-2/5-LOX inhibitors and antitumor agents.
Year : 2019
Volume : 169
First Page : 168
Last Page : 184
Authors : Li Z, Wang ZC, Li X, Abbas M, Wu SY, Ren SZ, Liu QX, Liu Y, Chen PW, Duan YT, Lv PC, Zhu HL.
Abstract : In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against cancer cell lines (IC50 = 6.43-10.97 μM for F10, HeLa, A549 and MCF-7 cells), lower toxicity to non-cancer cells than celecoxib (A33: IC50 = 194.01 μM vs.celecoxib: IC50 = 97.87 μM for 293T cells), and excellent inhibitory activities on COX-2 (IC50 = 0.17 μM) and 5-LOX (IC50 = 0.68 μM). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced apoptosis of F10 cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for cancer therapy.
|
Inhibition of soyabean 15-LOX preincubated for 5 mins followed by susbtrate addition measured after 10 mins by colorimetric method
|
Glycine max
|
38.91
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, biological evaluation and docking study of novel indole-2-amide as anti-inflammatory agents with dual inhibition of COX and 5-LOX.
Year : 2019
Volume : 180
First Page : 41
Last Page : 50
Authors : Huang Y, Zhang B, Li J, Liu H, Zhang Y, Yang Z, Liu W.
Abstract : In this work, a series of novel indole-2-amide compounds were designed, synthesized, characterized and the anti-inflammatory activity in vivo were evaluated. Compounds 8a, 10b, 12h, and 12l exhibited marked anti-inflammatory activity in 2,4-Dinitrofluorobenzenethe (DNFB) - induced mice auricle edema model. Further, compounds 8a, 10b and 12h exhibited potential in vitro COX-2 inhibitory activity (IC<sub>50</sub> = 21.86, 23.3 and 23.21 nM, respectively), while the reference drug celecoxib was 11.20 nM. The most promising compound 10b was exhibited the highest selectivity for COX-2 (selectivity index (COX-1/COX-2) = 17.45) and moderate 5-LOX inhibitory activity (IC<sub>50</sub> = 66 nM), which comparable to positive controlled zileuton (IC<sub>50</sub> = 38.91 nM). In addition, the test results showed compounds 10b and 12h no significant cytotoxic activity on normal cells (RAW264.7). Further, at the active sites of the COX-1, COX-2 co-crystals, 3b and 4l showed higher binding forces in the molecular docking study, which consistent with the results of in vitro experiments. These results demonstrated that these compounds had dual inhibitory activity of COX/5-LOX, providing clues for further searching for safer and more effective anti-inflammatory drugs.
|
Inhibition of recombinant human 5-LOX expressed in Escherichia coli at 20 uM using arachidonic acid as substrate by UV-vis spectrophotometric method relative to control
|
Homo sapiens
|
90.52
%
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and identification of novel coumaperine derivatives for inhibition of human 5-LOX: Antioxidant, pseudoperoxidase and docking studies.
Year : 2019
Volume : 27
Issue : 4
First Page : 604
Last Page : 619
Authors : Muthuraman S, Sinha S, Vasavi CS, Waidha KM, Basu B, Munussami P, Balamurali MM, Doble M, Saravana Kumar R.
Abstract : 5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition. CP-209, a catechol type dihydroxyl derivative and CP-262-F2, a vicinal trihydroxyl derivative exhibited, 82.7% and 82.5% inhibition of 5-LOX respectively at 20 µM. Their IC<sub>50</sub> values are 2.1 ± 0.2 µM and 2.3 ± 0.2 µM respectively, and are comparable to zileuton, IC<sub>50</sub> = 1.4 ± 0.2 µM. CP-155, a methylenedioxy derivative (a natural product) and CP-194, a 2,4,6-trimethoxy derivative showed 76.0% and 77.1% inhibition of 5-LOX respectively at 20 µM. Antioxidant study revealed that CP-209 and 262-F2 (at 20 µM) scavenged DPPH radical by 76.8% and 71.3% respectively. On the other hand, CP-155 and 194 showed very poor DPPH radical scavenging activity. Pseudo peroxidase assay confirmed that the mode of action of CP-209 and 262-F2 were by redox process, similar to zileuton, affecting the oxidation state of the metal ion in the enzyme. On the contrary, CP-155 and 194 probably act through some other mechanism which does not involve the disruption of the oxidation state of the metal in the enzyme. Molecular docking of CP-155 and 194 to the active site of 5-LOX and binding energy calculation suggested that they are non-competitive inhibitors. The In-Silico ADME/TOX analysis shows the active compounds (CP-155, 194, 209 and 262-F2) are with good drug likeliness and reduced toxicity compared to existing drug. These studies indicate that there is a great potential for coumaperine derivatives to be developed as anti-inflammatory drug.
|
Inhibition of human 5-LOX using arachidonic acid as substrate measured after 10 mins by ELISA
|
Homo sapiens
|
590.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and identification of novel coumaperine derivatives for inhibition of human 5-LOX: Antioxidant, pseudoperoxidase and docking studies.
Year : 2019
Volume : 27
Issue : 4
First Page : 604
Last Page : 619
Authors : Muthuraman S, Sinha S, Vasavi CS, Waidha KM, Basu B, Munussami P, Balamurali MM, Doble M, Saravana Kumar R.
Abstract : 5-Lipoxygenase (5-LOX) is a key enzyme involved in the biosynthesis of pro-inflammatory leukotrienes, leading to asthma. Developing potent 5-LOX inhibitors especially, natural product based ones, are highly attractive. Coumaperine, a natural product found in white pepper and its derivatives were herein developed as 5-LOX inhibitors. We have synthesized twenty four derivatives, characterized and evaluated their 5-LOX inhibition potential. Coumaperine derivatives substituted with multiple hydroxy and multiple methoxy groups exhibited best 5-LOX inhibition. CP-209, a catechol type dihydroxyl derivative and CP-262-F2, a vicinal trihydroxyl derivative exhibited, 82.7% and 82.5% inhibition of 5-LOX respectively at 20 µM. Their IC<sub>50</sub> values are 2.1 ± 0.2 µM and 2.3 ± 0.2 µM respectively, and are comparable to zileuton, IC<sub>50</sub> = 1.4 ± 0.2 µM. CP-155, a methylenedioxy derivative (a natural product) and CP-194, a 2,4,6-trimethoxy derivative showed 76.0% and 77.1% inhibition of 5-LOX respectively at 20 µM. Antioxidant study revealed that CP-209 and 262-F2 (at 20 µM) scavenged DPPH radical by 76.8% and 71.3% respectively. On the other hand, CP-155 and 194 showed very poor DPPH radical scavenging activity. Pseudo peroxidase assay confirmed that the mode of action of CP-209 and 262-F2 were by redox process, similar to zileuton, affecting the oxidation state of the metal ion in the enzyme. On the contrary, CP-155 and 194 probably act through some other mechanism which does not involve the disruption of the oxidation state of the metal in the enzyme. Molecular docking of CP-155 and 194 to the active site of 5-LOX and binding energy calculation suggested that they are non-competitive inhibitors. The In-Silico ADME/TOX analysis shows the active compounds (CP-155, 194, 209 and 262-F2) are with good drug likeliness and reduced toxicity compared to existing drug. These studies indicate that there is a great potential for coumaperine derivatives to be developed as anti-inflammatory drug.
|
Inhibition of recombinant human 5-lipoxygenase expressed in Escherichia coli BL21 (DE3) cells using arachidonic acid as substrate preincubated for 10 mins followed by susbtrate addition and measured after 10 mins by reverse phase HPLC method
|
Homo sapiens
|
500.0
nM
|
|
Journal : J Nat Prod
Title : Myxochelin- and Pseudochelin-Derived Lipoxygenase Inhibitors from a Genetically Engineered <i>Myxococcus xanthus</i> Strain.
Year : 2019
Volume : 82
Issue : 9
First Page : 2544
Last Page : 2549
Authors : Sester A, Winand L, Pace S, Hiller W, Werz O, Nett M.
Abstract : Precursor-directed biosynthesis was used to introduce selected aryl carboxylic acids into the pseudochelin pathway, which had recently been assembled in <i>Myxococcus xanthus</i>. Overall, 14 previously undescribed analogues of the natural products myxochelin B and pseudochelin A were generated and structurally characterized. A subset of 10 derivatives together with their parental molecules were evaluated for their activity toward human 5-lipoxygenase. This testing revealed pseudochelin A as the most potent 5-lipoxygenase inhibitor among the naturally occurring compounds, whereas myxochelin A is the least active. Replacement of the catechol moieties in myxochelin B and pseudochelin A affected the bioactivity to different degrees.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
9.14
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
18.01
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.03
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.02
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.02
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.03
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of 5-Lipoxygenase (unknown origin)
|
Homo sapiens
|
600.0
nM
|
|
Journal : J Med Chem
Title : Immobilized Metal Affinity Chromatography as a Drug Discovery Platform for Metalloenzyme Inhibitors.
Year : 2020
Volume : 63
Issue : 20.0
First Page : 12116
Last Page : 12127
Authors : Roth L,Gotsbacher MP,Codd R
Abstract : Immobilized metal-ion affinity chromatography (IMAC) used to purify recombinant proteins features a resin-bound 1:1 Ni(II)-iminodiacetic acid (IDA) complex. This hemi-saturated Ni(II)-IDA system containing exchangeable sites at the metal ion is re-cast as a surrogate of a coordinatively-unsaturated metalloenzyme active site, with utility for selecting compounds with metal-binding groups from mixtures as potential metalloenzyme inhibitors. Exchanging Ni(II) for other metal ions could broaden the scope of metalloenzyme target. This work examined the performance of Cu(II)-, Fe(III)-, Ga(III)-, Ni(II)-, or Zn(II)-IMAC resins to reversibly bind experimental or clinical metalloenzyme inhibitors of Zn(II)-ACE1, Zn(II)-HDAC, Fe(II)/(III)-5-LO or Cu(II)-tyrosinase from a curated mixture (1-17). Each IMAC system gave a distinct selection profile. The Zn(II)-IMAC system selectively bound the thiol-containing Zn(II)-ACE1 inhibitors captopril and omapatrilat, and the Fe(III)-IMAC system selectively bound the Fe(II)/(III)-5-LO inhibitor licofelone, demonstrating a remarkable IMAC-metalloenzyme metal ion match. IMAC provides a simple, water-compatible platform, which could accelerate metalloenzyme inhibitor discovery.
|
Inhibition of recombinant human 5-LO expressed in Escherichia coli BL21(DE3) assessed as reduction in LTB4 and 5-H(P)ETE formation using arachidonic acid as substrate preincubated with enzyme for 10 mins followed by substrate addition and measured after 10 mins by RP-HPLC method
|
Homo sapiens
|
810.0
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors.
Year : 2020
Volume : 202
First Page : 112518
Last Page : 112518
Authors : Dinh CP,Ville A,Neukirch K,Viault G,Temml V,Koeberle A,Werz O,Schuster D,Stuppner H,Richomme P,Helesbeux JJ,Séraphin D
Abstract : Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring.
|
Inhibition of 5-LO in human PMNL cells assessed as reduction in LTB4, 5-H(P)ETE, 12-HETE and 15-HETE products formation using arachidonic acid as substrate preincubated for 10 mins followed by addition of substrate and measured after 10 mins by RP-HPLC method
|
Homo sapiens
|
521.0
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors.
Year : 2020
Volume : 202
First Page : 112518
Last Page : 112518
Authors : Dinh CP,Ville A,Neukirch K,Viault G,Temml V,Koeberle A,Werz O,Schuster D,Stuppner H,Richomme P,Helesbeux JJ,Séraphin D
Abstract : Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring.
|
Inhibition of human recombinant 5-LOX assessed as reduction in LTB4 level using 800 uM arachidonic acid as substrate preincubated with enzyme for 10 mins followed by substrate addition and measured after 10 mins by ELISA
|
Homo sapiens
|
660.0
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis, inhibitory activity and in silico docking of dual COX/5-LOX inhibitors with quinone and resorcinol core.
Year : 2020
Volume : 204
First Page : 112620
Last Page : 112620
Authors : Sisa M,Dvorakova M,Temml V,Jarosova V,Vanek T,Landa P
Abstract : Based on the significant anti-inflammatory activity of natural quinone primin (5a), series of 1,4-benzoquinones, hydroquinones, and related resorcinols were designed, synthesized, characterized and tested for their ability to inhibit the activity of cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) enzymes. Structural modifications resulted in the identification of two compounds 5b (2-methoxy-6-undecyl-1,4-benzoquinone) and 6b (2-methoxy-6-undecyl-1,4-hydroquinone) as potent dual COX/5-LOX inhibitors. The IC values evaluated in vitro using enzymatic assay were for compound 5b IC = 1.07, 0.57, and 0.34 μM and for compound 6b IC = 1.07, 0.55, and 0.28 μM for COX-1, COX-2, and 5-LOX enzyme, respectively. In addition, compound 6d was identified as the most potent 5-LOX inhibitor (IC = 0.14 μM; reference inhibitor zileuton IC = 0.66 μM) from the tested compounds while its inhibitory potential against COX enzymes (IC = 2.65 and 2.71 μM for COX-1 and COX-2, respectively) was comparable with the reference inhibitor ibuprofen (IC = 4.50 and 2.46 μM, respectively). The most important structural modification leading to increased inhibitory activity towards both COXs and 5-LOX was the elongation of alkyl chain in position 6 from 5 to 11 carbons. Moreover, the monoacetylation in ortho position of bromo-hydroquinone 13 led to the discovery of potent (IC = 0.17 μM) 5-LOX inhibitor 17 (2-bromo-6-methoxy-1,4-benzoquinone) while bromination stabilized the hydroquinone form. Docking analysis revealed the interaction of compounds with Tyr355 and Arg120 in the catalytic site of COX enzymes, while the hydrophobic parts of the molecules filled the hydrophobic substrate channel leading up to Tyr385. In the allosteric catalytic site of 5-LOX, compounds bound to Tyr142 and formed aromatic interactions with Arg138. Taken together, we identified optimal alkyl chain length for dual COX/5-LOX inhibition and investigated other structural modifications influencing COX and 5-LOX inhibitory activity.
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Inhibition of recombinant human 5LOX expressed in baculovirus infected Sf insect cells using linoleic acid as substrate preincubated for 5 mins followed by substrate addition
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Homo sapiens
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630.0
nM
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Journal : Eur J Med Chem
Title : Design, synthesis, in-vitro, in-vivo and in-silico studies of pyrrolidine-2,5-dione derivatives as multitarget anti-inflammatory agents.
Year : 2020
Volume : 186
First Page : 111863
Last Page : 111863
Authors : Jan MS,Ahmad S,Hussain F,Ahmad A,Mahmood F,Rashid U,Abid OU,Ullah F,Ayaz M,Sadiq A
Abstract : In recent years, drug discovery paradigm has been shifted from conventional single target inhibition toward multitarget design concept. In current research, we have reported synthesis, in-vitro, in-vivo and acute toxicity determination of N-substituted pyrrolidine-2,5-dione derivatives as multitarget anti-inflammatory agents. We synthesized cycloalkyl, alkyl and aryl carbonyl derivatives by the Michael addition of ketones to N-substituted maleimides using self-assembled three component system as an organocatalyst. Anti-inflammatory potential of the compounds was determined by using different in-vitro assays, like cyclooxygenase-1, cyclooxygenase-2 and 5-lipoxygenase, albumin denaturation and anti-protease assays. Amongst the synthesized compounds, 13a-e series of compounds showed inhibition in low micromolar to submicromolar ranges. These compounds also demonstrated COX-2 selectivity. Compound 13e with IC value 0.98 μM and SI of 31.5 emerged as the most potent inhibitor of COX-2. Based on in-vitro results, in-vivo anti-inflammatory investigations were performed on compounds 3b and 13evia carrageenan induced paw edema test. The possible mode of action of compounds 3b and 13e were ascertained with various mediators like histamine, bradykinin, prostaglandin and leukotriene. In-vivo acute toxicity study showed the safety of synthesized compounds up to 1000 mg/kg dose. The selectivity of the compounds against cyclooxygenase isoforms was supported by docking simulations. Selective COX-2 inhibitors showed significant interactions with the amino acid residues present in additional secondary COX-2 enzyme pocket. Furthermore, in-silico pharmacokinetic predictions confer the drug-like characteristics.
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Inhibition of human 5-Lipoxygenase using H2DCFDA as substrate preincubated for 5 mins and measured by Spectrophotometric assay
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Homo sapiens
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150.0
nM
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Journal : Eur J Med Chem
Title : Tuning melatonin receptor subtype selectivity in oxadiazolone-based analogues: Discovery of QR2 ligands and NRF2 activators with neurogenic properties.
Year : 2020
Volume : 190
First Page : 112090
Last Page : 112090
Authors : Herrera-Arozamena C,Estrada-Valencia M,Pérez C,Lagartera L,Morales-García JA,Pérez-Castillo A,Franco-Gonzalez JF,Michalska P,Duarte P,León R,López MG,Mills A,Gago F,García-Yagüe ÁJ,Fernández-Ginés R,Cuadrado A,Rodríguez-Franco MI
Abstract : New multi-target indole and naphthalene derivatives containing the oxadiazolone scaffold as a bioisostere of the melatonin acetamido group have been developed. The novel compounds were characterized at melatonin receptors MTR and MTR, quinone reductase 2 (QR2), lipoxygenase-5 (LOX-5), and monoamine oxidases (MAO-A and MAO-B), and also as radical scavengers. We found that selectivity within the oxadiazolone series can be modulated by modifying the side chain functionality and co-planarity with the indole or naphthalene ring. In phenotypic assays, several oxadiazolone-based derivatives induced signalling mediated by the transcription factor NRF2 and promoted the maturation of neural stem-cells into a neuronal phenotype. Activation of NRF2 could be due to the binding of indole derivatives to KEAP1, as deduced from surface plasmon resonance (SPR) experiments. Molecular modelling studies using the crystal structures of QR2 and the KEAP1 Kelch-domain, as well as the recently described X-ray free-electron laser (XFEL) structures of chimeric MTR and MTR, provided a rationale for the experimental data and afforded valuable insights for future drug design endeavours.
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Inhibition of soybean LOX using arachidonic acid as substrate incubated for 5 mins
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Glycine max
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300.0
nM
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