|
In vitro inhibition of rabbit lens aldose reductase at 10e-4 M.
|
Oryctolagus cuniculus
|
40.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids.
Year : 1986
Volume : 29
Issue : 11
First Page : 2347
Last Page : 2351
Authors : Cerelli MJ, Curtis DL, Dunn JP, Nelson PH, Peak TM, Waterbury LD.
Abstract : A number of dibenztropone, dibenzsuberone, dibenzoxepin, and dibenzthiepin acetic acids were synthesized and tested for antiinflammatory/analgesic activity and also for their ability to inhibit rabbit lens aldose reductase (AR). It was found that the structural requirements for antiinflammatory/analgesic activity, believed to be mediated by inhibition of cyclooxygenase, were much more stringent than were those for AR inhibition. For example, the introduction of a hydroxyl group into positions 1, 4, 6, 7, or 8 on dibenzsuberone-2-acetic acid (1a) had relatively little effect on AR inhibition, but caused wide variations in antiinflammatory/analgesic activity.
|
In vitro inhibition of rabbit lens aldose reductase at 10e-5 M.
|
Oryctolagus cuniculus
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids.
Year : 1986
Volume : 29
Issue : 11
First Page : 2347
Last Page : 2351
Authors : Cerelli MJ, Curtis DL, Dunn JP, Nelson PH, Peak TM, Waterbury LD.
Abstract : A number of dibenztropone, dibenzsuberone, dibenzoxepin, and dibenzthiepin acetic acids were synthesized and tested for antiinflammatory/analgesic activity and also for their ability to inhibit rabbit lens aldose reductase (AR). It was found that the structural requirements for antiinflammatory/analgesic activity, believed to be mediated by inhibition of cyclooxygenase, were much more stringent than were those for AR inhibition. For example, the introduction of a hydroxyl group into positions 1, 4, 6, 7, or 8 on dibenzsuberone-2-acetic acid (1a) had relatively little effect on AR inhibition, but caused wide variations in antiinflammatory/analgesic activity.
|
In vitro inhibition of rabbit lens aldose reductase at 10e-6 M.
|
Oryctolagus cuniculus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory and aldose reductase inhibitory activity of some tricyclic arylacetic acids.
Year : 1986
Volume : 29
Issue : 11
First Page : 2347
Last Page : 2351
Authors : Cerelli MJ, Curtis DL, Dunn JP, Nelson PH, Peak TM, Waterbury LD.
Abstract : A number of dibenztropone, dibenzsuberone, dibenzoxepin, and dibenzthiepin acetic acids were synthesized and tested for antiinflammatory/analgesic activity and also for their ability to inhibit rabbit lens aldose reductase (AR). It was found that the structural requirements for antiinflammatory/analgesic activity, believed to be mediated by inhibition of cyclooxygenase, were much more stringent than were those for AR inhibition. For example, the introduction of a hydroxyl group into positions 1, 4, 6, 7, or 8 on dibenzsuberone-2-acetic acid (1a) had relatively little effect on AR inhibition, but caused wide variations in antiinflammatory/analgesic activity.
|
In vitro inhibition of cyclooxygenase-1 via inhibition of TXB2 generation in the presence of 1 uM arachidonic acid in human platelet
|
None
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of cyclooxygenase-2 selectivity into ketoprofen.
Year : 2002
Volume : 12
Issue : 4
First Page : 533
Last Page : 537
Authors : Palomer A, Pascual J, Cabré M, Borràs L, González G, Aparici M, Carabaza A, Cabré F, García ML, Mauleón D.
Abstract : We have recently described how to achieve COX-2 selectivity from the non-selective inhibitor indomethacin (1) using a combination of a pharmacophore and computer 3-D models based on the known X-ray crystal structures of cyclooxygenases. In the present study we have focused on the design of COX-2 selective analogues of the NSAID ketoprofen (2). The design is similarly based on the combined use of the previous pharmacophore together with traditional medicinal chemistry techniques motivated by the comparative modeling of the 3-D structures of 2 docked into the COX active sites. The analysis includes use of the program GRID to detect isoenzyme differences near the active site region and is aimed at suggesting modifications of the basic benzophenone frame of the lead compound 2. The resulting series of compounds bearing this central framework is exemplified by the potent and selective COX-2 inhibitor 17 (LM-1669).
|
In vitro inhibition of PGE-2 generation by LPS-stimulated monocytes isolated from human blood.
|
None
|
26.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of cyclooxygenase-2 selectivity into ketoprofen.
Year : 2002
Volume : 12
Issue : 4
First Page : 533
Last Page : 537
Authors : Palomer A, Pascual J, Cabré M, Borràs L, González G, Aparici M, Carabaza A, Cabré F, García ML, Mauleón D.
Abstract : We have recently described how to achieve COX-2 selectivity from the non-selective inhibitor indomethacin (1) using a combination of a pharmacophore and computer 3-D models based on the known X-ray crystal structures of cyclooxygenases. In the present study we have focused on the design of COX-2 selective analogues of the NSAID ketoprofen (2). The design is similarly based on the combined use of the previous pharmacophore together with traditional medicinal chemistry techniques motivated by the comparative modeling of the 3-D structures of 2 docked into the COX active sites. The analysis includes use of the program GRID to detect isoenzyme differences near the active site region and is aimed at suggesting modifications of the basic benzophenone frame of the lead compound 2. The resulting series of compounds bearing this central framework is exemplified by the potent and selective COX-2 inhibitor 17 (LM-1669).
|
Percent inhibition of edema was measured by adjuvant arthritis paw edema (rat) assay
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Bulky amine analogues of ketoprofen: potent antiinflammatory agents.
Year : 1984
Volume : 27
Issue : 12
First Page : 1682
Last Page : 1690
Authors : Schlegel DC, Zenitz BL, Fellows CA, Laskowski SC, Behn DC, Phillips DK, Botton I, Speight PT.
Abstract : Replacement of the carboxyl group of 2-(3-benzoylphenyl)propionic acid (Ketoprofen) with various bulky amines has produced a series of highly active antiinflammatory agents that have reduced intestinal ulcerogenicity and have better therapeutic ratios in the 21-day adjuvant arthritis assay in rats than currently marketed nonsteroidal antiinflammatory drugs. Activity is maintained on reduction of these 2-(3-benzoylphenyl)propyl bulky amines to the corresponding alcohols or methylene analogues, on conversion of the ketone function to a primary amine or oxime, and on introduction of a 4-halo substitutent (Cl or F) on the terminal aromatic ring. Removal of the alpha-CH3 group greatly reduces the antiinflammatory activity of the series. These compounds have been synthesized by the reductive amination of 2-(3-bromophenyl)propionaldehyde with the respective amine followed by lithiation of this product and condensation with the appropriate benzonitrile.
|
Antiinflammatory efficacy is measured by the percent inhibition of paw volume during the 3 week adjuvant arthritis test at 0.002 mM/kg (0.51 mg)
|
Rattus norvegicus
|
68.0
%
|
|
Journal : J. Med. Chem.
Title : Bulky amine analogues of ketoprofen: potent antiinflammatory agents.
Year : 1984
Volume : 27
Issue : 12
First Page : 1682
Last Page : 1690
Authors : Schlegel DC, Zenitz BL, Fellows CA, Laskowski SC, Behn DC, Phillips DK, Botton I, Speight PT.
Abstract : Replacement of the carboxyl group of 2-(3-benzoylphenyl)propionic acid (Ketoprofen) with various bulky amines has produced a series of highly active antiinflammatory agents that have reduced intestinal ulcerogenicity and have better therapeutic ratios in the 21-day adjuvant arthritis assay in rats than currently marketed nonsteroidal antiinflammatory drugs. Activity is maintained on reduction of these 2-(3-benzoylphenyl)propyl bulky amines to the corresponding alcohols or methylene analogues, on conversion of the ketone function to a primary amine or oxime, and on introduction of a 4-halo substitutent (Cl or F) on the terminal aromatic ring. Removal of the alpha-CH3 group greatly reduces the antiinflammatory activity of the series. These compounds have been synthesized by the reductive amination of 2-(3-bromophenyl)propionaldehyde with the respective amine followed by lithiation of this product and condensation with the appropriate benzonitrile.
|
Antiinflammatory efficacy is measured by the percent inhibition of paw volume during the 3 week adjuvant arthritis test at 0.006 mM/kg (0.152 mg)
|
Rattus norvegicus
|
31.0
%
|
|
Journal : J. Med. Chem.
Title : Bulky amine analogues of ketoprofen: potent antiinflammatory agents.
Year : 1984
Volume : 27
Issue : 12
First Page : 1682
Last Page : 1690
Authors : Schlegel DC, Zenitz BL, Fellows CA, Laskowski SC, Behn DC, Phillips DK, Botton I, Speight PT.
Abstract : Replacement of the carboxyl group of 2-(3-benzoylphenyl)propionic acid (Ketoprofen) with various bulky amines has produced a series of highly active antiinflammatory agents that have reduced intestinal ulcerogenicity and have better therapeutic ratios in the 21-day adjuvant arthritis assay in rats than currently marketed nonsteroidal antiinflammatory drugs. Activity is maintained on reduction of these 2-(3-benzoylphenyl)propyl bulky amines to the corresponding alcohols or methylene analogues, on conversion of the ketone function to a primary amine or oxime, and on introduction of a 4-halo substitutent (Cl or F) on the terminal aromatic ring. Removal of the alpha-CH3 group greatly reduces the antiinflammatory activity of the series. These compounds have been synthesized by the reductive amination of 2-(3-bromophenyl)propionaldehyde with the respective amine followed by lithiation of this product and condensation with the appropriate benzonitrile.
|
Antiinflammatory efficacy is measured by the percent inhibition of paw volume during the 3 week adjuvant arthritis test at 0.009 mM/kg (2.29 mg)
|
Rattus norvegicus
|
82.0
%
|
|
Journal : J. Med. Chem.
Title : Bulky amine analogues of ketoprofen: potent antiinflammatory agents.
Year : 1984
Volume : 27
Issue : 12
First Page : 1682
Last Page : 1690
Authors : Schlegel DC, Zenitz BL, Fellows CA, Laskowski SC, Behn DC, Phillips DK, Botton I, Speight PT.
Abstract : Replacement of the carboxyl group of 2-(3-benzoylphenyl)propionic acid (Ketoprofen) with various bulky amines has produced a series of highly active antiinflammatory agents that have reduced intestinal ulcerogenicity and have better therapeutic ratios in the 21-day adjuvant arthritis assay in rats than currently marketed nonsteroidal antiinflammatory drugs. Activity is maintained on reduction of these 2-(3-benzoylphenyl)propyl bulky amines to the corresponding alcohols or methylene analogues, on conversion of the ketone function to a primary amine or oxime, and on introduction of a 4-halo substitutent (Cl or F) on the terminal aromatic ring. Removal of the alpha-CH3 group greatly reduces the antiinflammatory activity of the series. These compounds have been synthesized by the reductive amination of 2-(3-bromophenyl)propionaldehyde with the respective amine followed by lithiation of this product and condensation with the appropriate benzonitrile.
|
The mean increase in paw volume was compared between drug treated groups and placebo to calculate the percent inhibition in rats at 0.02 mmol/kg by carrageenan Edema Assay; 60-69
|
Rattus norvegicus
|
60.0
%
|
|
Journal : J. Med. Chem.
Title : Bulky amine analogues of ketoprofen: potent antiinflammatory agents.
Year : 1984
Volume : 27
Issue : 12
First Page : 1682
Last Page : 1690
Authors : Schlegel DC, Zenitz BL, Fellows CA, Laskowski SC, Behn DC, Phillips DK, Botton I, Speight PT.
Abstract : Replacement of the carboxyl group of 2-(3-benzoylphenyl)propionic acid (Ketoprofen) with various bulky amines has produced a series of highly active antiinflammatory agents that have reduced intestinal ulcerogenicity and have better therapeutic ratios in the 21-day adjuvant arthritis assay in rats than currently marketed nonsteroidal antiinflammatory drugs. Activity is maintained on reduction of these 2-(3-benzoylphenyl)propyl bulky amines to the corresponding alcohols or methylene analogues, on conversion of the ketone function to a primary amine or oxime, and on introduction of a 4-halo substitutent (Cl or F) on the terminal aromatic ring. Removal of the alpha-CH3 group greatly reduces the antiinflammatory activity of the series. These compounds have been synthesized by the reductive amination of 2-(3-bromophenyl)propionaldehyde with the respective amine followed by lithiation of this product and condensation with the appropriate benzonitrile.
|
The percent inhibition was calculated from the average differences in hind paw volume between the adjuvant injected controls and the adjuvant-injected medicated rats at 0.08 mmol/kg; 0.009-82
|
Rattus norvegicus
|
0.009
%
|
|
Journal : J. Med. Chem.
Title : Bulky amine analogues of ketoprofen: potent antiinflammatory agents.
Year : 1984
Volume : 27
Issue : 12
First Page : 1682
Last Page : 1690
Authors : Schlegel DC, Zenitz BL, Fellows CA, Laskowski SC, Behn DC, Phillips DK, Botton I, Speight PT.
Abstract : Replacement of the carboxyl group of 2-(3-benzoylphenyl)propionic acid (Ketoprofen) with various bulky amines has produced a series of highly active antiinflammatory agents that have reduced intestinal ulcerogenicity and have better therapeutic ratios in the 21-day adjuvant arthritis assay in rats than currently marketed nonsteroidal antiinflammatory drugs. Activity is maintained on reduction of these 2-(3-benzoylphenyl)propyl bulky amines to the corresponding alcohols or methylene analogues, on conversion of the ketone function to a primary amine or oxime, and on introduction of a 4-halo substitutent (Cl or F) on the terminal aromatic ring. Removal of the alpha-CH3 group greatly reduces the antiinflammatory activity of the series. These compounds have been synthesized by the reductive amination of 2-(3-bromophenyl)propionaldehyde with the respective amine followed by lithiation of this product and condensation with the appropriate benzonitrile.
|
In vitro inhibitory activity against ovine cyclooxygenase-1 (COX-1) at 200 uM; Inactive
|
None
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Novel cyclooxygenase-1 inhibitors discovered using affinity fingerprints.
Year : 2004
Volume : 47
Issue : 20
First Page : 4875
Last Page : 4880
Authors : Hsu N, Cai D, Damodaran K, Gomez RF, Keck JG, Laborde E, Lum RT, Macke TJ, Martin G, Schow SR, Simon RJ, Villar HO, Wick MM, Beroza P.
Abstract : We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor. These compounds are structurally distinct from those used to build the model and were discovered by testing only 62 library compounds. The discovery of these leads demonstrates the efficiency with which affinity fingerprints can identify novel bioactive chemotypes from known drugs.
|
Inhibition of CXCL8-induced chemotaxis of human polymorphonuclear cells at 10e-8 M
|
Homo sapiens
|
64.0
%
|
|
Journal : J. Med. Chem.
Title : 2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors.
Year : 2005
Volume : 48
Issue : 13
First Page : 4312
Last Page : 4331
Authors : Allegretti M, Bertini R, Cesta MC, Bizzarri C, Di Bitondo R, Di Cioccio V, Galliera E, Berdini V, Topai A, Zampella G, Russo V, Di Bello N, Nano G, Nicolini L, Locati M, Fantucci P, Florio S, Colotta F.
Abstract : The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNs chemotaxis. We report here molecular modeling studies showing a putative interaction site of 1 in the TM region of CXCR1. The binding model was confirmed by alanine scanning mutagenesis and photoaffinity labeling experiments. The molecular model driven medicinal chemistry optimization of 1 led to a new class of potent and specific inhibitors of CXCL8 biological activity. Among these, repertaxin (13) was selected as a clinical candidate drug for prevention of post-ischemia reperfusion injury.
|
Inhibition of recombinant human AKR1C3 at 50 uM
|
Homo sapiens
|
12.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Nonsteroidal anti-inflammatory drugs and their analogues as inhibitors of aldo-keto reductase AKR1C3: new lead compounds for the development of anticancer agents.
Year : 2005
Volume : 15
Issue : 23
First Page : 5170
Last Page : 5175
Authors : Gobec S, Brozic P, Rizner TL.
Abstract : Nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin, flufenamic acid, and related compounds have been recently identified as potent inhibitors of AKR1C3. We report that some other NSAIDs (diclofenac and naproxen) also inhibit AKR1C3, with the IC(50) values in the low micromolar range. In order to obtain more information about the structure-activity relationship and to identify new leads, a series of compounds designed on the basis of NSAIDs were synthesized and screened on AKR1C3. The most active compounds were 2-[(2,2-diphenylacetyl)amino]benzoic acid 4 (IC(50)=11microM) and 3-phenoxybenzoic acid 10 (IC(50)=0.68microM). These compounds represent promising starting points for the development of new anticancer agents.
|
Inhibition of COX1 in human whole blood
|
Homo sapiens
|
330.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New NSAIDs-NO hybrid molecules with antiproliferative properties on human prostatic cancer cell lines.
Year : 2008
Volume : 18
Issue : 16
First Page : 4655
Last Page : 4657
Authors : Bézière N, Goossens L, Pommery J, Vezin H, Touati N, Hénichart JP, Pommery N.
Abstract : The design of profen hybrids containing a NO donor moiety connected to an aliphatic spacer led to compounds with a similar cyclooxygenase inhibition compared to their parent profen and with significant antiproliferative activities on PC3 cells. However, inhibition of COX-2 pathway alone did not seem sufficient to inhibit cancer cell proliferation, and NO-release in a time-dependent manner strongly contributes to this activity.
|
Inhibition of COX2 in human whole blood
|
Homo sapiens
|
690.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New NSAIDs-NO hybrid molecules with antiproliferative properties on human prostatic cancer cell lines.
Year : 2008
Volume : 18
Issue : 16
First Page : 4655
Last Page : 4657
Authors : Bézière N, Goossens L, Pommery J, Vezin H, Touati N, Hénichart JP, Pommery N.
Abstract : The design of profen hybrids containing a NO donor moiety connected to an aliphatic spacer led to compounds with a similar cyclooxygenase inhibition compared to their parent profen and with significant antiproliferative activities on PC3 cells. However, inhibition of COX-2 pathway alone did not seem sufficient to inhibit cancer cell proliferation, and NO-release in a time-dependent manner strongly contributes to this activity.
|
Antiproliferative activity against human PC3 cells at 100 uM after 72 hrs by MTT assay
|
Homo sapiens
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New NSAIDs-NO hybrid molecules with antiproliferative properties on human prostatic cancer cell lines.
Year : 2008
Volume : 18
Issue : 16
First Page : 4655
Last Page : 4657
Authors : Bézière N, Goossens L, Pommery J, Vezin H, Touati N, Hénichart JP, Pommery N.
Abstract : The design of profen hybrids containing a NO donor moiety connected to an aliphatic spacer led to compounds with a similar cyclooxygenase inhibition compared to their parent profen and with significant antiproliferative activities on PC3 cells. However, inhibition of COX-2 pathway alone did not seem sufficient to inhibit cancer cell proliferation, and NO-release in a time-dependent manner strongly contributes to this activity.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
-9.4
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Inhibition of ovine cyclooxygenase 1 assessed as prostaglandin F2alpha level at 10 uM by enzyme immunoassay relative to control
|
Ovis aries
|
16.0
%
|
|
Journal : J. Med. Chem.
Title : New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide.
Year : 2008
Volume : 51
Issue : 24
First Page : 7800
Last Page : 7805
Authors : Sinning C, Watzer B, Coste O, Nüsing RM, Ott I, Ligresti A, Di Marzo V, Imming P.
Abstract : N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide (AM404) is a metabolite of the well-known analgesic paracetamol. AM404 inhibits endocannabinoid cellular uptake, binds weakly to CB1 and CB2 cannabinoid receptors, and is formed by fatty acid amide hydrolase (FAAH) in vivo. We prepared three derivatives of this new (endo)cannabinoid using bioisosteric replacement (1), homology (2), and derivatization (3) of the 4-aminophenol moiety in AM404 and tested them against CB1, CB2, and FAAH. We found affinities toward both cannabinoid receptors equal to or greater than that of AM404. Shortening the acyl chain from C20 to C2 led to three new paracetamol analogues: N-(1H-indazol-5-yl)acetamide (5), N-(4-hydroxybenzyl)acetamide (6), and N-(4-hydroxy-3-methoxyphenyl)acetamide (7). Again, 5, 6, and 7 were tested against CB1, CB2, and FAAH without significant activity. However, 5 and 7 behaved like inhibitors of cyclooxygenases in whole blood assays. Finally, 5 (50 mg/kg) and 6 (275 mg/kg) displayed analgesic activities comparable to paracetamol (200 mg/kg) in the mouse formalin test.
|
Inhibition of human recombinant cyclooxygenase 2 assessed as prostaglandin F2alpha level at 10 uM by enzyme immunoassay relative to control
|
Homo sapiens
|
41.0
%
|
|
Journal : J. Med. Chem.
Title : New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide.
Year : 2008
Volume : 51
Issue : 24
First Page : 7800
Last Page : 7805
Authors : Sinning C, Watzer B, Coste O, Nüsing RM, Ott I, Ligresti A, Di Marzo V, Imming P.
Abstract : N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide (AM404) is a metabolite of the well-known analgesic paracetamol. AM404 inhibits endocannabinoid cellular uptake, binds weakly to CB1 and CB2 cannabinoid receptors, and is formed by fatty acid amide hydrolase (FAAH) in vivo. We prepared three derivatives of this new (endo)cannabinoid using bioisosteric replacement (1), homology (2), and derivatization (3) of the 4-aminophenol moiety in AM404 and tested them against CB1, CB2, and FAAH. We found affinities toward both cannabinoid receptors equal to or greater than that of AM404. Shortening the acyl chain from C20 to C2 led to three new paracetamol analogues: N-(1H-indazol-5-yl)acetamide (5), N-(4-hydroxybenzyl)acetamide (6), and N-(4-hydroxy-3-methoxyphenyl)acetamide (7). Again, 5, 6, and 7 were tested against CB1, CB2, and FAAH without significant activity. However, 5 and 7 behaved like inhibitors of cyclooxygenases in whole blood assays. Finally, 5 (50 mg/kg) and 6 (275 mg/kg) displayed analgesic activities comparable to paracetamol (200 mg/kg) in the mouse formalin test.
|
Antioxidant activity assessed as inhibition of lipid peroxidation at 100 uM
|
None
|
69.3
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological screening of some novel amidocarbamate derivatives of ketoprofen.
Year : 2010
Volume : 45
Issue : 7
First Page : 3162
Last Page : 3168
Authors : Sahoo PK, Behera P.
Abstract : A series of novel ketoprofen derivatives 4a-j bearing both amide and carbamate functionalities were prepared using benzotriazole. Selective reduction of ketoprofen produced hydroxy derivative 2, which reacts with one or 2 mol of 1-benzotriazole carboxylic acid chloride (1) gave benzotriazole derivatives 3a and 3b respectively. Antioxidative screenings revealed that the prepared compounds 3b and 4a-j possess excellent lipid peroxidation inhibition at 0.1 mM concentration. Two of the compounds 3b and 4 g also showed high soybean lipoxygenase inhibition activity, where as the amidocarbamate derivatives of ketoprofen showed only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses.
|
DRUGMATRIX: Cyclooxygenase COX-1 enzyme inhibition (substrate: Arachidonic acid)
|
Homo sapiens
|
14.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Cyclooxygenase COX-2 enzyme inhibition (substrate: Arachidonic acid)
|
None
|
785.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
TP_TRANSPORTER: inhibition of MTX uptake in Xenopus laevis oocytes
|
Xenopus laevis
|
500.0
nM
|
|
Journal : Eur. J. Pharmacol.
Title : Interaction between methotrexate and nonsteroidal anti-inflammatory drugs in organic anion transporter.
Year : 2000
Volume : 409
Issue : 1
First Page : 31
Last Page : 36
Authors : Uwai Y, Saito H, Inui K.
Abstract : The antifolate drug methotrexate is mainly eliminated from the body by renal tubular secretion via organic anion transporters. In clinical situations, severe methotrexate toxicity, due to an increase in serum concentrations, was observed after coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) or probenecid. In this study, we examined the effects of NSAIDs and probenecid on methotrexate transport via the rat renal organic anion transporter rOAT1, using Xenopus laevis oocytes. [3H]Methotrexate uptake was markedly stimulated in the rOAT1 cRNA-injected oocytes, and this uptake was inhibited by probenecid and various NSAIDs, whereas the influence of salicylate was less. The Dixon plots showed that probenecid, indomethacin and salicylate competitively inhibited rOAT1 with apparent K(i) values of 15.8 microM, 4.2 microM and 1.0 mM, respectively. These findings demonstrate that rOAT1 is the major site of the transporter-mediated interaction between methotrexate and NSAIDs and/or probenecid, leading to a decrease in renal excretion of methotrexate.
|
TP_TRANSPORTER: inhibition of PAH uptake (PAH: 2 uM, Ketoprofen: 1000 uM) in Xenopus laevis oocytes
|
Xenopus laevis
|
100.0
%
|
|
Journal : Mol. Pharmacol.
Title : Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes.
Year : 1999
Volume : 55
Issue : 1
First Page : 847
Last Page : 854
Authors : Apiwattanakul N, Sekine T, Chairoungdua A, Kanai Y, Nakajima N, Sophasan S, Endou H.
Abstract : Organic anion transporter 1 (OAT1) is the para-aminohippurate (PAH) transporter in the basolateral membrane of the proximal tubule. The present study investigated whether or not nonsteroidal anti-inflammatory drugs (NSAIDs) are transported by OAT1. All of the NSAIDs tested inhibited [14C]PAH uptake via OAT1 expressed in Xenopus laevis oocytes. Ibuprofen, indomethacin, salicylurate, and naproxen showed the strongest potency to inhibit [14C]PAH uptake (Ki approximately 2-10 microM); acetylsalicylate, salicylate, and phenacetin exhibited moderate potency (Ki approximately 300-400 microM), and acetaminophen (paracetamol) exhibited the weakest inhibitory potency (Ki approximately 2 mM). Radiolabeled acetylsalicylate, salicylate, and indomethacin were taken up by OAT1 and the uptake rate of these three NSAIDs was enhanced by the outwardly directed dicarboxylate gradient. The efflux of the preloaded [14C]PAH from the oocytes via OAT1 was trans-stimulated by PAH and glutarate added to the media. The addition of salicylate, acetylsalicylate, or salicylurate into the media also trans-stimulated the efflux of PAH, whereas indomethacin did not. The present study indicates that OAT1 is responsible for the renal uptake and secretion of NSAIDs.
|
Antioxidant activity assessed as inhibition of AAPH-induced lipid peroxidation at 1 X 10'-4 M
|
None
|
69.3
%
|
|
Journal : Med Chem Res
Title : The novel amidocarbamate derivatives of ketoprofen: synthesis and biological activity.
Year : 2011
Volume : 20
Issue : 2
First Page : 210
Last Page : 219
Authors : Rajić Z, Hadjipavlou-Litina D, Pontiki E, Balzarini J, Zorc B.
Abstract : A series of novel ketoprofen derivatives <b>4a</b>-<b>j</b> bearing both amide and carbamate functionalities were prepared using the benzotriazole method of carboxylic and hydroxy group activation. Selective reduction of ketoprofen produced hydroxy derivative <b>2</b>, which in the reaction with one or two moles of 1-benzotriazole carboxylic acid chloride (<b>1</b>) gave benzotriazole derivatives <b>3a</b> and <b>3b</b>, respectively. Compounds <b>3a</b> and <b>3b</b> with various amines afforded amidocarbamates <b>4a</b>-<b>j</b>. Antioxidative screenings revealed that the prepared compounds <b>3b</b> and <b>4a</b>-<b>j</b> possess excellent lipid peroxidation inhibition at 0.1 mM concentration, higher than 95% for the derivatives bearing aromatic, cycloalkyl or heterocyclic substituents. Two of the compounds, <b>3b</b> and <b>4g</b>, also show high soybean lipoxygenase inhibition activity (95 and 83.5%, respectively). On the other hand, the amidocarbamate derivatives of ketoprofen show only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses. Most compounds were endowed with a moderate (IC<sub>50</sub>: 10-25 μM) cytostatic activity.
|
Antioxidant activity assessed as DPPH radical scavenging activity at 1 X 10'-4 M after 60 min
|
None
|
7.2
%
|
|
Journal : Med Chem Res
Title : The novel amidocarbamate derivatives of ketoprofen: synthesis and biological activity.
Year : 2011
Volume : 20
Issue : 2
First Page : 210
Last Page : 219
Authors : Rajić Z, Hadjipavlou-Litina D, Pontiki E, Balzarini J, Zorc B.
Abstract : A series of novel ketoprofen derivatives <b>4a</b>-<b>j</b> bearing both amide and carbamate functionalities were prepared using the benzotriazole method of carboxylic and hydroxy group activation. Selective reduction of ketoprofen produced hydroxy derivative <b>2</b>, which in the reaction with one or two moles of 1-benzotriazole carboxylic acid chloride (<b>1</b>) gave benzotriazole derivatives <b>3a</b> and <b>3b</b>, respectively. Compounds <b>3a</b> and <b>3b</b> with various amines afforded amidocarbamates <b>4a</b>-<b>j</b>. Antioxidative screenings revealed that the prepared compounds <b>3b</b> and <b>4a</b>-<b>j</b> possess excellent lipid peroxidation inhibition at 0.1 mM concentration, higher than 95% for the derivatives bearing aromatic, cycloalkyl or heterocyclic substituents. Two of the compounds, <b>3b</b> and <b>4g</b>, also show high soybean lipoxygenase inhibition activity (95 and 83.5%, respectively). On the other hand, the amidocarbamate derivatives of ketoprofen show only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses. Most compounds were endowed with a moderate (IC<sub>50</sub>: 10-25 μM) cytostatic activity.
|
Antioxidant activity assessed as DPPH radical scavenging activity at 1 X 10'-4 M after 20 min
|
None
|
8.1
%
|
|
Journal : Med Chem Res
Title : The novel amidocarbamate derivatives of ketoprofen: synthesis and biological activity.
Year : 2011
Volume : 20
Issue : 2
First Page : 210
Last Page : 219
Authors : Rajić Z, Hadjipavlou-Litina D, Pontiki E, Balzarini J, Zorc B.
Abstract : A series of novel ketoprofen derivatives <b>4a</b>-<b>j</b> bearing both amide and carbamate functionalities were prepared using the benzotriazole method of carboxylic and hydroxy group activation. Selective reduction of ketoprofen produced hydroxy derivative <b>2</b>, which in the reaction with one or two moles of 1-benzotriazole carboxylic acid chloride (<b>1</b>) gave benzotriazole derivatives <b>3a</b> and <b>3b</b>, respectively. Compounds <b>3a</b> and <b>3b</b> with various amines afforded amidocarbamates <b>4a</b>-<b>j</b>. Antioxidative screenings revealed that the prepared compounds <b>3b</b> and <b>4a</b>-<b>j</b> possess excellent lipid peroxidation inhibition at 0.1 mM concentration, higher than 95% for the derivatives bearing aromatic, cycloalkyl or heterocyclic substituents. Two of the compounds, <b>3b</b> and <b>4g</b>, also show high soybean lipoxygenase inhibition activity (95 and 83.5%, respectively). On the other hand, the amidocarbamate derivatives of ketoprofen show only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses. Most compounds were endowed with a moderate (IC<sub>50</sub>: 10-25 μM) cytostatic activity.
|
Antioxidant activity assessed as DPPH radical scavenging activity at 5 X 10'-5 M after 60 min
|
None
|
3.1
%
|
|
Journal : Med Chem Res
Title : The novel amidocarbamate derivatives of ketoprofen: synthesis and biological activity.
Year : 2011
Volume : 20
Issue : 2
First Page : 210
Last Page : 219
Authors : Rajić Z, Hadjipavlou-Litina D, Pontiki E, Balzarini J, Zorc B.
Abstract : A series of novel ketoprofen derivatives <b>4a</b>-<b>j</b> bearing both amide and carbamate functionalities were prepared using the benzotriazole method of carboxylic and hydroxy group activation. Selective reduction of ketoprofen produced hydroxy derivative <b>2</b>, which in the reaction with one or two moles of 1-benzotriazole carboxylic acid chloride (<b>1</b>) gave benzotriazole derivatives <b>3a</b> and <b>3b</b>, respectively. Compounds <b>3a</b> and <b>3b</b> with various amines afforded amidocarbamates <b>4a</b>-<b>j</b>. Antioxidative screenings revealed that the prepared compounds <b>3b</b> and <b>4a</b>-<b>j</b> possess excellent lipid peroxidation inhibition at 0.1 mM concentration, higher than 95% for the derivatives bearing aromatic, cycloalkyl or heterocyclic substituents. Two of the compounds, <b>3b</b> and <b>4g</b>, also show high soybean lipoxygenase inhibition activity (95 and 83.5%, respectively). On the other hand, the amidocarbamate derivatives of ketoprofen show only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses. Most compounds were endowed with a moderate (IC<sub>50</sub>: 10-25 μM) cytostatic activity.
|
Antioxidant activity assessed as DPPH radical scavenging activity at 5 X 10'-5 M after 20 min
|
None
|
6.4
%
|
|
Journal : Med Chem Res
Title : The novel amidocarbamate derivatives of ketoprofen: synthesis and biological activity.
Year : 2011
Volume : 20
Issue : 2
First Page : 210
Last Page : 219
Authors : Rajić Z, Hadjipavlou-Litina D, Pontiki E, Balzarini J, Zorc B.
Abstract : A series of novel ketoprofen derivatives <b>4a</b>-<b>j</b> bearing both amide and carbamate functionalities were prepared using the benzotriazole method of carboxylic and hydroxy group activation. Selective reduction of ketoprofen produced hydroxy derivative <b>2</b>, which in the reaction with one or two moles of 1-benzotriazole carboxylic acid chloride (<b>1</b>) gave benzotriazole derivatives <b>3a</b> and <b>3b</b>, respectively. Compounds <b>3a</b> and <b>3b</b> with various amines afforded amidocarbamates <b>4a</b>-<b>j</b>. Antioxidative screenings revealed that the prepared compounds <b>3b</b> and <b>4a</b>-<b>j</b> possess excellent lipid peroxidation inhibition at 0.1 mM concentration, higher than 95% for the derivatives bearing aromatic, cycloalkyl or heterocyclic substituents. Two of the compounds, <b>3b</b> and <b>4g</b>, also show high soybean lipoxygenase inhibition activity (95 and 83.5%, respectively). On the other hand, the amidocarbamate derivatives of ketoprofen show only weak reducing activity against 1,1-diphenyl-2-picrylhydrazyl radicals. No selective antiviral effects were noted for the tested compounds against a broad variety of DNA and RNA viruses. Most compounds were endowed with a moderate (IC<sub>50</sub>: 10-25 μM) cytostatic activity.
|
Inhibition of Homo sapiens (human) recombinant cyclooxygenase-2 assessed as formation of PGF2a at 200 uM by enzyme immunoassay
|
Homo sapiens
|
78.0
%
|
|
Journal : Med Chem Res
Title : Compounds against inflammation and oxidative insult as potential agents for neurodegenerative disorders
Year : 2012
Volume : 21
Issue : 9
First Page : 2280
Last Page : 2291
Authors : Doulgkeris CM, Siskou IC, Xanthopoulou N, Lagouri V, Kravaritou C, Eleftheriou P, Kourounakis PN, Rekka EA
|
Inhibition of Ovis aries (sheep) COX1 assessed as formation of PGF2a at 200 uM by enzyme immunoassay
|
Ovis aries
|
86.0
%
|
|
Journal : Med Chem Res
Title : Compounds against inflammation and oxidative insult as potential agents for neurodegenerative disorders
Year : 2012
Volume : 21
Issue : 9
First Page : 2280
Last Page : 2291
Authors : Doulgkeris CM, Siskou IC, Xanthopoulou N, Lagouri V, Kravaritou C, Eleftheriou P, Kourounakis PN, Rekka EA
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
119.22
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
112.11
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Antiinflammatory activity in Wistar albino rat assessed as inhibition of adjuvant-induced arthritis at 2 mg/kg, po administered for 14 days prior to adjuvant challenge relative to control
|
Rattus norvegicus
|
84.0
%
|
|
Journal : J. Med. Chem.
Title : 6,11-Dihydro-11-oxodibenz [b,e] oxepinacetic acids with potent antiinflammatory activity.
Year : 1976
Volume : 19
Issue : 7
First Page : 941
Last Page : 946
Authors : Ueno K, Kubo S, Tagawa H, Yoshioka T, Tsukada W.
Abstract : A series of 6,11-dihydro-11-oxodibenz[b,e]oxepinacetic acids was synthesized and the antiinflammatory activity determined. Studies on 29 compounds revealed certain structure-activity relationships. In the carrageenan edema test, eight compounds exhibited higher antiinflammatory activities than did indomethacin. Several compounds (2, 9, 14, 22, 25) also proved to have activities superior or comparable to indomethacin in suppressing chronic as well as acute inflammation and carrageenan-induced hyperesthesia. Gastric irritation and lethality rates were less frequently observed with these compounds.
|
Antiinflammatory activity in Wistar albino rat assessed as inhibition of adjuvant-induced arthritis at 1 mg/kg, po administered for 14 days followed by adjuvant challenge relative to control
|
Rattus norvegicus
|
42.0
%
|
|
Journal : J. Med. Chem.
Title : 6,11-Dihydro-11-oxodibenz [b,e] oxepinacetic acids with potent antiinflammatory activity.
Year : 1976
Volume : 19
Issue : 7
First Page : 941
Last Page : 946
Authors : Ueno K, Kubo S, Tagawa H, Yoshioka T, Tsukada W.
Abstract : A series of 6,11-dihydro-11-oxodibenz[b,e]oxepinacetic acids was synthesized and the antiinflammatory activity determined. Studies on 29 compounds revealed certain structure-activity relationships. In the carrageenan edema test, eight compounds exhibited higher antiinflammatory activities than did indomethacin. Several compounds (2, 9, 14, 22, 25) also proved to have activities superior or comparable to indomethacin in suppressing chronic as well as acute inflammation and carrageenan-induced hyperesthesia. Gastric irritation and lethality rates were less frequently observed with these compounds.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 50 mg/kg, ip administered prior to carrageenan challenge measured at 1 hr by plethysmometric analysis relative to control
|
Mus musculus
|
66.7
%
|
|
Journal : Eur. J. Med. Chem.
Title : Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.
Year : 2014
Volume : 83
First Page : 534
Last Page : 546
Authors : Łażewska D, Więcek M, Ner J, Kamińska K, Kottke T, Schwed JS, Zygmunt M, Karcz T, Olejarz A, Kuder K, Latacz G, Grosicki M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 50 mg/kg, ip administered prior to carrageenan challenge measured at 2 hrs by plethysmometric analysis relative to control
|
Mus musculus
|
70.7
%
|
|
Journal : Eur. J. Med. Chem.
Title : Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.
Year : 2014
Volume : 83
First Page : 534
Last Page : 546
Authors : Łażewska D, Więcek M, Ner J, Kamińska K, Kottke T, Schwed JS, Zygmunt M, Karcz T, Olejarz A, Kuder K, Latacz G, Grosicki M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 50 mg/kg, ip administered prior to carrageenan challenge measured at 3 hrs by plethysmometric analysis relative to control
|
Mus musculus
|
77.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.
Year : 2014
Volume : 83
First Page : 534
Last Page : 546
Authors : Łażewska D, Więcek M, Ner J, Kamińska K, Kottke T, Schwed JS, Zygmunt M, Karcz T, Olejarz A, Kuder K, Latacz G, Grosicki M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 25 mg/kg, ip administered prior to carrageenan challenge measured at 1 hr by plethysmometric analysis relative to control
|
Mus musculus
|
20.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.
Year : 2014
Volume : 83
First Page : 534
Last Page : 546
Authors : Łażewska D, Więcek M, Ner J, Kamińska K, Kottke T, Schwed JS, Zygmunt M, Karcz T, Olejarz A, Kuder K, Latacz G, Grosicki M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 25 mg/kg, ip administered prior to carrageenan challenge measured at 2 hrs by plethysmometric analysis relative to control
|
Mus musculus
|
55.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.
Year : 2014
Volume : 83
First Page : 534
Last Page : 546
Authors : Łażewska D, Więcek M, Ner J, Kamińska K, Kottke T, Schwed JS, Zygmunt M, Karcz T, Olejarz A, Kuder K, Latacz G, Grosicki M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 25 mg/kg, ip administered prior to carrageenan challenge measured at 3 hrs by plethysmometric analysis relative to control
|
Mus musculus
|
67.3
%
|
|
Journal : Eur. J. Med. Chem.
Title : Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.
Year : 2014
Volume : 83
First Page : 534
Last Page : 546
Authors : Łażewska D, Więcek M, Ner J, Kamińska K, Kottke T, Schwed JS, Zygmunt M, Karcz T, Olejarz A, Kuder K, Latacz G, Grosicki M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 10 mg/kg, ip administered prior to carrageenan challenge measured at 1 hr by plethysmometric analysis relative to control
|
Mus musculus
|
26.7
%
|
|
Journal : Eur. J. Med. Chem.
Title : Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.
Year : 2014
Volume : 83
First Page : 534
Last Page : 546
Authors : Łażewska D, Więcek M, Ner J, Kamińska K, Kottke T, Schwed JS, Zygmunt M, Karcz T, Olejarz A, Kuder K, Latacz G, Grosicki M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 10 mg/kg, ip administered prior to carrageenan challenge measured at 2 hrs by plethysmometric analysis relative to control
|
Mus musculus
|
55.1
%
|
|
Journal : Eur. J. Med. Chem.
Title : Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.
Year : 2014
Volume : 83
First Page : 534
Last Page : 546
Authors : Łażewska D, Więcek M, Ner J, Kamińska K, Kottke T, Schwed JS, Zygmunt M, Karcz T, Olejarz A, Kuder K, Latacz G, Grosicki M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 10 mg/kg, ip administered prior to carrageenan challenge measured at 3 hrs by plethysmometric analysis relative to control
|
Mus musculus
|
62.7
%
|
|
Journal : Eur. J. Med. Chem.
Title : Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.
Year : 2014
Volume : 83
First Page : 534
Last Page : 546
Authors : Łażewska D, Więcek M, Ner J, Kamińska K, Kottke T, Schwed JS, Zygmunt M, Karcz T, Olejarz A, Kuder K, Latacz G, Grosicki M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 μM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken.
|
Inhibition of purified ovine COX1 pre-treated for 1 hr before 10-acetyl-3,7-dihydroxyphenoxazin substrate addition in absence of porcine liver esterase by fluorescence assay
|
Ovis aries
|
800.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Propyphenazone-based analogues as prodrugs and selective cyclooxygenase-2 inhibitors.
Year : 2014
Volume : 5
Issue : 9
First Page : 983
Last Page : 988
Authors : Radwan MF, Dalby KN, Kaoud TS.
Abstract : Improving the gastrointestinal safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important goal. Herein, we report two strategies, using the nonacidic propyphenazone structure, with potential to overcome the side effects of NSAIDs. Propyphenazone was employed to temporarily mask the free acid group of the widely used NSAIDs ibuprofen, diclofenac, and ketoprofen to develop three mutual prodrugs hypothesized to have minimal GI irritation. The three prodrugs exhibit in vivo anti-inflammatory and analgesic activities with improved potency over each parent drug when compared to a nonhydrolyzable control betahistine-propyphenazone (BET-MP). Additionally, ANT-MP formed by the irreversible coupling of propyphenazone and 4-aminoantipyrine, displayed exceptional COXII selectivity (COXII IC50 of 0.97 ± 0.04 μM, compared to no observed inhibition of COXI at 160 μM). Inhibition of COXII suppresses inflammatory diseases without affecting COXI-mediated GI tract events. ANT-MP exhibited maximal analgesic effect when tested in vivo in an abdominal writhing assay (100% protection) and its anti-inflammatory activity showed a peak at 2 h in a carrageenan-induced paw edema model. Its unique selectivity toward the COXII enzyme was investigated using molecular modeling techniques.
|
Inhibition of purified ovine COX1 at saturation drug level pre-treated for 1 hr before 10-acetyl-3,7-dihydroxyphenoxazin substrate addition in absence of porcine liver esterase by fluorescence assay
|
Ovis aries
|
100.0
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Propyphenazone-based analogues as prodrugs and selective cyclooxygenase-2 inhibitors.
Year : 2014
Volume : 5
Issue : 9
First Page : 983
Last Page : 988
Authors : Radwan MF, Dalby KN, Kaoud TS.
Abstract : Improving the gastrointestinal safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important goal. Herein, we report two strategies, using the nonacidic propyphenazone structure, with potential to overcome the side effects of NSAIDs. Propyphenazone was employed to temporarily mask the free acid group of the widely used NSAIDs ibuprofen, diclofenac, and ketoprofen to develop three mutual prodrugs hypothesized to have minimal GI irritation. The three prodrugs exhibit in vivo anti-inflammatory and analgesic activities with improved potency over each parent drug when compared to a nonhydrolyzable control betahistine-propyphenazone (BET-MP). Additionally, ANT-MP formed by the irreversible coupling of propyphenazone and 4-aminoantipyrine, displayed exceptional COXII selectivity (COXII IC50 of 0.97 ± 0.04 μM, compared to no observed inhibition of COXI at 160 μM). Inhibition of COXII suppresses inflammatory diseases without affecting COXI-mediated GI tract events. ANT-MP exhibited maximal analgesic effect when tested in vivo in an abdominal writhing assay (100% protection) and its anti-inflammatory activity showed a peak at 2 h in a carrageenan-induced paw edema model. Its unique selectivity toward the COXII enzyme was investigated using molecular modeling techniques.
|
Inhibition of human recombinant COX2 at saturation drug level pre-treated for 1 hr before 10-acetyl-3,7-dihydroxyphenoxazin substrate addition in absence of porcine liver esterase by fluorescence assay
|
Homo sapiens
|
100.0
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Propyphenazone-based analogues as prodrugs and selective cyclooxygenase-2 inhibitors.
Year : 2014
Volume : 5
Issue : 9
First Page : 983
Last Page : 988
Authors : Radwan MF, Dalby KN, Kaoud TS.
Abstract : Improving the gastrointestinal safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important goal. Herein, we report two strategies, using the nonacidic propyphenazone structure, with potential to overcome the side effects of NSAIDs. Propyphenazone was employed to temporarily mask the free acid group of the widely used NSAIDs ibuprofen, diclofenac, and ketoprofen to develop three mutual prodrugs hypothesized to have minimal GI irritation. The three prodrugs exhibit in vivo anti-inflammatory and analgesic activities with improved potency over each parent drug when compared to a nonhydrolyzable control betahistine-propyphenazone (BET-MP). Additionally, ANT-MP formed by the irreversible coupling of propyphenazone and 4-aminoantipyrine, displayed exceptional COXII selectivity (COXII IC50 of 0.97 ± 0.04 μM, compared to no observed inhibition of COXI at 160 μM). Inhibition of COXII suppresses inflammatory diseases without affecting COXI-mediated GI tract events. ANT-MP exhibited maximal analgesic effect when tested in vivo in an abdominal writhing assay (100% protection) and its anti-inflammatory activity showed a peak at 2 h in a carrageenan-induced paw edema model. Its unique selectivity toward the COXII enzyme was investigated using molecular modeling techniques.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 50 mg/kg, po administered prior to carrageenan challenge measured after 1 hr by plethysmometry relative to control
|
Mus musculus
|
67.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.
Year : 2015
Volume : 103
First Page : 238
Last Page : 251
Authors : Kamińska K, Ziemba J, Ner J, Schwed JS, Łażewska D, Więcek M, Karcz T, Olejarz A, Latacz G, Kuder K, Kottke T, Zygmunt M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 50 mg/kg, po administered prior to carrageenan challenge measured after 2 hrs by plethysmometry relative to control
|
Mus musculus
|
71.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.
Year : 2015
Volume : 103
First Page : 238
Last Page : 251
Authors : Kamińska K, Ziemba J, Ner J, Schwed JS, Łażewska D, Więcek M, Karcz T, Olejarz A, Latacz G, Kuder K, Kottke T, Zygmunt M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 50 mg/kg, po administered prior to carrageenan challenge measured after 3 hrs by plethysmometry relative to control
|
Mus musculus
|
77.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.
Year : 2015
Volume : 103
First Page : 238
Last Page : 251
Authors : Kamińska K, Ziemba J, Ner J, Schwed JS, Łażewska D, Więcek M, Karcz T, Olejarz A, Latacz G, Kuder K, Kottke T, Zygmunt M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 25 mg/kg, po administered prior to carrageenan challenge measured after 1 hr by plethysmometry relative to control
|
Mus musculus
|
20.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.
Year : 2015
Volume : 103
First Page : 238
Last Page : 251
Authors : Kamińska K, Ziemba J, Ner J, Schwed JS, Łażewska D, Więcek M, Karcz T, Olejarz A, Latacz G, Kuder K, Kottke T, Zygmunt M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 25 mg/kg, po administered prior to carrageenan challenge measured after 2 hrs by plethysmometry relative to control
|
Mus musculus
|
54.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.
Year : 2015
Volume : 103
First Page : 238
Last Page : 251
Authors : Kamińska K, Ziemba J, Ner J, Schwed JS, Łażewska D, Więcek M, Karcz T, Olejarz A, Latacz G, Kuder K, Kottke T, Zygmunt M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 25 mg/kg, po administered prior to carrageenan challenge measured after 3 hrs by plethysmometry relative to control
|
Mus musculus
|
67.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.
Year : 2015
Volume : 103
First Page : 238
Last Page : 251
Authors : Kamińska K, Ziemba J, Ner J, Schwed JS, Łażewska D, Więcek M, Karcz T, Olejarz A, Latacz G, Kuder K, Kottke T, Zygmunt M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 10 mg/kg, po administered prior to carrageenan challenge measured after 1 hr by plethysmometry relative to control
|
Mus musculus
|
27.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.
Year : 2015
Volume : 103
First Page : 238
Last Page : 251
Authors : Kamińska K, Ziemba J, Ner J, Schwed JS, Łażewska D, Więcek M, Karcz T, Olejarz A, Latacz G, Kuder K, Kottke T, Zygmunt M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 10 mg/kg, po administered prior to carrageenan challenge measured after 2 hrs by plethysmometry relative to control
|
Mus musculus
|
55.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.
Year : 2015
Volume : 103
First Page : 238
Last Page : 251
Authors : Kamińska K, Ziemba J, Ner J, Schwed JS, Łażewska D, Więcek M, Karcz T, Olejarz A, Latacz G, Kuder K, Kottke T, Zygmunt M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.
|
Antiinflammatory activity in albino Swiss mouse assessed as inhibition of carrageenan-induced paw edema at 10 mg/kg, po administered prior to carrageenan challenge measured after 3 hrs by plethysmometry relative to control
|
Mus musculus
|
63.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : (2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.
Year : 2015
Volume : 103
First Page : 238
Last Page : 251
Authors : Kamińska K, Ziemba J, Ner J, Schwed JS, Łażewska D, Więcek M, Karcz T, Olejarz A, Latacz G, Kuder K, Kottke T, Zygmunt M, Sapa J, Karolak-Wojciechowska J, Stark H, Kieć-Kononowicz K.
Abstract : Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.
|
Antiinflammatory activity in rat assessed as reduction of carrageenan-induced paw oedema at 0.15 mmol/kg, ip administered 5 mins before carrageenan challenge measured after 3.5 hrs
|
Rattus norvegicus
|
47.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Esters of some non-steroidal anti-inflammatory drugs with cinnamyl alcohol are potent lipoxygenase inhibitors with enhanced anti-inflammatory activity.
Year : 2015
Volume : 25
Issue : 22
First Page : 5028
Last Page : 5031
Authors : Theodosis-Nobelos P, Kourti M, Tziona P, Kourounakis PN, Rekka EA.
Abstract : Novel esters of non steroidal anti-inflammatory drugs, α-lipoic acid and indol-3-acetic acid with cinnamyl alcohol were synthesised by a straightforward method and at high yields (60-98%). They reduced acute inflammation more than the parent acids and are potent inhibitors of soybean lipoxygenase. Selected structures decreased plasma lipidemic indices in Triton-induced hyperlipidemia to rats. Therefore, the synthesised compounds may add to the current knowledge about agents acting against various inflammatory disorders.
|
Inhibition of Ovine COX-1 preincubated for 15 mins by fluorescence analysis
|
Ovis aries
|
67.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Synthesis and Evaluation of Novel Erlotinib-NSAID Conjugates as More Comprehensive Anticancer Agents.
Year : 2015
Volume : 6
Issue : 10
First Page : 1086
Last Page : 1090
Authors : Zhang Y, Tortorella MD, Liao J, Qin X, Chen T, Luo J, Guan J, Talley JJ, Tu Z.
Abstract : A series of novel anticancer agents were designed and synthesized based on coupling of different nonsteroidal anti-inflammatory drugs (NSAIDs) with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers where both EGFR overexpression and inflammation play a direct role in disease progression.
|
Inhibition of recombinant human COX-2 preincubated for 15 mins by fluorescence analysis
|
Homo sapiens
|
61.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Synthesis and Evaluation of Novel Erlotinib-NSAID Conjugates as More Comprehensive Anticancer Agents.
Year : 2015
Volume : 6
Issue : 10
First Page : 1086
Last Page : 1090
Authors : Zhang Y, Tortorella MD, Liao J, Qin X, Chen T, Luo J, Guan J, Talley JJ, Tu Z.
Abstract : A series of novel anticancer agents were designed and synthesized based on coupling of different nonsteroidal anti-inflammatory drugs (NSAIDs) with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers where both EGFR overexpression and inflammation play a direct role in disease progression.
|
Anti-inflammatory activity in rat assessed as reduction of carrageenan-induced paw edema at 150 umol/kg, ip after 3.5 hrs relative to control
|
Rattus norvegicus
|
47.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Amides of non-steroidal anti-inflammatory drugs with thiomorpholine can yield hypolipidemic agents with improved anti-inflammatory activity.
Year : 2016
Volume : 26
Issue : 3
First Page : 910
Last Page : 913
Authors : Theodosis-Nobelos P, Kourti M, Gavalas A, Rekka EA.
Abstract : Novel amides of non steroidal anti-inflammatory drugs (NSAIDs), α-lipoic acid and indole-3-acetic acid with thiomorpholine were synthesised by a simple method and at high yields (60-92%). All the NSAID derivatives highly decreased lipidemic indices in the plasma of Triton treated hyperlipidemic rats. The most potent compound was the indomethacin derivative, which decreased total cholesterol, triglycerides and LDL cholesterol by 73%, 80% and 83%, respectively. They reduced acute inflammation equally or more than most parent acids. Hence, it could be concluded that amides of common NSAIDs with thiomorpholine acquire considerable hypolipidemic potency, while they preserve or augment their anti-inflammatory activity, thus addressing significant risk factors for atherogenesis.
|
Antiinflammatory activity against albino rat assessed as inhibition of carrageenin induced paw edema at 100 mg/kg, po administered for 1 hr followed by carrageenin challenge measured after 4 hrs
|
Rattus norvegicus
|
63.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline-thiazolidine-based hybrids.
Year : 2016
Volume : 113
First Page : 145
Last Page : 166
Authors : Havrylyuk D, Roman O, Lesyk R.
Abstract : The features of the chemistry of 4-thiazolidinone and pyrazole/pyrazolines as pharmacologically attractive scaffolds were described in a number of reviews in which the main approaches to the synthesis of mentioned heterocycles and their biological activity were analyzed. However, the pyrazole/pyrazoline-thiazolidine-based hybrids as biologically active compounds is poorly discussed in the context of pharmacophore hybrid approach. Therefore, the purpose of this review is to summarize the data about the synthesis and modification of heterocyclic systems with thiazolidine and pyrazoline or pyrazole fragments in molecules as promising objects of modern bioorganic and medicinal chemistry. The description of biological activity was focused on SAR analysis and mechanistic insights of mentioned hybrids.
|
Antinociceptive activity in Swiss mouse assessed as inhibition of capsaicin induced nociception by measuring paw licking time at 100 mg/kg administered via oral gavage for 1 hr followed by capsaicin challenge measured for 5 mins post dose relative to control
|
Mus musculus
|
81.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and antinociceptive activity of new 2-substituted 4-(trifluoromethyl)-5,6-dihydrobenzo[h]quinazolines.
Year : 2016
Volume : 26
Issue : 19
First Page : 4808
Last Page : 4814
Authors : Bonacorso HG, Rosa WC, Oliveira SM, Brusco I, Pozza CCD, Nogara PA, Wiethan CW, Rodrigues MB, Frizzo CP, Zanatta N.
Abstract : A useful synthetic route for an initial new series of 2-substituted 4-(trifluoromethyl)-5,6-dihydrobenzo[h]quinazolines (3), as well as an evaluation of their analgesic effect in a mice pain model, is reported. Five new quinazolines were formed from the cyclocondensation reactions of 2,2,2-trifluoro-1-(1-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)ethanone (1) with some well-known amidine salts [NH2CR(=NH)] (2), in which R=H, Me, Ph, NH2 and SMe, at a 40-70% yield. Subsequently, due to the importance of the pyrrole nucleus, a 2-(pyrrol-1-yl)quinazoline (4) was obtained through a Clauson-Kaas reaction from the respective 2-(amino)quinazoline, in a reaction with 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation demonstrated that four 5,6-dihydrobenzo[h]quinazolines (compounds of 3c (R=Ph), 3d (R=NH2), 3e (R=SMe), and 4 (R=pyrrol-1-yl); 100mg/kg, p.o.) and ketoprofen (100mg/kg, p.o.) significantly reduced the spontaneous nociception in a capsaicin-induced test. Moreover, in comparison with ketoprofen (100 and 300mg/kg, p.o.), compound 3c (30-300mg/kg, p.o.) showed an anti-hyperalgesic action in an arthritic pain model without locomotor alterations in the mice, suggesting that quinazoline 3c is a promising prototype scaffold for new analgesic drugs in the treatment of pathological pain such as that in arthritis.
|
Antinociceptive activity in Swiss mouse assessed as inhibition of capsaicin-induced nociception at 100 mg/kg, po administered 1 hr followed by capsaicin challenge measured for 5 mins relative to vehicle-treated control
|
Mus musculus
|
80.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis of novel trifluoromethyl-substituted spiro-[chromeno[4,3-d]pyrimidine-5,1'-cycloalkanes], and evaluation of their analgesic effects in a mouse pain model.
Year : 2017
Volume : 27
Issue : 7
First Page : 1551
Last Page : 1556
Authors : Bonacorso HG, Rosa WC, Oliveira SM, Brusco I, Brum ES, Rodrigues MB, Frizzo CP, Zanatta N.
Abstract : Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-d]pyrimidines (7-10), as well as an evaluation of their analgesic effect in a mouse pain model. The nine new chromeno[4,3-d]pyrimidines (7-9) were synthesized from the cyclocondensation reactions of three 2,2,2-trifluoro-1-(4-methoxyspiro[chromene-2,1'-cycloalkane]-3-yl)ethanones (3) containing 5-, 6- and 7-membered spirocycloalkanes, with some well-known amidine salts (4-6) [NH2CR(NH)]-in which R=Me, Ph, and NH2-at yields of 60-95%. Subsequently, three new 2-(pyrrol-1-yl)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (10) were obtained through a Clauson-Kaas reaction between the respective 2-(amino)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (9) and 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation showed that these 4-(trifluoromethyl)chromeno[4,3-d]pyrimidines (100mg/kg, p.o.) and Ketoprofen (100mg/kg, p.o.) significantly reduced capsaicin-induced spontaneous nociception. Moreover, the 2-pyrrolyl-spirocyclohexane derivative 10b (100 and 300mg/kg, p.o.) had an anti-allodynic effect comparable to Ketoprofen (100 and 300mg/kg, p.o.) in the arthritic pain model, without causing locomotor alterations in the mice. These results suggest that the compound 10b is a promising molecule for new analgesic drugs in the treatment of pathological pain, such as in arthritis.
|
Antinociceptive activity in Swiss mouse assessed as inhibition of CFA-induced mechanical allodynia at 100 mg/kg, po after 2 hrs relative to vehicle-treated control
|
Mus musculus
|
65.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis of novel trifluoromethyl-substituted spiro-[chromeno[4,3-d]pyrimidine-5,1'-cycloalkanes], and evaluation of their analgesic effects in a mouse pain model.
Year : 2017
Volume : 27
Issue : 7
First Page : 1551
Last Page : 1556
Authors : Bonacorso HG, Rosa WC, Oliveira SM, Brusco I, Brum ES, Rodrigues MB, Frizzo CP, Zanatta N.
Abstract : Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-d]pyrimidines (7-10), as well as an evaluation of their analgesic effect in a mouse pain model. The nine new chromeno[4,3-d]pyrimidines (7-9) were synthesized from the cyclocondensation reactions of three 2,2,2-trifluoro-1-(4-methoxyspiro[chromene-2,1'-cycloalkane]-3-yl)ethanones (3) containing 5-, 6- and 7-membered spirocycloalkanes, with some well-known amidine salts (4-6) [NH2CR(NH)]-in which R=Me, Ph, and NH2-at yields of 60-95%. Subsequently, three new 2-(pyrrol-1-yl)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (10) were obtained through a Clauson-Kaas reaction between the respective 2-(amino)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (9) and 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation showed that these 4-(trifluoromethyl)chromeno[4,3-d]pyrimidines (100mg/kg, p.o.) and Ketoprofen (100mg/kg, p.o.) significantly reduced capsaicin-induced spontaneous nociception. Moreover, the 2-pyrrolyl-spirocyclohexane derivative 10b (100 and 300mg/kg, p.o.) had an anti-allodynic effect comparable to Ketoprofen (100 and 300mg/kg, p.o.) in the arthritic pain model, without causing locomotor alterations in the mice. These results suggest that the compound 10b is a promising molecule for new analgesic drugs in the treatment of pathological pain, such as in arthritis.
|
Inhibition of ovine COX1 assessed as reduction in PGH2 production by enzyme immunoassay
|
Ovis aries
|
110.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological properties of aryl methyl sulfones.
Year : 2018
Volume : 26
Issue : 14
First Page : 4113
Last Page : 4126
Authors : Navarro L, Rosell G, Sánchez S, Boixareu N, Pors K, Pouplana R, Campanera JM, Pujol MD.
Abstract : A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC50 COX-1 = 0.04 and COX-2 = 0.10 μM, and naproxen: IC50 COX-1 = 11.3 and COX-2 = 3.36 μM). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies. The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.
|
Inhibition of ovine COX2 assessed as reduction in PGH2 production by enzyme immunoassay
|
Ovis aries
|
180.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and biological properties of aryl methyl sulfones.
Year : 2018
Volume : 26
Issue : 14
First Page : 4113
Last Page : 4126
Authors : Navarro L, Rosell G, Sánchez S, Boixareu N, Pors K, Pouplana R, Campanera JM, Pujol MD.
Abstract : A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC50 COX-1 = 0.04 and COX-2 = 0.10 μM, and naproxen: IC50 COX-1 = 11.3 and COX-2 = 3.36 μM). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies. The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.
|
Anti-inflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 20 mg/kg, ip measured at 1 hr post dose relative to control
|
Rattus norvegicus
|
23.3
%
|
|
Journal : Eur J Med Chem
Title : Novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 antagonists and PDE4/7 inhibitors: A new approach for the treatment of pain.
Year : 2018
Volume : 158
First Page : 517
Last Page : 533
Authors : Chłoń-Rzepa G, Ślusarczyk M, Jankowska A, Gawalska A, Bucki A, Kołaczkowski M, Świerczek A, Pociecha K, Wyska E, Zygmunt M, Kazek G, Sałat K, Pawłowski M.
Abstract : A series of novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids designed using a structure-based computational approach was synthesized and assayed to evaluate their ability to block human TRPA1 channel and inhibit PDE4B/7A activity. We identified compounds 16 and 27 which showed higher potency against TRPA1 compared to HC-030031. In turn, compound 36 was the most promising multifunctional TRPA1 antagonist and PDE4B/7A dual inhibitor with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Compound 36 as a combined TRPA1/PDE4B/PDE7A ligand was characterized by a distinct binding mode in comparison to 16 and 27, in the given protein targets. The inhibition of both cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect of 36in vivo. Moreover, the potent anti-inflammatory and analgesic efficacy of 36 was observed in animal models of pain and inflammation (formalin test in mice and carrageenan-induced paw edema in rats). This compound also displayed significant antiallodynic properties in the early phase of chemotherapy-induced peripheral neuropathy in mice. In turn, the pure TRPA1 antagonists 16 and 27 revealed a statistically significant antiallodynic effect in the formalin test and in the von Frey test performed in both phases of oxaliplatin-induced allodynia. Antiallodynic activity of the test compounds 16, 27 and 36 was observed at a dose range comparable to that of the reference drug - pregabalin. In conclusion, the proposed approach of pain treatment based on the concomitant blocking of TRPA1 channel and PDE4B/7A inhibitory activity appears to be interesting research direction for the future search for novel analgesics.
|
Anti-inflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 20 mg/kg, ip measured at 2 hrs post dose relative to control
|
Rattus norvegicus
|
54.2
%
|
|
Journal : Eur J Med Chem
Title : Novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 antagonists and PDE4/7 inhibitors: A new approach for the treatment of pain.
Year : 2018
Volume : 158
First Page : 517
Last Page : 533
Authors : Chłoń-Rzepa G, Ślusarczyk M, Jankowska A, Gawalska A, Bucki A, Kołaczkowski M, Świerczek A, Pociecha K, Wyska E, Zygmunt M, Kazek G, Sałat K, Pawłowski M.
Abstract : A series of novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids designed using a structure-based computational approach was synthesized and assayed to evaluate their ability to block human TRPA1 channel and inhibit PDE4B/7A activity. We identified compounds 16 and 27 which showed higher potency against TRPA1 compared to HC-030031. In turn, compound 36 was the most promising multifunctional TRPA1 antagonist and PDE4B/7A dual inhibitor with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Compound 36 as a combined TRPA1/PDE4B/PDE7A ligand was characterized by a distinct binding mode in comparison to 16 and 27, in the given protein targets. The inhibition of both cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect of 36in vivo. Moreover, the potent anti-inflammatory and analgesic efficacy of 36 was observed in animal models of pain and inflammation (formalin test in mice and carrageenan-induced paw edema in rats). This compound also displayed significant antiallodynic properties in the early phase of chemotherapy-induced peripheral neuropathy in mice. In turn, the pure TRPA1 antagonists 16 and 27 revealed a statistically significant antiallodynic effect in the formalin test and in the von Frey test performed in both phases of oxaliplatin-induced allodynia. Antiallodynic activity of the test compounds 16, 27 and 36 was observed at a dose range comparable to that of the reference drug - pregabalin. In conclusion, the proposed approach of pain treatment based on the concomitant blocking of TRPA1 channel and PDE4B/7A inhibitory activity appears to be interesting research direction for the future search for novel analgesics.
|
Anti-inflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 20 mg/kg, ip measured at 3 hrs post dose relative to control
|
Rattus norvegicus
|
66.0
%
|
|
Journal : Eur J Med Chem
Title : Novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 antagonists and PDE4/7 inhibitors: A new approach for the treatment of pain.
Year : 2018
Volume : 158
First Page : 517
Last Page : 533
Authors : Chłoń-Rzepa G, Ślusarczyk M, Jankowska A, Gawalska A, Bucki A, Kołaczkowski M, Świerczek A, Pociecha K, Wyska E, Zygmunt M, Kazek G, Sałat K, Pawłowski M.
Abstract : A series of novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids designed using a structure-based computational approach was synthesized and assayed to evaluate their ability to block human TRPA1 channel and inhibit PDE4B/7A activity. We identified compounds 16 and 27 which showed higher potency against TRPA1 compared to HC-030031. In turn, compound 36 was the most promising multifunctional TRPA1 antagonist and PDE4B/7A dual inhibitor with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Compound 36 as a combined TRPA1/PDE4B/PDE7A ligand was characterized by a distinct binding mode in comparison to 16 and 27, in the given protein targets. The inhibition of both cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect of 36in vivo. Moreover, the potent anti-inflammatory and analgesic efficacy of 36 was observed in animal models of pain and inflammation (formalin test in mice and carrageenan-induced paw edema in rats). This compound also displayed significant antiallodynic properties in the early phase of chemotherapy-induced peripheral neuropathy in mice. In turn, the pure TRPA1 antagonists 16 and 27 revealed a statistically significant antiallodynic effect in the formalin test and in the von Frey test performed in both phases of oxaliplatin-induced allodynia. Antiallodynic activity of the test compounds 16, 27 and 36 was observed at a dose range comparable to that of the reference drug - pregabalin. In conclusion, the proposed approach of pain treatment based on the concomitant blocking of TRPA1 channel and PDE4B/7A inhibitory activity appears to be interesting research direction for the future search for novel analgesics.
|
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
|
6.88
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-2.29
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
8.94
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
8.02
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
24.16
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
5.45
%
|
|
|
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
|
-5.87
%
|
|
|
Inhibition of COX1 in human platelet rich plasma in assessed as inhibition of ADP-induced platelet aggregation at 10 uM incubated for 5 mins by turbidimetry based Born's method relative to control
|
Homo sapiens
|
25.0
%
|
|
Journal : J Med Chem
Title : Bioisosteric Development of Multitarget Nonsteroidal Anti-Inflammatory Drug-Carbonic Anhydrases Inhibitor Hybrids for the Management of Rheumatoid Arthritis.
Year : 2020
Volume : 63
Issue : 5
First Page : 2325
Last Page : 2342
Authors : Bua S, Lucarini L, Micheli L, Menicatti M, Bartolucci G, Selleri S, Di Cesare Mannelli L, Ghelardini C, Masini E, Carta F, Gratteri P, Nocentini A, Supuran CT.
Abstract : Multitarget nonsteroidal anti-inflammatory drug (NSAID)-carbonic anhydrase inhibitor (CAI) agents for the management of rheumatoid arthritis are reported. The evidence of the plasma stability of the amide-linked hybrids previously reported prompted us to investigate their pain-relieving mechanism of action. A bioisosteric amide to ester substitution yielded a series of derivatives showing potent target CAs inhibition and to undergo cleavage in rat or human plasma depending on the NSAID portion. A selection of derivatives were assayed <i>in vitro</i> to indirectly evaluate their effect on COX-1 and COX-2. MD simulations demonstrated that the entire hybrids are also able to efficiently bind the COX active site. In a rat model of RA, the most promising derivative (<b>5c</b>) showed major antihyperalgesic action compared with the equimolar coadministration of the single agents. The gathered data provided new insights on the action mechanism of these multitarget compounds, which induce markedly improved pain relief compared with the parent NSAIDs.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
11.21
%
|
|
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
|
0.0
%
|
|
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
|
0.0
%
|
|
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.
