|
Inhibition of proliferation measured by inhibition of [3H]thymidine incorporation by HMVEC-L cells
|
Homo sapiens
|
50.0
ug
|
|
Journal : J. Med. Chem.
Title : Novel esters and amides of nonsteroidal antiinflammatory carboxylic acids as antioxidants and antiproliferative agents.
Year : 1999
Volume : 42
Issue : 2
First Page : 267
Last Page : 276
Authors : Hellberg MR, Namil A, Delgado P, David KC, Kessler TL, Graff G, Haggard KS, Nixon JC.
Abstract : A series of phenolic antioxidant ester and amide derivatives of the nonsteroidal antiinflammatory drug naproxen was designed to have both antiinflammatory and cytoprotective activity. Compounds were evaluated in vitro both for antioxidant activity, as assessed indirectly by thiobarbituric acid reactive substance (TBARS) formation in a membrane lipid peroxidation assay, and for antiproliferative activity, as indexed by the inhibition of DNA synthesis in cultured human vascular endothelial cells. Compounds of this series exhibited potent antioxidant activity, with IC50 values (1.6-11.63 microM) 2-6-fold lower than that of Trolox (6-hydroxy-2,5, 7,8-tetramethylchroman-2-carboxylic acid) and 400-1300-fold lower than that of vitamin E. Structural modifications of the ester or amide substructure (5a and 6a) did not affect antioxidant activity, but methylation of the 6-hydroxy substituent resulted in compound 6f which was devoid of antioxidant activity. Although indistinguishable in antioxidant activity, the amide derivatives tended to be more potent as antiproliferative agents than the corresponding esters. The IC50's for the amide derivatives (3, 5a-e, 8) ranged from 2 to 7 microM, while the IC50's for the structurally related esters (1, 2a-c, 6a-e) ranged from 9 to 22 microM. Moreover, studies with compound 6a indicate that the observed inhibition of DNA synthesis is reversible, suggesting that the antiproliferative activity is due to a cytostatic rather than cytotoxic activity of the compounds. Thus, the antioxidant-naproxen derivatives represent a novel series of agents that both protect against free-radical damage and possess cytostatic activity in vascular endothelial cells. Studies are in progress to assess the utility of these compounds as potential components of an ocular irrigating solution.
|
In vitro inhibitory activity against Prostaglandin G/H synthase in rat neutrophils
|
None
|
60.0
nM
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents.
Year : 1986
Volume : 29
Issue : 6
First Page : 1099
Last Page : 1113
Authors : Blythin DJ, Kaminski JJ, Domalski MS, Spitler J, Solomon DM, Conn DJ, Wong SC, Verbiar LL, Bober LA, Chiu PJ.
Abstract : A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.
|
Compound was tested in vitro for inhibition of human platelet Prostaglandin G/H synthase 1 at 10 uM
|
None
|
350.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses and biological evaluation of two new naproxen analogs
Year : 1996
Volume : 6
Issue : 19
First Page : 2281
Last Page : 2282
Authors : Kyung Woon Jung, Janda KD, Sanfilippo PJ, Wachter M
|
Analgesic activity (50 mg/kg, sc)in phenylquinone-induced abdominal constriction assay(PAC)
|
Rattus norvegicus
|
54.0
%
|
|
Journal : J. Med. Chem.
Title : New cyclooxygenase-2/5-lipoxygenase inhibitors. 3. 7-tert-butyl-2, 3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: variations at the 5 position.
Year : 1998
Volume : 41
Issue : 18
First Page : 3515
Last Page : 3529
Authors : Janusz JM, Young PA, Ridgeway JM, Scherz MW, Enzweiler K, Wu LI, Gan L, Chen J, Kellstein DE, Green SA, Tulich JL, Rosario-Jansen T, Magrisso IJ, Wehmeyer KR, Kuhlenbeck DL, Eichhold TH, Dobson RL.
Abstract : We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position: amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.
|
Compound was tested in vivo for antiinflammatory activity against chronic adjuvant arthritic rat by prophylactic inhibition 2 degree paw after peroral administration of 1 mg/kg of dose
|
Rattus norvegicus
|
14.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents.
Year : 1986
Volume : 29
Issue : 6
First Page : 1099
Last Page : 1113
Authors : Blythin DJ, Kaminski JJ, Domalski MS, Spitler J, Solomon DM, Conn DJ, Wong SC, Verbiar LL, Bober LA, Chiu PJ.
Abstract : A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.
|
Compound was tested in vivo for antiinflammatory activity against chronic adjuvant arthritic rat by therapeutic inhibition 2 degree paw after peroral administration of 0.3 mg/kg of dose
|
Rattus norvegicus
|
27.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents.
Year : 1986
Volume : 29
Issue : 6
First Page : 1099
Last Page : 1113
Authors : Blythin DJ, Kaminski JJ, Domalski MS, Spitler J, Solomon DM, Conn DJ, Wong SC, Verbiar LL, Bober LA, Chiu PJ.
Abstract : A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.
|
Compound was tested in vivo for antiinflammatory activity against chronic adjuvant arthritic rat by therapeutic inhibition 2 degree paw after peroral administration of 1 mg/kg of dose
|
Rattus norvegicus
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents.
Year : 1986
Volume : 29
Issue : 6
First Page : 1099
Last Page : 1113
Authors : Blythin DJ, Kaminski JJ, Domalski MS, Spitler J, Solomon DM, Conn DJ, Wong SC, Verbiar LL, Bober LA, Chiu PJ.
Abstract : A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.
|
Compound was tested in vivo for antiinflammatory activity against chronic adjuvant arthritic rat by therapeutic inhibition 2 degree paw after peroral administration of 25 mg/kg of dose
|
Rattus norvegicus
|
58.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents.
Year : 1986
Volume : 29
Issue : 6
First Page : 1099
Last Page : 1113
Authors : Blythin DJ, Kaminski JJ, Domalski MS, Spitler J, Solomon DM, Conn DJ, Wong SC, Verbiar LL, Bober LA, Chiu PJ.
Abstract : A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.
|
Compound was tested in vivo for antiinflammatory activity against chronic adjuvant arthritic rat by therapeutic inhibition 2 degree paw after peroral administration of 3 mg/kg of dose
|
Rattus norvegicus
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents.
Year : 1986
Volume : 29
Issue : 6
First Page : 1099
Last Page : 1113
Authors : Blythin DJ, Kaminski JJ, Domalski MS, Spitler J, Solomon DM, Conn DJ, Wong SC, Verbiar LL, Bober LA, Chiu PJ.
Abstract : A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.
|
Compound was tested in vivo for antiinflammatory activity against chronic adjuvant arthritic rat by therapeutic inhibition 2 degree paw after peroral administration of 5 mg/kg of dose
|
Rattus norvegicus
|
44.0
%
|
|
Journal : J. Med. Chem.
Title : Antiinflammatory activity of substituted 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-triones. Atypical nonsteroidal antiinflammatory agents.
Year : 1986
Volume : 29
Issue : 6
First Page : 1099
Last Page : 1113
Authors : Blythin DJ, Kaminski JJ, Domalski MS, Spitler J, Solomon DM, Conn DJ, Wong SC, Verbiar LL, Bober LA, Chiu PJ.
Abstract : A novel class of antiinflammatory drugs, which are substituted derivatives of the fused tricyclic system 6-hydroxypyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione, is described. Synthetic procedures and structure determination with the assistance of X-ray crystallography are discussed. Semiempirical molecular orbital calculations are used to investigate the relative stability of the possible isomers and tautomers of the title compounds. A biological profile of the class, and of several of the more potent analogues, in several antiinflammatory models, including the adjuvant-induced arthritis and the collagen II models, is defined. Several members of the class are shown to possess extremely low ulcerogenic effects in spite of exhibiting cyclooxygenase inhibition. A preliminary bioavailability study of two of the lead structures is presented. The compounds 6-72 appear to constitute a class of drugs that shows interesting potential antiarthritic activity and also exhibits an activity profile different from that of the standard classical NSAI drugs, as determined by a comparison of the profile of this class of drug with that of several standard agents. Certain findings from toxicological studies have precluded the further development of compounds within this group, although related structural types are being investigated.
|
Percent inhibition was determined in vivo in male Dawley rats at a dose of 10 mg/kg by rat carrageenan-induced hyperalgesia assay
|
Rattus norvegicus
|
66.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib).
Year : 1997
Volume : 40
Issue : 9
First Page : 1347
Last Page : 1365
Authors : Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers RS, Rogier DJ, Yu SS, AndersonGD, Burton EG, Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen AW, Zhang YY, Isakson PC.
Abstract : A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
|
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 lipopolysaccharide-induced PGE-2 production at 10e-5 M
|
Mus musculus
|
99.0
%
|
|
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 CXCL8-induced chemotaxis of human polymorphonuclear cells at 10e-8 M
|
Homo sapiens
|
35.0
%
|
|
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
|
Homo sapiens
|
480.0
nM
|
|
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.
|
Anti-inflammatory activity against paw edema induced by carrageenan in fischer rat at 300 umol/kg, ip
|
Rattus norvegicus
|
51.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacochemical study of novel polyfunctional molecules combining anti-inflammatory, antioxidant, and hypocholesterolemic properties.
Year : 2006
Volume : 16
Issue : 4
First Page : 825
Last Page : 829
Authors : Doulgkeris CM, Galanakis D, Kourounakis AP, Tsiakitzis KC, Gavalas AM, Eleftheriou PT, Victoratos P, Rekka EA, Kourounakis PN.
Abstract : We have designed and synthesized a series of novel molecules having a residue of a classical NSAID and an antioxidant moiety, both attached through amide bonds to a known nootropic structure, an L-proline, trans-4-hydroxy-L-proline or DL-pipecolinic acid residue. The compounds were found to retain anti-inflammatory and antioxidant activities, to acquire hypocholesterolemic action, and to possess a greatly reduced gastrointestinal toxicity. The novel molecules could find useful applications, among others, in slowing the progression or delaying the onset of neurodegenerative diseases.
|
Inhibition of beta amyloid protein 42 in SH-SY5Y cell lines overexpressing SPA4CT at 300 uM
|
Homo sapiens
|
3.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent.
Year : 2006
Volume : 16
Issue : 8
First Page : 2219
Last Page : 2223
Authors : Stock N, Munoz B, Wrigley JD, Shearman MS, Beher D, Peachey J, Williamson TL, Bain G, Chen W, Jiang X, St-Jacques R, Prasit P.
Abstract : The subtle modification of a selection of Abeta42 inhibiting non-steroidal anti-inflammatory drugs (NSAIDs), through synthesis of the geminal dimethyl analogues, was anticipated to ablate their cyclooxygenase activity whilst maintaining Abeta42 inhibition. Methylflurbiprofen 6 exhibited similar in vitro Abeta42 inhibition to its parent NSAID Flurbiprofen and was further evaluated in the Tg2576 mouse model of Alzheimer's disease and an animal model of gastro-intestinal (GI) impairment, but proved unviable for further clinical development.
|
Inhibition of carrageenan-induced paw edema in Sprague-Dawley rat at 10 mg/kg, po
|
Rattus norvegicus
|
68.3
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists.
Year : 2007
Volume : 50
Issue : 1
First Page : 21
Last Page : 39
Authors : Kaila N, Janz K, DeBernardo S, Bedard PW, Camphausen RT, Tam S, Tsao DH, Keith JC, Nickerson-Nutter C, Shilling A, Young-Sciame R, Wang Q.
Abstract : Leukocyte recruitment of sites of inflammation and tissue injury involves leukocyte rolling along the endothelial wall, followed by firm adherence of the leukocyte, and finally transmigration of the leukocyte across cell junctions into the underlying tissue. The initial rolling step is mediated by the interaction of leukocyte glycoproteins containing active moieties such as sialyl Lewisx (sLex) with P-selectin expressed on endothelial cells. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of inflammatory diseases such as arthritis. High-throughput screening of the Wyeth chemical library identified the quinoline salicylic acid class of compounds (1) as antagonists of P-selectin, with potency in in vitro and cell-based assays far superior to that of sLex. Through iterative medicinal chemistry, we identified analogues with improved P-selectin activity, decreased inhibition of dihydrooratate dehydrogenase, and acceptable CYP profiles. Lead compound 36 was efficacious in the rat AIA model of rheumatoid arthritis.
|
Antiinflammatory activity against carrageenan-induced paw edema in rat at 30 mg/kg, po after 4 hrs
|
Rattus norvegicus
|
81.81
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of condensed heterocyclic 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives of naproxen.
Year : 2007
Volume : 17
Issue : 16
First Page : 4504
Last Page : 4508
Authors : Amir M, Kumar H, Javed SA.
Abstract : Some 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a-f and 5a-d) have been synthesized by cyclisation of 4-amino-5-[1-(6-methoxy-2-naphthyl)ethyl]-3-mercapto-(4H)-1,2,4-triazole (3) with various substituted aromatic acids and aryl/alkyl isothiocyanates, through a single step reaction. The target compounds were pharmacologically evaluated for their anti-inflammatory and analgesic potentials by known experimental models. Several of these showed significant activity. Very low ulcerogenic index was observed for potent compounds.
|
Analgesic activity in rat at 30 mg/kg, po
|
Rattus norvegicus
|
73.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of condensed heterocyclic 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives of naproxen.
Year : 2007
Volume : 17
Issue : 16
First Page : 4504
Last Page : 4508
Authors : Amir M, Kumar H, Javed SA.
Abstract : Some 6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a-f and 5a-d) have been synthesized by cyclisation of 4-amino-5-[1-(6-methoxy-2-naphthyl)ethyl]-3-mercapto-(4H)-1,2,4-triazole (3) with various substituted aromatic acids and aryl/alkyl isothiocyanates, through a single step reaction. The target compounds were pharmacologically evaluated for their anti-inflammatory and analgesic potentials by known experimental models. Several of these showed significant activity. Very low ulcerogenic index was observed for potent compounds.
|
Inhibition of COX1 at 100 uM
|
None
|
39.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and in silico biological activity evaluation of new N-substituted pyrazolo-oxazin-2-one systems.
Year : 2008
Volume : 16
Issue : 6
First Page : 3059
Last Page : 3066
Authors : Benaamane N, Nedjar-Kolli B, Bentarzi Y, Hammal L, Geronikaki A, Eleftheriou P, Lagunin A.
Abstract : Cyclisation of pyrazolo-beta-enaminones 3 readily obtained from 4-aceto acetyl pyrazol 2 with triphosgene led to the formation of N-substituted pyrazolo-1,3-oxazin-2-ones 4 in good yields. Estimation of pharmacotherapeutic potential, possible molecule mechanisms of action, toxic/side effects and interaction with drug-metabolizing enzymes were made for synthesised compounds on the basis of prediction of activity spectra for substances (PASS) prediction results and their analysis by PharmaExpert software. COX inhibition predicted by PASS was confirmed by experimental evaluation.
|
Antiinflammatory activity against carrageenan-induced paw edema in Sprague-Dawley rat at 10 mg/kg, iv
|
Rattus norvegicus
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Reactions of functionalized sulfonamides: application to lowering the lipophilicity of cytosolic phospholipase A2alpha inhibitors.
Year : 2009
Volume : 52
Issue : 4
First Page : 1156
Last Page : 1171
Authors : Chen L, Wang W, Lee KL, Shen MW, Murphy EA, Zhang W, Xu X, Tam S, Nickerson-Nutter C, Goodwin DG, Clark JD, McKew JC.
Abstract : The cPLA(2)alpha inhibitors we reported earlier were potent in both isolated enzyme and rat whole blood assays but have high plogD(7.4). To address these issues, reactions of electrophilic sulfonamides 9-12 were employed to incorporate various heterocyclic or heteroatom-based reagents into cPLA(2)alpha inhibitors. For example, reactions of 9 with sulfur nucleophiles such as thiophenol allowed rapid assembly of thioether analogues that were converted into the corresponding sulfoxides to afford less lipophilic derivatives. Reactions of 10 and 11 with various nitrogen nucleophiles, including aromatic heterocycles and aliphatic amines, provided an efficient way to introduce polarity into cPLA(2)alpha inhibitors. Finally, we report the first application of (2-formylphenyl)methanesulfonyl chloride, 13. Reductive amination of 2-formylphenylmethane sulfonamides allowed the introduction of various nitrogen nucleophiles. Several inhibitors obtained herein have plogD(7.4) values 3-4 units lower than previously synthesized compounds and yet maintain in vitro potency.
|
Inhibition of IgE-specific antigen-induced PGF2alpha release in rat MC9 cells at 0.20 uM
|
Rattus norvegicus
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Reactions of functionalized sulfonamides: application to lowering the lipophilicity of cytosolic phospholipase A2alpha inhibitors.
Year : 2009
Volume : 52
Issue : 4
First Page : 1156
Last Page : 1171
Authors : Chen L, Wang W, Lee KL, Shen MW, Murphy EA, Zhang W, Xu X, Tam S, Nickerson-Nutter C, Goodwin DG, Clark JD, McKew JC.
Abstract : The cPLA(2)alpha inhibitors we reported earlier were potent in both isolated enzyme and rat whole blood assays but have high plogD(7.4). To address these issues, reactions of electrophilic sulfonamides 9-12 were employed to incorporate various heterocyclic or heteroatom-based reagents into cPLA(2)alpha inhibitors. For example, reactions of 9 with sulfur nucleophiles such as thiophenol allowed rapid assembly of thioether analogues that were converted into the corresponding sulfoxides to afford less lipophilic derivatives. Reactions of 10 and 11 with various nitrogen nucleophiles, including aromatic heterocycles and aliphatic amines, provided an efficient way to introduce polarity into cPLA(2)alpha inhibitors. Finally, we report the first application of (2-formylphenyl)methanesulfonyl chloride, 13. Reductive amination of 2-formylphenylmethane sulfonamides allowed the introduction of various nitrogen nucleophiles. Several inhibitors obtained herein have plogD(7.4) values 3-4 units lower than previously synthesized compounds and yet maintain in vitro potency.
|
Inhibition of arachidonic acid-induced PGF2-alpha release in rat MC9 cells at 0.33 uM
|
Rattus norvegicus
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Reactions of functionalized sulfonamides: application to lowering the lipophilicity of cytosolic phospholipase A2alpha inhibitors.
Year : 2009
Volume : 52
Issue : 4
First Page : 1156
Last Page : 1171
Authors : Chen L, Wang W, Lee KL, Shen MW, Murphy EA, Zhang W, Xu X, Tam S, Nickerson-Nutter C, Goodwin DG, Clark JD, McKew JC.
Abstract : The cPLA(2)alpha inhibitors we reported earlier were potent in both isolated enzyme and rat whole blood assays but have high plogD(7.4). To address these issues, reactions of electrophilic sulfonamides 9-12 were employed to incorporate various heterocyclic or heteroatom-based reagents into cPLA(2)alpha inhibitors. For example, reactions of 9 with sulfur nucleophiles such as thiophenol allowed rapid assembly of thioether analogues that were converted into the corresponding sulfoxides to afford less lipophilic derivatives. Reactions of 10 and 11 with various nitrogen nucleophiles, including aromatic heterocycles and aliphatic amines, provided an efficient way to introduce polarity into cPLA(2)alpha inhibitors. Finally, we report the first application of (2-formylphenyl)methanesulfonyl chloride, 13. Reductive amination of 2-formylphenylmethane sulfonamides allowed the introduction of various nitrogen nucleophiles. Several inhibitors obtained herein have plogD(7.4) values 3-4 units lower than previously synthesized compounds and yet maintain in vitro potency.
|
Inhibition of sheep COX1 at 2.52 ug/mL
|
Ovis aries
|
57.96
%
|
|
Journal : J. Nat. Prod.
Title : Phenolic glycosides from Dirca palustris.
Year : 1999
Volume : 62
Issue : 11
First Page : 1558
Last Page : 1561
Authors : Ramsewak RS, Nair MG, DeWitt DL, Mattson WG, Zasada J.
Abstract : Five novel phenolic glycosides (1-5) were isolated from the MeOH extract of the dried twigs of Dirca palustris, as confirmed by their (1)H NMR, (13)C NMR, and MS data. Compounds 1-3 were not active against cyclooxygenase I (COX-I), but compound 4 (200 microg/mL) and compound 5 (125 microg/mL) showed 12.5 and 9.2% inhibition of the COX-I enzyme, respectively. Compounds 1-5 did not exhibit cyclooxygenase II (COX-II) enzyme inhibition. Compound 5 did not show any antioxidant activity using the liposome assay; however, compounds 1-4 displayed antioxidant activity at 60 microg/mL, with compound 2 being the most efficacious.
|
Antiinflammatory activity in mouse assessed as inhibition of phorbol myristyl palmitate-induced ear lobe edema at 0.1 umol/ear after 6 hrs relative to control
|
Mus musculus
|
28.0
%
|
|
Journal : J. Nat. Prod.
Title : Chamazulene carboxylic acid and matricin: a natural profen and its natural prodrug, identified through similarity to synthetic drug substances.
Year : 2006
Volume : 69
Issue : 7
First Page : 1041
Last Page : 1045
Authors : Ramadan M, Goeters S, Watzer B, Krause E, Lohmann K, Bauer R, Hempel B, Imming P.
Abstract : Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
|
Antiinflammatory activity in mouse assessed as inhibition of phorbol myristyl palmitate-induced ear lobe edema at 0.1 umol/ear after 24 hrs relative to control
|
Mus musculus
|
21.0
%
|
|
Journal : J. Nat. Prod.
Title : Chamazulene carboxylic acid and matricin: a natural profen and its natural prodrug, identified through similarity to synthetic drug substances.
Year : 2006
Volume : 69
Issue : 7
First Page : 1041
Last Page : 1045
Authors : Ramadan M, Goeters S, Watzer B, Krause E, Lohmann K, Bauer R, Hempel B, Imming P.
Abstract : Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
|
Antiinflammatory activity in mouse assessed as inhibition of phorbol myristyl palmitate-induced ear lobe edema at 0.1 umol/ear after 48 hrs relative to control
|
Mus musculus
|
18.0
%
|
|
Journal : J. Nat. Prod.
Title : Chamazulene carboxylic acid and matricin: a natural profen and its natural prodrug, identified through similarity to synthetic drug substances.
Year : 2006
Volume : 69
Issue : 7
First Page : 1041
Last Page : 1045
Authors : Ramadan M, Goeters S, Watzer B, Krause E, Lohmann K, Bauer R, Hempel B, Imming P.
Abstract : Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
|
Antiinflammatory activity in mouse assessed as inhibition of phorbol myristyl palmitate-induced ear lobe edema at 1 umol/ear after 6 hrs relative to control
|
Mus musculus
|
45.0
%
|
|
Journal : J. Nat. Prod.
Title : Chamazulene carboxylic acid and matricin: a natural profen and its natural prodrug, identified through similarity to synthetic drug substances.
Year : 2006
Volume : 69
Issue : 7
First Page : 1041
Last Page : 1045
Authors : Ramadan M, Goeters S, Watzer B, Krause E, Lohmann K, Bauer R, Hempel B, Imming P.
Abstract : Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
|
Antiinflammatory activity in mouse assessed as inhibition of phorbol myristyl palmitate-induced ear lobe edema at 1 umol/ear after 48 hrs relative to control
|
Mus musculus
|
25.0
%
|
|
Journal : J. Nat. Prod.
Title : Chamazulene carboxylic acid and matricin: a natural profen and its natural prodrug, identified through similarity to synthetic drug substances.
Year : 2006
Volume : 69
Issue : 7
First Page : 1041
Last Page : 1045
Authors : Ramadan M, Goeters S, Watzer B, Krause E, Lohmann K, Bauer R, Hempel B, Imming P.
Abstract : Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
|
Antiinflammatory activity in mouse assessed as inhibition of phorbol myristyl palmitate-induced ear lobe edema at 1 umol/ear after 24 hrs relative to control
|
Mus musculus
|
36.0
%
|
|
Journal : J. Nat. Prod.
Title : Chamazulene carboxylic acid and matricin: a natural profen and its natural prodrug, identified through similarity to synthetic drug substances.
Year : 2006
Volume : 69
Issue : 7
First Page : 1041
Last Page : 1045
Authors : Ramadan M, Goeters S, Watzer B, Krause E, Lohmann K, Bauer R, Hempel B, Imming P.
Abstract : Chamazulene carboxylic acid (1) is a natural profen with anti-inflammatory activity and a degradation product of proazulenic sesquiterpene lactones, e.g., matricin. Both 1 and proazulenes occur in chamomile (Matricaria recutita), yarrow (Achillea millefolium), and a few other Asteraceae species. It was isolated in improved yields, characterized physicochemically, and found to be an inhibitor of cyclooxygenase-2, but not of cyclooxygenase-1. It had anti-inflammatory activity in several animal models with local and systemic application. When human volunteers were given matricin orally, plasma levels of 1 were found to be in the micromolar range. Matricin was converted to 1 in artificial gastric fluid, but not in artificial intestinal fluid. Matricin and the yarrow proazulenes are proposed to be anti-inflammatory through conversion to 1. Intriguingly, the biological activity of the natural compound 1 was found because of its similarity to fully synthetic drug substances. This is the reverse process of the common lead function of natural compounds in drug discovery.
|
Inhibition of HSL in Wistar rat isolated fat cells at 10 uM by spectrophotometric assay
|
Rattus norvegicus
|
64.0
%
|
|
Journal : J. Med. Chem.
Title : Combining ligand-based pharmacophore modeling, quantitative structure-activity relationship analysis and in silico screening for the discovery of new potent hormone sensitive lipase inhibitors.
Year : 2008
Volume : 51
Issue : 20
First Page : 6478
Last Page : 6494
Authors : Taha MO, Dahabiyeh LA, Bustanji Y, Zalloum H, Saleh S.
Abstract : Hormone sensitive lipase (HSL) has been recently implicated in diabetes and obesity, prompting attempts to discover new HSL inhibitors. Toward this end, we explored the pharmacophoric space of HSL inhibitors using four diverse sets of compounds. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of yielding a self-consistent and predictive quantitative structure-activity relationship (QSAR) (r = 0.822, n = 99, F = 11.1, r LOO (2) = 0.521, r PRESS (2) against 23 external test inhibitors = 0.522). Interestingly, two pharmacophoric models emerged in the QSAR equation suggesting at least two binding modes. These pharmacophores were employed to screen the National Cancer Institute (NCI) list of compounds and our in-house built database of established drugs and agrochemicals. Active hits included the safe herbicidal agent bifenox (IC 50 = 0.43 microM) and the nonsteroidal anti-inflammatory naproxen (IC 50 = 1.20 microM). Our active hits undermined the traditional believe that HSL inhibitors should possess covalent bond-forming groups.
|
Inhibition of carrageenan-induced paw edema in Sprague-Dawley rat administered 2 hrs before carrageenan challenge at 10 mg/kg, po
|
Rattus norvegicus
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Indole cytosolic phospholipase A2 alpha inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid, efipladib.
Year : 2008
Volume : 51
Issue : 12
First Page : 3388
Last Page : 3413
Authors : McKew JC, Lee KL, Shen MW, Thakker P, Foley MA, Behnke ML, Hu B, Sum FW, Tam S, Hu Y, Chen L, Kirincich SJ, Michalak R, Thomason J, Ipek M, Wu K, Wooder L, Ramarao MK, Murphy EA, Goodwin DG, Albert L, Xu X, Donahue F, Ku MS, Keith J, Nickerson-Nutter CL, Abraham WM, Williams C, Hegen M, Clark JD.
Abstract : The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.
|
Inhibition of PGF2alpha production in mouse MC9 cells
|
Mus musculus
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Indole cytosolic phospholipase A2 alpha inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid, efipladib.
Year : 2008
Volume : 51
Issue : 12
First Page : 3388
Last Page : 3413
Authors : McKew JC, Lee KL, Shen MW, Thakker P, Foley MA, Behnke ML, Hu B, Sum FW, Tam S, Hu Y, Chen L, Kirincich SJ, Michalak R, Thomason J, Ipek M, Wu K, Wooder L, Ramarao MK, Murphy EA, Goodwin DG, Albert L, Xu X, Donahue F, Ku MS, Keith J, Nickerson-Nutter CL, Abraham WM, Williams C, Hegen M, Clark JD.
Abstract : The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.
|
Inhibition of PGF2apha production in arachidonic acid-stimulated mouse MC9 cells
|
Mus musculus
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : Indole cytosolic phospholipase A2 alpha inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid, efipladib.
Year : 2008
Volume : 51
Issue : 12
First Page : 3388
Last Page : 3413
Authors : McKew JC, Lee KL, Shen MW, Thakker P, Foley MA, Behnke ML, Hu B, Sum FW, Tam S, Hu Y, Chen L, Kirincich SJ, Michalak R, Thomason J, Ipek M, Wu K, Wooder L, Ramarao MK, Murphy EA, Goodwin DG, Albert L, Xu X, Donahue F, Ku MS, Keith J, Nickerson-Nutter CL, Abraham WM, Williams C, Hegen M, Clark JD.
Abstract : The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.
|
Inhibition of ovine COX1 at 100 uM
|
Ovis aries
|
72.0
%
|
|
Journal : J. Nat. Prod.
Title : Cyclooxygenase (COX)-1 and -2 inhibitory labdane diterpenes from Crassocephalum mannii.
Year : 2008
Volume : 71
Issue : 6
First Page : 1070
Last Page : 1073
Authors : Hegazy ME, Ohta S, Abdel-Latif FF, Albadry HA, Ohta E, Paré PW, Hirata T.
Abstract : Two new labdane diterpenes, 8alpha,19-dihydroxylabd-13 E-en-15-oic acid (1) and 13,14,15,16-tetranorlabdane-8alpha,12,14-triol (2), as well as an acetylated derivative, 8alpha-O-beta-D-glucopyranosyllabd-13 E-ene-15,19-diol-8alpha-2',3',4',6'-hexaacetate (3a), were isolated from the aerial parts of Crassocephalum mannii. The structures of 1, 2, and 3a were elucidated by spectroscopic data analysis. Selective inhibitory activity for 1 and 2 and their acetate derivatives, 1a and 2a, against cyclooxygenases (COX-1 and COX-2) was detected.
|
Inhibition of human recombinant COX2 at 100 uM
|
Homo sapiens
|
86.0
%
|
|
Journal : J. Nat. Prod.
Title : Cyclooxygenase (COX)-1 and -2 inhibitory labdane diterpenes from Crassocephalum mannii.
Year : 2008
Volume : 71
Issue : 6
First Page : 1070
Last Page : 1073
Authors : Hegazy ME, Ohta S, Abdel-Latif FF, Albadry HA, Ohta E, Paré PW, Hirata T.
Abstract : Two new labdane diterpenes, 8alpha,19-dihydroxylabd-13 E-en-15-oic acid (1) and 13,14,15,16-tetranorlabdane-8alpha,12,14-triol (2), as well as an acetylated derivative, 8alpha-O-beta-D-glucopyranosyllabd-13 E-ene-15,19-diol-8alpha-2',3',4',6'-hexaacetate (3a), were isolated from the aerial parts of Crassocephalum mannii. The structures of 1, 2, and 3a were elucidated by spectroscopic data analysis. Selective inhibitory activity for 1 and 2 and their acetate derivatives, 1a and 2a, against cyclooxygenases (COX-1 and COX-2) was detected.
|
Inhibition of recombinant Curvularia lunata trihydroxynaphthalene reductase
|
Cochliobolus lunatus
|
9.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Towards the first inhibitors of trihydroxynaphthalene reductase from Curvularia lunata: synthesis of artificial substrate, homology modelling and initial screening.
Year : 2008
Volume : 16
Issue : 11
First Page : 5881
Last Page : 5889
Authors : Brunskole M, Stefane B, Zorko K, Anderluh M, Stojan J, Lanisnik Rizner T, Gobec S.
Abstract : Trihydroxynaphthalene reductase (3HNR) is an essential enzyme in the biosynthesis of fungal melanin and it represents an emerging target for the development of new fungicides and antimicotics. To promote the discovery of new inhibitors, an improved chemical synthesis of the artificial substrate 2,3-dihydro-2,5-dihydroxy-4H-benzopyran-4-one (DDBO) was developed. A series of compounds were screened on 3HNR from Curvularia lunata, a known plant pathogen and an opportunistic human pathogen, and several structurally diverse hits were obtained. Homology modelling of 3HNR from C. lunata can explain their binding modes and will enable further structure-based design of new and improved inhibitors.
|
Antiinflammatory activity in Albino mouse assessed as inhibition of carrageenan-induced foot paw edema at 30 mg/kg, po administered 1 hr before carrageenan challenge measured after 2 hrs
|
Mus musculus
|
66.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzophenone-N-ethyl piperidine ether analogues--synthesis and efficacy as anti-inflammatory agent.
Year : 2009
Volume : 19
Issue : 7
First Page : 1887
Last Page : 1891
Authors : Khanum SA, Girish V, Suparshwa SS, Khanum NF.
Abstract : A sequence of substituted benzophenone-N-ethyl piperidine ether analogues has been synthesized and evaluated as orally active anti-inflammatory agents with reduced side effects. The anti-inflammatory and ulcerogenic activities of the compounds were compared with naproxen, indomethacin, and phenylbutazone. These analogues showed an interesting anti-inflammatory activity in carrageenan-induced foot pad edema assay. In the air-pouch test, some of the analogues reduced the total number of leukocytes of the exudate, which indicates inhibition of prostaglandin production. Side effects of the compounds were examined on gastric mucosa, in the liver and stomach. None of the compounds illustrated significant side effects compared with standard drugs like indomethacin and naproxen.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 40 mg/kg, po administered 30 mins before carrageenan challenge measured after 0.5 hrs
|
Rattus norvegicus
|
9.4
%
|
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 40 mg/kg, po administered 30 mins before carrageenan challenge measured after 0.5 hrs
|
Rattus norvegicus
|
9.4
%
|
|
Journal : Bioorg. Med. Chem.
Title : Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies.
Year : 2009
Volume : 17
Issue : 10
First Page : 3665
Last Page : 3670
Authors : Abdel-Azeem AZ, Abdel-Hafez AA, El-Karamany GS, Farag HH.
Abstract : The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6-8) of some acidic NSAIDs (1-3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6-8) were confirmed by IR, (1)H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6-8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t(1/2) approximately 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6-8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4days. In addition, docking of the mutual ester prodrugs (6-8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 40 mg/kg, po administered 30 mins before carrageenan challenge measured after 1 hr
|
Rattus norvegicus
|
16.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies.
Year : 2009
Volume : 17
Issue : 10
First Page : 3665
Last Page : 3670
Authors : Abdel-Azeem AZ, Abdel-Hafez AA, El-Karamany GS, Farag HH.
Abstract : The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6-8) of some acidic NSAIDs (1-3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6-8) were confirmed by IR, (1)H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6-8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t(1/2) approximately 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6-8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4days. In addition, docking of the mutual ester prodrugs (6-8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 40 mg/kg, po administered 30 mins before carrageenan challenge measured after 2 hrs
|
Rattus norvegicus
|
28.1
%
|
|
Journal : Bioorg. Med. Chem.
Title : Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies.
Year : 2009
Volume : 17
Issue : 10
First Page : 3665
Last Page : 3670
Authors : Abdel-Azeem AZ, Abdel-Hafez AA, El-Karamany GS, Farag HH.
Abstract : The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6-8) of some acidic NSAIDs (1-3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6-8) were confirmed by IR, (1)H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6-8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t(1/2) approximately 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6-8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4days. In addition, docking of the mutual ester prodrugs (6-8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 40 mg/kg, po administered 30 mins before carrageenan challenge measured after 3 hrs
|
Rattus norvegicus
|
46.9
%
|
|
Journal : Bioorg. Med. Chem.
Title : Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies.
Year : 2009
Volume : 17
Issue : 10
First Page : 3665
Last Page : 3670
Authors : Abdel-Azeem AZ, Abdel-Hafez AA, El-Karamany GS, Farag HH.
Abstract : The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6-8) of some acidic NSAIDs (1-3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6-8) were confirmed by IR, (1)H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6-8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t(1/2) approximately 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6-8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4days. In addition, docking of the mutual ester prodrugs (6-8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 40 mg/kg, po administered 30 mins before carrageenan challenge measured after 4 hrs
|
Rattus norvegicus
|
37.5
%
|
|
Journal : Bioorg. Med. Chem.
Title : Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies.
Year : 2009
Volume : 17
Issue : 10
First Page : 3665
Last Page : 3670
Authors : Abdel-Azeem AZ, Abdel-Hafez AA, El-Karamany GS, Farag HH.
Abstract : The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6-8) of some acidic NSAIDs (1-3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6-8) were confirmed by IR, (1)H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6-8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t(1/2) approximately 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6-8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4days. In addition, docking of the mutual ester prodrugs (6-8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 40 mg/kg, po administered 30 mins before carrageenan challenge measured after 5 hrs
|
Rattus norvegicus
|
18.8
%
|
|
Journal : Bioorg. Med. Chem.
Title : Chlorzoxazone esters of some non-steroidal anti-inflammatory (NSAI) carboxylic acids as mutual prodrugs: design, synthesis, pharmacological investigations and docking studies.
Year : 2009
Volume : 17
Issue : 10
First Page : 3665
Last Page : 3670
Authors : Abdel-Azeem AZ, Abdel-Hafez AA, El-Karamany GS, Farag HH.
Abstract : The discovery of the inducible isoform of cyclooxygenase enzyme (COX-2) spurred the search for anti-inflammatory agents devoid of the undesirable effects associated with classical NSAIDs. New chlorzoxazone ester prodrugs (6-8) of some acidic NSAIDs (1-3) were designed, synthesized and evaluated as mutual prodrugs with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (6-8) were confirmed by IR, (1)H NMR, mass spectroscopy (MS) and their purity was ascertained by TLC and elemental analyses. In vitro chemical stability revealed that the synthesized ester prodrugs (6-8) are chemically stable in hydrochloric acid buffer pH 1.2 as a non-enzymatic simulated gastric fluid (SGF) and in phosphate buffer pH 7.4 as non-enzymatic simulated intestinal fluid (SIF). In 80% human plasma, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis at relatively faster rate (t(1/2) approximately 37 and 34 min for prodrugs 6 and 7, respectively). Mutual ester prodrugs (6-8) were evaluated for their anti-inflammatory and muscle relaxation activities. Scanning electromicrographs of the stomach showed that the ester prodrugs induced very little irritancy in the gastric mucosa of rats after oral administration for 4days. In addition, docking of the mutual ester prodrugs (6-8) into COX-2 active site was conducted in order to predict the affinity and orientation of these prodrugs at the enzyme active site.
|
Binding affinity to beta-amyloid plaques
|
None
|
5.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel anilinophthalimide derivatives as potential probes for beta-amyloid plaque in the brain.
Year : 2010
Volume : 18
Issue : 3
First Page : 1337
Last Page : 1343
Authors : Duan XH, Qiao JP, Yang Y, Cui MC, Zhou JN, Liu BL.
Abstract : A group of novel 4,5-dianilinophthalimide derivatives has been synthesized in this study for potential use as beta-amyloid (Abeta) plaque probes. Staining of hippocampus tissue sections from Alzheimer's disease (AD) brain with the representative compound 9 indicated selective labeling of it to Abeta plaques. The binding affinity of radioiodinated [(125)I]9 for AD brain homogenates was 0.21 nM (K(d)), and of other derivatives ranged from 0.9 to 19.7 nM, except for N-methyl-4,5-dianilinophthalimide (K(i)>1000 nM). [(125)I]9 possessed the optimal lipophilicity with LogP value of 2.16, and its in vivo biodistribution in normal mice exhibited excellent initial brain uptake (5.16% ID/g at 2 min after injection) and a fast washout rate (0.56% ID/g at 60 min). The encouraging results suggest that this novel derivative of [(123)I]9 may have potential as an in vivo SPECT probe for detecting amyloid plaques in the brain.
|
Inhibition of ovine COX-1
|
Ovis aries
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Ethanesulfohydroxamic acid ester prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs): synthesis, nitric oxide and nitroxyl release, cyclooxygenase inhibition, anti-inflammatory, and ulcerogenicity index studies.
Year : 2011
Volume : 54
Issue : 5
First Page : 1356
Last Page : 1364
Authors : Huang Z, Velázquez CA, Abdellatif KR, Chowdhury MA, Reisz JA, DuMond JF, King SB, Knaus EE.
Abstract : The carboxylic acid group of the anti-inflammatory (AI) drugs indo-methacin, (S)-naproxen and ibuprofen was covalently linked via a two-carbon ethyl spacer to a sulfohydroxamic acid moiety (CH(2)CH(2)SO(2)NHOH) to furnish a group of hybrid ester prodrugs that release nitric oxide (NO) and nitroxyl (HNO). Biological data acquired for this hitherto unknown class of ethanesulfohydroxamic acid ester prodrugs showed (i) all compounds exhibited superior NO, but similar HNO, release properties relative to arylsulfohydroxamic acids, (ii) the (S)-naproxen and ibuprofen prodrug esters are more potent AI agents than their parent NSAID, (iii) the indomethacin prodrug ester, in contrast to indomethacin which is highly ulcerogenic, showed no visible stomach lesions [ulcer index (UI) = 0 for a 80 μmol/kg oral dose] while retaining potent AI activity, and iv) that the indomethacin prodrug ester, unlike indomethacin which is an ulcerogenic selective COX-1 inhibitor, is a selective COX-2 inhibitor (COX-2 selectivity index = 184) devoid of ulcerogenicity that is attributed to its high COX-2 SI and/or ability to release cytoprotective NO.
|
Antiinflammatory activity in rat assessed as inhibition of complete Freund's adjuvant-induced paw withdrawal threshold at 20 mg/kg, sc after 60 mins (Rvb = 4.8%)
|
Rattus norvegicus
|
23.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Decahydroquinoline amides as highly selective CB2 agonists: role of selectivity on in vivo efficacy in a rodent model of analgesia.
Year : 2011
Volume : 21
Issue : 8
First Page : 2359
Last Page : 2364
Authors : Manley PJ, Zartman A, Paone DV, Burgey CS, Henze DA, Della Penna K, Desai R, Leitl MD, Lemaire W, White RB, Yeh S, Urban MO, Kane SA, Hartman GD, Bilodeau MT, Trotter BW.
Abstract : A novel series of decahydroquinoline CB2 agonists is described. Optimization of the amide substituent led to improvements in CB2/CB1 selectivity as well as physical properties. Two key compounds were examined in the rat CFA model of acute inflammatory pain. A moderately selective CB2 agonist was active in this model. A CB2 agonist lacking functional CB1 activity was inactive in this model despite high in vivo exposure both peripherally and centrally.
|
Binding affinity to amyloid beta fibrils
|
None
|
5.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel imaging agents for β-amyloid plaque based on the N-benzoylindole core.
Year : 2011
Volume : 21
Issue : 18
First Page : 5594
Last Page : 5597
Authors : Yang Y, Duan XH, Deng JY, Jin B, Jia HM, Liu BL.
Abstract : We report the synthesis and evaluation of a series of N-benzoylindole derivatives as novel potential imaging agents for β-amyloid plaques. In vitro binding studies using Aβ(1-40) aggregates versus [(125)I]TZDM showed that all these derivatives demonstrated high binding affinities (K(i) values ranged from 8.4 to 121.6 nM). Moreover, two radioiodinated compounds [(125)I]7 and [(125)I]14 were prepared. Autoradiography for [(125)I]14 displayed intense and specific labeling of Aβ plaques in the brain sections of AD model mice (C57, APP/PS1) with low background. In vivo biodistribution in normal mice exhibited sufficient initial brain uptake for imaging (2.19% and 2.00%ID/g at 2 min postinjection for [(125)I]7 and [(125)I]14, respectively). Although additional modifications are necessary to improve brain uptake and clearance from the brain, the N-benzoylindole may be served as a backbone structure to develop novel β-amyloid imaging probes.
|
DRUGMATRIX: Cyclooxygenase COX-1 enzyme inhibition (substrate: Arachidonic acid)
|
Homo sapiens
|
211.0
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
|
Inhibition of human recombinant COX-2 assessed as PGF2alpha production at 200 uM by enzyme immunoassay
|
Homo sapiens
|
68.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Fragment-based design, docking, synthesis, biological evaluation and structure-activity relationships of 2-benzo/benzisothiazolimino-5-aryliden-4-thiazolidinones as cycloxygenase/lipoxygenase inhibitors.
Year : 2012
Volume : 47
First Page : 111
Last Page : 124
Authors : Eleftheriou P, Geronikaki A, Hadjipavlou-Litina D, Vicini P, Filz O, Filimonov D, Poroikov V, Chaudhaery SS, Roy KK, Saxena AK.
Abstract : Balanced modulation of several targets is one of the current strategies for the treatment of multi-factorial diseases. Based on the knowledge of inflammation mechanisms, it was inferred that the balanced inhibition of cyclooxygenase-1/cyclooxygenase-2/lipoxygenase might be a promising approach for treatment of such a multifactorial disease state as inflammation. Detection of fragments responsible for interaction with enzyme's binding site provides the basis for designing new molecules with increased affinity and selectivity. A new chemoinformatics approach was proposed and applied to create a fragment library that was used to design novel inhibitors of cycloxygenase-1/cycloxygenase-2/lipoxygenase enzymes. Potential binding sites were elucidated by docking. Synthesis of novel compounds, and the in vitro/in vivo biological testing confirmed the results of computational studies. The benzothiazolyl moiety was proved to be of great significance for developing more potent inhibitors.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 30 mg/kg after 2 hrs
|
Rattus norvegicus
|
71.7
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, pharmacological evaluation and docking studies of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs as COX-2 inhibitors.
Year : 2012
Volume : 22
Issue : 2
First Page : 820
Last Page : 823
Authors : Raghavendra NM, Jyothsna A, Venkateswara Rao A, Subrahmanyam CV.
Abstract : The existing NSAIDs having number of toxicities emphasises the need for discovery of new non-toxic anti-inflammatory agents. In this Letter, we present the simple two step chemical synthesis, in vivo pharmacological screening and docking study of few N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs. Different amino benzothiazoles were chloroacetylated and further reacted with substituted piperazines in presence of a base to get N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs (A1-C4). These compounds were evaluated for anti-inflammatory activity by carragenan induced paw oedema method. Promising compounds were screened for toxicity by evaluating the ulcerogenic potential. Molecular docking experiments were carried out against COX-2 enzyme using Surflex-Dock GeomX programme of Sybyl software on Dell T-1500 workstation to confirm the mechanism of action of active compounds among the series. In silico study reveal the binding interactions of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs with COX-2 protein and is in agreement with the in vivo anti-inflammatory activity.
|
Antiinflammatory activity in Wistar albino rat assessed as inhibition of carageenaan-induced paw edema at 45 mg/kg, po administered 1 hr prior to carageenaan-challenge measured at 4 hrs relative to control
|
Rattus norvegicus
|
81.23
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and pharmacological evaluation of pyrazolo[4,3-c]cinnoline derivatives as potential anti-inflammatory and antibacterial agents.
Year : 2012
Volume : 57
First Page : 176
Last Page : 184
Authors : Tonk RK, Bawa S, Chawla G, Deora GS, Kumar S, Rathore V, Mulakayala N, Rajaram A, Kalle AM, Afzal O.
Abstract : A series of pyrazolo[4,3-c]cinnoline derivatives was synthesized, characterized and evaluated for anti-inflammatory and antibacterial activity. Test compounds that exhibited good anti-inflammatory activity were further screened for their ulcerogenic and lipid peroxidation activity. Compounds 4d and 4l showed promising anti-inflammatory activity with reduced ulcerogenic and lipid peroxidation activity when compared to naproxen. Docking results of these two compounds with COX-2 (PDB ID: 1CX2) also exhibited a strong binding profile. Among the test derivatives, compound 4i displayed significant antibacterial property against gram-negative (Escherichia coli and Pseudomonas aeruginosa) and gram-positive (Staphylococcus aureus) bacteria. However, compound 4b emerged as the best dual anti-inflammatory-antibacterial agent in the present study.
|
Antiinflammatory activity in Wistar albino rat assessed as inhibition of carageenaan-induced paw edema at 45 mg/kg, po administered 1 hr prior to carageenaan-challenge measured at 3 hrs relative to control
|
Rattus norvegicus
|
78.84
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and pharmacological evaluation of pyrazolo[4,3-c]cinnoline derivatives as potential anti-inflammatory and antibacterial agents.
Year : 2012
Volume : 57
First Page : 176
Last Page : 184
Authors : Tonk RK, Bawa S, Chawla G, Deora GS, Kumar S, Rathore V, Mulakayala N, Rajaram A, Kalle AM, Afzal O.
Abstract : A series of pyrazolo[4,3-c]cinnoline derivatives was synthesized, characterized and evaluated for anti-inflammatory and antibacterial activity. Test compounds that exhibited good anti-inflammatory activity were further screened for their ulcerogenic and lipid peroxidation activity. Compounds 4d and 4l showed promising anti-inflammatory activity with reduced ulcerogenic and lipid peroxidation activity when compared to naproxen. Docking results of these two compounds with COX-2 (PDB ID: 1CX2) also exhibited a strong binding profile. Among the test derivatives, compound 4i displayed significant antibacterial property against gram-negative (Escherichia coli and Pseudomonas aeruginosa) and gram-positive (Staphylococcus aureus) bacteria. However, compound 4b emerged as the best dual anti-inflammatory-antibacterial agent in the present study.
|
Anti-inflammatory activity in Rattus norvegicus Wistar (rat) assessed as inhibition of carrageenan-induced edema volume at 50.0 mg/kg, po measured after 120 min
|
Rattus norvegicus
|
58.0
%
|
|
Journal : Med Chem Res
Title : Synthesis and evaluation of novel prodrugs of naproxen
Year : 2011
Volume : 20
Issue : 5
First Page : 648
Last Page : 655
Authors : Sharma PC, Yadav S, Pahwa R, Kaushik D, Jain S
|
Anti-inflammatory activity in Rattus norvegicus Wistar (rat) assessed as inhibition of carrageenan-induced edema volume at 50.0 mg/kg, po measured after 90 min
|
Rattus norvegicus
|
42.0
%
|
|
Journal : Med Chem Res
Title : Synthesis and evaluation of novel prodrugs of naproxen
Year : 2011
Volume : 20
Issue : 5
First Page : 648
Last Page : 655
Authors : Sharma PC, Yadav S, Pahwa R, Kaushik D, Jain S
|
Anti-inflammatory activity in Rattus norvegicus Wistar (rat) assessed as inhibition of carrageenan-induced edema volume at 50.0 mg/kg, po measured after 60 min
|
Rattus norvegicus
|
32.0
%
|
|
Journal : Med Chem Res
Title : Synthesis and evaluation of novel prodrugs of naproxen
Year : 2011
Volume : 20
Issue : 5
First Page : 648
Last Page : 655
Authors : Sharma PC, Yadav S, Pahwa R, Kaushik D, Jain S
|
Analgesic activity in Mus musculus (mouse) assessed as inhibition of acetic acid-induced writhing at 50 mg/kg, po pretreated 1 hr before acetic acid challenge
|
Mus musculus
|
61.36
%
|
|
Journal : Med Chem Res
Title : Synthesis and evaluation of novel prodrugs of naproxen
Year : 2011
Volume : 20
Issue : 5
First Page : 648
Last Page : 655
Authors : Sharma PC, Yadav S, Pahwa R, Kaushik D, Jain S
|
Anti-inflammatory activity in Rattus norvegicus Wistar (rat) assessed as inhibition of carrageenan-induced edema volume at 50.0 mg/kg, po measured after 30 min
|
Rattus norvegicus
|
10.0
%
|
|
Journal : Med Chem Res
Title : Synthesis and evaluation of novel prodrugs of naproxen
Year : 2011
Volume : 20
Issue : 5
First Page : 648
Last Page : 655
Authors : Sharma PC, Yadav S, Pahwa R, Kaushik D, Jain S
|
Inhibition of Homo sapiens (human) recombinant cyclooxygenase-2 assessed as formation of PGF2a at 200 uM by enzyme immunoassay
|
Homo sapiens
|
88.0
%
|
|
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
|
52.0
%
|
|
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
|
Anti-inflammatory activity in Rattus norvegicus Fischer-344 (rat) assessed as inhibition of carrageenan-induced paw oedema at 0.30 mmol/kg, ip administered 5 min before FCA challenge measured after 3 hr relative to control
|
Rattus norvegicus
|
51.0
%
|
|
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
|
Competitive inhibition of human recombinant COX2 assessed as inhibition of PGF2a production at 200 uM by enzyme immunoassay
|
Homo sapiens
|
65.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of some 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones as dual anti-inflammatory/antimicrobial agents.
Year : 2013
Volume : 21
Issue : 2
First Page : 532
Last Page : 539
Authors : Apostolidis I, Liaras K, Geronikaki A, Hadjipavlou-Litina D, Gavalas A, Soković M, Glamočlija J, Ćirić A.
Abstract : As a part of our ongoing studies in developing new derivatives as dual antimicrobial/anti-inflammatory agents we describe the synthesis of novel 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones. All newly synthesized compounds were tested for their anti-inflammatory activity using carrageenan mouse paw edema bioassay. Their COX-1/LOX inhibitory activities were also determined. Moreover, all compounds were evaluated for their antimicrobial and antifungal activities against a panel of Gram positive, Gram negative bacteria and moulds. All tested compounds exhibited better antimicrobial activity than commercial drugs, bifonazole, ketoconazole, ampicillin and streptomycin.
|
Inhibition of ovine COX1 assessed as inhibition of PGF2a production by enzyme immunoassay
|
Ovis aries
|
46.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of some 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones as dual anti-inflammatory/antimicrobial agents.
Year : 2013
Volume : 21
Issue : 2
First Page : 532
Last Page : 539
Authors : Apostolidis I, Liaras K, Geronikaki A, Hadjipavlou-Litina D, Gavalas A, Soković M, Glamočlija J, Ćirić A.
Abstract : As a part of our ongoing studies in developing new derivatives as dual antimicrobial/anti-inflammatory agents we describe the synthesis of novel 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones. All newly synthesized compounds were tested for their anti-inflammatory activity using carrageenan mouse paw edema bioassay. Their COX-1/LOX inhibitory activities were also determined. Moreover, all compounds were evaluated for their antimicrobial and antifungal activities against a panel of Gram positive, Gram negative bacteria and moulds. All tested compounds exhibited better antimicrobial activity than commercial drugs, bifonazole, ketoconazole, ampicillin and streptomycin.
|
Inhibition of ovine COX1
|
Ovis aries
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hybrid fluorescent conjugates of COX-2 inhibitors: search for a COX-2 isozyme imaging cancer biomarker.
Year : 2013
Volume : 23
Issue : 1
First Page : 163
Last Page : 168
Authors : Bhardwaj A, Kaur J, Sharma SK, Huang Z, Wuest F, Knaus EE.
Abstract : The observation that the cyclooxygenase-2 (COX-2) isozyme is over-expressed in multiple types of cancer, relative to that in adjacent non-cancerous tissue, prompted this investigation to prepare a group of hybrid fluorescent conjugates wherein the COX inhibitors ibuprofen, (S)-naproxen, acetyl salicylic acid, a chlororofecoxib analog and celecoxib were coupled via a linker group to an acridone, dansyl or rhodamine B fluorophore. Within this group of compounds, the ibuprofen-acridone conjugate (10) showed potent and selective COX-2 inhibition (COX-2 IC(50)=0.67 μM; SI=110.6), but its fluorescence emission (λ(em)=417, 440 nm) was not suitable for fluorescent imaging of cancer cells that over-express the COX-2 isozyme. In comparison, the celecoxib-dansyl conjugate (25) showed a slightly lower COX-2 potency and selectivity (COX-2 IC(50)=1.1 μM; SI>90) than the conjugate 10, and it possesses a better fluorescence emission (λ(em)=500 nm). Ultimately, a celecoxib-rhodamine B conjugate (28) that exhibited moderate COX-2 potency and selectivity (COX-2 IC(50)=3.9 μM; SI>25) having the best fluorescence emission (λ(em)=580 nm) emerged as the most promising biomarker for fluorescence imaging using a colon cancer cell line that over-expresses the COX-2 isozyme.
|
Antiinflammatory activity in Duncan Hartley guinea pig assessed as Inhibition of carrageenan-induced PGE2 production at 10 mg/kg, po
|
Cavia porcellus
|
60.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation.
Year : 2013
Volume : 23
Issue : 4
First Page : 1114
Last Page : 1119
Authors : Arhancet GB, Walker DP, Metz S, Fobian YM, Heasley SE, Carter JS, Springer JR, Jones DE, Hayes MJ, Shaffer AF, Jerome GM, Baratta MT, Zweifel B, Moore WM, Masferrer JL, Vazquez ML.
Abstract : Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure-activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies.
|
Antiinflammatory activity in Kunming mouse assessed as inhibition of xylene-induced auricle tumefaction at 200 uM/kg, tid qd for 5 days relative to control
|
Mus musculus
|
30.63
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of enzymatically cleavable NSAIDs prodrugs derived from self-immolative dendritic scaffolds for the treatment of inflammatory diseases.
Year : 2013
Volume : 21
Issue : 14
First Page : 4192
Last Page : 4200
Authors : Wei J, Shi J, Zhang J, He G, Pan J, He J, Zhou R, Guo L, Ouyang L.
Abstract : It has been reported that delivery systems based on dendritic prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) improved the properties of drug molecules and reduced the side effects and irritation on the gastric mucosa. To find a more effective way in NSAIDs dendritic prodrugs, in this paper, three different dendritic scaffolds of enzymatically cleavable naproxen conjugates have been synthesized in a convergent approach and well characterized by NMR and MS techniques. These self-immolative dendritic NISADs prodrugs programmed to release multiple molecules of the potent naproxen after a single enzymatic activation step, and in 50% human plasma, the drug released from the compound T3 reaching 47.3% after 24h in vitro assay. Moreover, all prodrugs were also found to maintain more significant anti-inflammatory activity, no significant cytotoxicity against HEK293 cells and less degree of ulcerogenic potential in vivo than their monomeric counterpart naproxen. These results provided an effective entry to the development of new dendritic NSAIDs prodrugs.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
114.77
%
|
|
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
|
103.46
%
|
|
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 bovine COX-1 assessed as PGF2-alpha formation using arachidonic acid as substrate at 20 uM by enzyme immunoassay
|
Bos taurus
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Design of novel potent antihyperlipidemic agents with antioxidant/anti-inflammatory properties: exploiting phenothiazine's strong antioxidant activity.
Year : 2014
Volume : 57
Issue : 6
First Page : 2568
Last Page : 2581
Authors : Matralis AN, Kourounakis AP.
Abstract : Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis.
|
Inhibition of human recombinant COX-2 assessed as PGF2-alpha formation using arachidonic acid as substrate at 20 uM by enzyme immunoassay
|
Homo sapiens
|
55.0
%
|
|
Journal : J. Med. Chem.
Title : Design of novel potent antihyperlipidemic agents with antioxidant/anti-inflammatory properties: exploiting phenothiazine's strong antioxidant activity.
Year : 2014
Volume : 57
Issue : 6
First Page : 2568
Last Page : 2581
Authors : Matralis AN, Kourounakis AP.
Abstract : Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis.
|
In vivo antiinflammatory activity in mouse assessed as decrease in carrageenan-induced paw edema at 0.30 mmol/kg, ip administered immediately after carrageenan injection measured after 3.5 hrs
|
Mus musculus
|
51.0
%
|
|
Journal : J. Med. Chem.
Title : Design of novel potent antihyperlipidemic agents with antioxidant/anti-inflammatory properties: exploiting phenothiazine's strong antioxidant activity.
Year : 2014
Volume : 57
Issue : 6
First Page : 2568
Last Page : 2581
Authors : Matralis AN, Kourounakis AP.
Abstract : Because atherosclerosis is an inflammatory process involving a series of pathological events such as dyslipidemia, oxidative stress, and blood clotting mechanisms, we hereby report the synthesis and evaluation of novel compounds in which antioxidant, anti-inflammatory, and squalene synthase (SQS) inhibitory/hypolipidemic activities are combined in simple molecules through design. The coupling of two different pharmacophores afforded compounds 1-12, whose biological profile was markedly improved compared to those of parent lead structures (i.e., the hypolipidemic 2-hydroxy-2-aryl-(benzo)oxa(or thia)zine and the antioxidant phenothiazine). Most derivatives strongly inhibited in vitro microsomal lipid and LDL peroxidation, exhibiting potent free-radical scavenging activity. They further significantly inhibited SQS activity and showed remarkable antidyslipidemic activity in vivo in animal models of acute and high-fat-induced hyperlipidemia. Finally, several compounds showed anti-inflammatory activity in vitro, inhibiting cycloxygenase (COX-1/2) activity. The multimodal properties of the new compounds and especially their combined antioxidant/SQS/COX inhibitory activity render them interesting lead compounds for further evaluation against atherosclerosis.
|
Antiinflammatory activity in mouse assessed as inhibition of xylene-induced ear swelling at 150 mg/kg, ig administered 90 mins prior to xylene challenge measured after 30 mins
|
Mus musculus
|
36.65
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of novel limonin derivatives as anti-inflammatory and analgesic agents with high water solubility.
Year : 2014
Volume : 24
Issue : 7
First Page : 1851
Last Page : 1855
Authors : Yang Y, Wang X, Zhu Q, Gong G, Luo D, Jiang A, Yang L, Xu Y.
Abstract : A novel series of water-soluble derivatives of limonin were synthesized by introducing various tertiary amines onto the C (7)-position of limonin. Ten target compounds were characterized and screened for their anti-inflammatory and analgesic activity in vivo. Compound 3c exhibited the strongest analgesic and anti-inflammatory activity among the limonin and its derivatives tested; its analgesic activity is more potent than that of aspirin and its anti-inflammatory activity is stronger than that of naproxen.
|
Antiinflammatory activity in rabbit assessed as inhibition of edema at 200 ug per site by reversed passive arthus test
|
Oryctolagus cuniculus
|
55.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiinflammatory activity of cis-4,5,6,7,8,8a,9-hexahydro-alpha-methyl-5H-fluorene-2-acetic acid.
Year : 1977
Volume : 20
Issue : 5
First Page : 726
Last Page : 728
Authors : Sprague PW, Heikes JE.
|
Antiinflammatory activity in Wistar rat mycobacterial adjuvant-induced arthritis model assessed as inhibition of swelling at 30 mg/kg/day, po measured on day 14 relative to control
|
Rattus norvegicus
|
65.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiinflammatory activity of 6-oxo-1-(beta-D-ribofuranosyl)nocotinic acid and related derivatives.
Year : 1978
Volume : 21
Issue : 5
First Page : 427
Last Page : 430
Authors : Miyai K, Tolman RL, Robins RK, Cheng CC.
Abstract : 5-Substituted 1-(beta-D-ribofuranosyl)pyridine-2-ones (6-oxonicotinic acid nucleosides) were prepared by direct glycosylation of 5-ntrio-, 5-carbomethoxy-, 5-carboxamido-, 5-amino, 5-carbobenzyloxyamino-, and 5-acetamido-2-trimethylsilyloxy or corresponding 2-methoxypyridine derivatives by the Hilbert-Johnson method. The glycosylation products were deblocked by conventional procedures and substituents at the 5 position were modified to give the 5-carboxamide, carboxyhydrazide, and carboxylic acid. Only 1-(beta-D-ribofuranosyl)pyridin-2-one-5-carboxylic acid [1-(beta-D-ribofuranosyl)-6-oxonicotinic acid (12), showed significant activity in treating adjuvant-induced arthritis in rats.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of cotton pellet-induced granuloma formation at 30 mg/kg, po after 5 days relative to control
|
Rattus norvegicus
|
46.0
%
|
|
Journal : J. Med. Chem.
Title : 4-(6-Methoxy-2-naphthyl)butan-2-one and related analogues, a novel structural class of antiinflammatory compounds.
Year : 1978
Volume : 21
Issue : 12
First Page : 1260
Last Page : 1264
Authors : Goudie AC, Gaster LM, Lake AW, Rose CJ, Freeman PC, Hughes BO, Miller D.
Abstract : A series of compounds related to 4-(6-methoxy-2-naphthyl)butan-2-one has been prepared and tested for antiinflammatory activity by the cotton pellet granuloma method. Compounds possessing a small lipophilic group such as methoxyl, methyl, or chloro in the 6 position in conjunction with a butan-2-one side chain in the 2 position of the naphthalene ring were most active. The indtroduction of a methyl group along the side chain was invariably deleterious. Good activity was generally retained by forming esters of a butan-2-ol side chain.
|
Antiinflammatory activity in rat assessed as inhibition of carrageenan-induced paw edema at 6 mg/kg, po relative to control
|
Rattus norvegicus
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : 4-(6-Methoxy-2-naphthyl)butan-2-one and related analogues, a novel structural class of antiinflammatory compounds.
Year : 1978
Volume : 21
Issue : 12
First Page : 1260
Last Page : 1264
Authors : Goudie AC, Gaster LM, Lake AW, Rose CJ, Freeman PC, Hughes BO, Miller D.
Abstract : A series of compounds related to 4-(6-methoxy-2-naphthyl)butan-2-one has been prepared and tested for antiinflammatory activity by the cotton pellet granuloma method. Compounds possessing a small lipophilic group such as methoxyl, methyl, or chloro in the 6 position in conjunction with a butan-2-one side chain in the 2 position of the naphthalene ring were most active. The indtroduction of a methyl group along the side chain was invariably deleterious. Good activity was generally retained by forming esters of a butan-2-ol side chain.
|
Antinociceptive activity against CD-1 mouse assessed as licking of hind paw or jumping at 100 mg/kg, po after 90 mins
|
Mus musculus
|
36.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, antinociceptive and anti-inflammatory effects of porphyrins.
Year : 2015
Volume : 23
Issue : 10
First Page : 2529
Last Page : 2537
Authors : Alonso-Castro AJ, Zapata-Morales JR, Hernández-Munive A, Campos-Xolalpa N, Pérez-Gutiérrez S, Pérez-González C.
Abstract : Porphyrins are natural compounds with several biological activities. We report the synthesis and the evaluation of the anti-inflammatory and antinociceptive effects of 4 porphyrins: 5,10,15,20-tetraphenylporphyrin (TPP), 5,10,15,20-tetra(4'-fluorophenyl)porphyrin (TpFPP), 5,10,15,20-tetra(4'-chlorophenyl)porphyrin (TpClPP), and 5,10,15,20-tetra(4'-bromophenyl)porphyrin (TpBrPP). The in vitro anti-inflammatory effects were evaluated on heat-induced hemolysis. The antinociceptive effects were evaluated using the hot plate and formalin tests. The in vivo anti-inflammatory assays were tested on the acute and chronic TPA (12-O-tetradecanoylphorbol 13-acetate) method to induce ear edema. The anti-arthritic effects were evaluated using carrageenan kaolin induced arthritis (CKIA). All porphyrins inhibited hemolysis with similar potency than naproxen (NPX). In the antinociceptive tests, all porphyrins tested at 200mg/kg showed similar effects compared to 100mg/kg NPX. In the in vivo anti-inflammatory acute assay, only three porphyrins (TPP, TpFPP and TpBrPP) decreased inflammation with similar activity than 2mg/ear indomethacin (IND). Further anti-inflammatory experiments were carried out with TPP, TpFPP and TpBrPP. In the in vivo anti-inflammatory chronic assay, porphyrins decreased inflammation with similar activity than 8mg/kg IND. Porphyrins tested at 200mg/kg showed anti-arthritic effects. The antinociceptive, anti-inflammatory and arthritic activities of porphyrins suggest that these compounds might be a good alternative for the treatment of inflammatory diseases.
|
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
|
11.0
%
|
|
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.
|
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
|
11.0
%
|
|
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.
|
Inhibition of COX in human Mahlavu cells after 48 hrs by fluorometric assay
|
Homo sapiens
|
70.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel triazolothiadiazines act as potent anticancer agents in liver cancer cells through Akt and ASK-1 proteins.
Year : 2016
Volume : 24
Issue : 4
First Page : 858
Last Page : 872
Authors : Aytaç PS, Durmaz I, Houston DR, Çetin-Atalay R, Tozkoparan B.
Abstract : Newly designed triazolothiadiazines incorporating with structural motifs of nonsteroidal analgesic anti-inflammatory drugs were synthesized and screened for their bioactivity against epithelial cancer cells. Compounds with bioactivities less then ∼5μM (IC50) were further analyzed and showed to induce apoptotic cell death and SubG1 cell cycle arrest in liver cancer cells. Among this group, two compounds (1g and 1h) were then studied to identify the mechanism of action. These molecules triggered oxidative stress induced apoptosis through ASK-1 protein activation and Akt protein inhibition as demonstrated by downstream targets such as GSK3β, β-catenin and cyclin D1. QSAR and molecular docking models provide insight into the mechanism of inhibition and indicate the optimal direction of future synthetic efforts. Furthermore, molecular docking results were confirmed with in vitro COX bioactivity studies. This study demonstrates that the novel triazolothiadiazine derivatives are promising drug candidates for epithelial cancers, especially liver cancer.
|
Inhibition of COX in human HuH7 cells after 48 hrs by fluorometric assay
|
Homo sapiens
|
70.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel triazolothiadiazines act as potent anticancer agents in liver cancer cells through Akt and ASK-1 proteins.
Year : 2016
Volume : 24
Issue : 4
First Page : 858
Last Page : 872
Authors : Aytaç PS, Durmaz I, Houston DR, Çetin-Atalay R, Tozkoparan B.
Abstract : Newly designed triazolothiadiazines incorporating with structural motifs of nonsteroidal analgesic anti-inflammatory drugs were synthesized and screened for their bioactivity against epithelial cancer cells. Compounds with bioactivities less then ∼5μM (IC50) were further analyzed and showed to induce apoptotic cell death and SubG1 cell cycle arrest in liver cancer cells. Among this group, two compounds (1g and 1h) were then studied to identify the mechanism of action. These molecules triggered oxidative stress induced apoptosis through ASK-1 protein activation and Akt protein inhibition as demonstrated by downstream targets such as GSK3β, β-catenin and cyclin D1. QSAR and molecular docking models provide insight into the mechanism of inhibition and indicate the optimal direction of future synthetic efforts. Furthermore, molecular docking results were confirmed with in vitro COX bioactivity studies. This study demonstrates that the novel triazolothiadiazine derivatives are promising drug candidates for epithelial cancers, especially liver cancer.
|
Binding affinity to Influenza A virus nucleoprotein by surface plasmon resonance analysis
|
influenza A virus
|
250.0
nM
|
|
Journal : J Med Chem
Title : From Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A Virus.
Year : 2018
Volume : 61
Issue : 16
First Page : 7202
Last Page : 7217
Authors : Dilly S, Fotso Fotso A, Lejal N, Zedda G, Chebbo M, Rahman F, Companys S, Bertrand HC, Vidic J, Noiray M, Alessi MC, Tarus B, Quideau S, Riteau B, Slama-Schwok A.
Abstract : The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. We previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here we designed and synthesized two new series of naproxen analogues called derivatives 2, 3, and 4 targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Derivative 2 presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Derivative 4 also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivatives 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
2.49
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Anti-inflammatory activity in C57BL/6 mouse assessed as inhibition of carrageenan-induced hind paw edema treated immediately after carrageenan challenge measured after 3.5 hrs relative to control
|
Mus musculus
|
51.0
%
|
|
Journal : ACS Med Chem Lett
Title : Optimizing the Pharmacological Profile of New Bifunctional Antihyperlipidemic/Antioxidant Morpholine Derivatives.
Year : 2019
Volume : 10
Issue : 1
First Page : 98
Last Page : 104
Authors : Matralis AN, Kourounakis AP.
Abstract : Among the causal risk factors directly promoting the development of coronary and peripheral atherosclerosis are reactive oxygen species and elevated low-density lipoprotein plasma levels. We hereby designed new potent squalene synthase (SQS) inhibitors that may simultaneously tackle the oxidative stress induced by lipid peroxidation. Using previously developed morpholine derivatives as a starting point, we conducted extensive structural changes by either substituting or modifying the morpholine ring, aiming at an optimal SQS-antioxidant pharmacological profile. Compounds <b>2</b>, <b>3</b>, and <b>7</b> emerged as the most potent bifunctional analogues, displaying IC<sub>50</sub> values for SQS inhibition of 0.014, 0.16, and 0.51 μΜ, respectively, and further significantly decreasing lipid peroxidation of hepatic microsomal membranes. The aforementioned activities were also confirmed <i>in vivo</i> since the most promising derivative <b>2</b> exhibited a remarkable antihyperlipidemic and antioxidant effect. In conclusion, rational drug design accompanied by structure-activity relationship studies led to compounds combining improved antioxidant and antihyperlipidemic activity that may serve as multifunctional agents against atherosclerosis.
|
Anti-inflammatory activity in rat assessed as inhibition of carrageenan-induced paw edema relative to control
|
Rattus norvegicus
|
85.02
%
|
|
Journal : Eur J Med Chem
Title : Naphthalene, a versatile platform in medicinal chemistry: Sky-high perspective.
Year : 2019
Volume : 161
First Page : 252
Last Page : 276
Authors : Makar S, Saha T, Singh SK.
Abstract : Naphthalene, a cytotoxic moiety, is an extensively explored aromatic conjugated system with applications in various pathophysiological conditions viz. anticancer, antimicrobial, anti-inflammatory, antiviral, antitubercular, antihypertensive, antidiabetic, anti-neurodegenerative, antipsychotic, anticonvulsant, antidepressant. Naphthalene epoxides and naphthoquinones are most reactive metabolites of naphthalene and are responsible for the covalent interaction with cysteine amino acid of cellular proteins for cytotoxic nature. Many naphthalene derived bioactive phytoconstituents are present in nature including podophyllotoxins (Etoposide, teniposide), bis-ANS 82, Rifampicin, Justiprocumin A, B, Patentiflorin A. The naphthalene-based molecules, viz. Naphyrone, tolnaftate, naftifine, nafcillin, terbinafine, propranolol, nabumetone, nafimidone, naproxen, duloxetine, lasofoxifene, bedaquiline etc. have also been approved by FDA and are being marketed as therapeutics. Thus, the naphthalene scaffold emerges as an important building block in drug discovery owing to its broad spectrum of biological activities through varying structural modifications. This review incorporates the pharmacological aspects of different types of chemically modified naphthalene-based molecules along with their activity profile. This compiled information may serve as a benchmark for the alteration of existing ligands to design novel potent molecules with lesser side effects.
|
Inhibition of human recombinant AKR1C3 using S-tetralol as substrate assessed as reduction in NADP+-dependent S-tetralol oxidation preincubated for 10 mins followed by protein addition by fluorometric assay
|
Homo sapiens
|
180.0
nM
|
|
Journal : J Med Chem
Title : Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor.
Year : 2016
Volume : 59
Issue : 16
First Page : 7431
Last Page : 7444
Authors : Adeniji A, Uddin MJ, Zang T, Tamae D, Wangtrakuldee P, Marnett LJ, Penning TM.
Abstract : Type 5 17β-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Δ(4)-androstene-3,17-dione and 5α-androstane-3,17-dione to testosterone (T) and 5α-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3. We examined a series of naproxen analogues and find that (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid (in which the methyl group of R-naproxen was replaced by an ethyl group) acts as a potent AKR1C3 inhibitor that displays selectivity for AKR1C3 over other AKR1C enzymes. This compound was devoid of inhibitory activity on COX isozymes and blocked AKR1C3 mediated production of T and induction of PSA in LNCaP-AKR1C3 cells as a model of a CRPC cell line. R-Profens are substrate selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R-profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease.
|
Inhibition of COX1 in ram seminal vesicles using arachidonic acid as substrate assessed as reduction in PGH2 conversion to PGG2 by measuring TMPD oxidation preincubated for 5 mins followed by substrate/TMPD addition measured for 5 mins by colorimetric assay
|
Ovis aries
|
61.0
nM
|
|
Journal : J Med Chem
Title : Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor.
Year : 2016
Volume : 59
Issue : 16
First Page : 7431
Last Page : 7444
Authors : Adeniji A, Uddin MJ, Zang T, Tamae D, Wangtrakuldee P, Marnett LJ, Penning TM.
Abstract : Type 5 17β-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Δ(4)-androstene-3,17-dione and 5α-androstane-3,17-dione to testosterone (T) and 5α-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3. We examined a series of naproxen analogues and find that (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid (in which the methyl group of R-naproxen was replaced by an ethyl group) acts as a potent AKR1C3 inhibitor that displays selectivity for AKR1C3 over other AKR1C enzymes. This compound was devoid of inhibitory activity on COX isozymes and blocked AKR1C3 mediated production of T and induction of PSA in LNCaP-AKR1C3 cells as a model of a CRPC cell line. R-Profens are substrate selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R-profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease.
|
Inhibition of COX2 (unknown origin) using arachidonic acid as substrate assessed as reduction in PGH2 conversion to PGG2 by measuring TMPD oxidation preincubated for 5 mins followed by substrate/TMPD addition measured for 5 mins by colorimetric assay
|
Homo sapiens
|
900.0
nM
|
|
Journal : J Med Chem
Title : Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor.
Year : 2016
Volume : 59
Issue : 16
First Page : 7431
Last Page : 7444
Authors : Adeniji A, Uddin MJ, Zang T, Tamae D, Wangtrakuldee P, Marnett LJ, Penning TM.
Abstract : Type 5 17β-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Δ(4)-androstene-3,17-dione and 5α-androstane-3,17-dione to testosterone (T) and 5α-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3. We examined a series of naproxen analogues and find that (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid (in which the methyl group of R-naproxen was replaced by an ethyl group) acts as a potent AKR1C3 inhibitor that displays selectivity for AKR1C3 over other AKR1C enzymes. This compound was devoid of inhibitory activity on COX isozymes and blocked AKR1C3 mediated production of T and induction of PSA in LNCaP-AKR1C3 cells as a model of a CRPC cell line. R-Profens are substrate selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R-profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
24.65
%
|
|
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
|
-0.26
%
|
|
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
|
-0.26
%
|
|
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.
|
Antiinflammatory activity in mouse model of xylene-induced ear swelling assessed as inhibition of swelling by measuring weight of the ear at 150 mg/kg, ig pretreated for 90 mins followed by xylene challenge and measured after 30 mins relative to control
|
Mus musculus
|
25.03
%
|
|
Journal : RSC Med Chem
Title : A practical synthesis of amino limonin/deoxylimonin derivatives as effective mitigators against inflammation and nociception
Year : 2020
Volume : 11
Issue : 7
First Page : 843
Last Page : 847
Authors : Wang, Shaochi, Han, Xueqing, Yang, Yun, Chen, Rui, Guo, Zhaoyi, Zhu, Qihua, Xu, Yungen
Abstract : A practical synthetic route, consisting of 5 steps, has been developed and applied successfully for converting limonin/deoxylimonin into the corresponding amino derivatives I-5a-I-5e and II-5a-II-5e. Deoxylimonin analogs II-5a and II-5b bearing an open A ring structure underwent ring closure reaction by employing the Mitsunobu procedure to afford II-6a and II-6b. All of the 12 newly synthesized compounds were subjected to preliminary screening for evaluating their inflammation and nociception inhibition efficacy. The most promising compounds, I-5b and II-5d, were selected for further investigation by a carrageenan-induced mouse paw edema model, both of which displayed a dose-response dependent manner and demonstrated superior anti inflammation capacity to that of indomethacin in the first 2 hours.
