|
In vitro potency against human Prostaglandin G/H synthase 2 in the human whole blood assay.
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : 2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors.
Year : 1999
Volume : 42
Issue : 7
First Page : 1274
Last Page : 1281
Authors : Black WC, Brideau C, Chan CC, Charleson S, Chauret N, Claveau D, Ethier D, Gordon R, Greig G, Guay J, Hughes G, Jolicoeur P, Leblanc Y, Nicoll-Griffith D, Ouimet N, Riendeau D, Visco D, Wang Z, Xu L, Prasit P.
Abstract : Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the phenyl ring with a 2- or 3-pyridyl ring. Thus the 3,5-difluorophenyl derivative 7 (L-776,967) and the 3-pyridyl derivative 13 (L-784,506) are particularly interesting as potential antiinflammatory agents with reduced side-effect profiles. Both exhibit good oral bioavailability and are potent in standard models of pain, fever, and inflammation yet have a much reduced effect on the GI integrity of rats compared to standard nonsteroidal antiflammatory drugs.
|
In vitro potency against human Prostaglandin G/H synthase 2 in transfected CHO cells.
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : 2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors.
Year : 1999
Volume : 42
Issue : 7
First Page : 1274
Last Page : 1281
Authors : Black WC, Brideau C, Chan CC, Charleson S, Chauret N, Claveau D, Ethier D, Gordon R, Greig G, Guay J, Hughes G, Jolicoeur P, Leblanc Y, Nicoll-Griffith D, Ouimet N, Riendeau D, Visco D, Wang Z, Xu L, Prasit P.
Abstract : Cyclopentenones containing a 4-(methylsulfonyl)phenyl group in the 3-position and a phenyl ring in the 2-position are selective inhibitors of cyclooxygenase-2 (COX-2). The selectivity for COX-2 over COX-1 is dramatically improved by substituting the 2-phenyl group with halogens in the meta position or by replacing the phenyl ring with a 2- or 3-pyridyl ring. Thus the 3,5-difluorophenyl derivative 7 (L-776,967) and the 3-pyridyl derivative 13 (L-784,506) are particularly interesting as potential antiinflammatory agents with reduced side-effect profiles. Both exhibit good oral bioavailability and are potent in standard models of pain, fever, and inflammation yet have a much reduced effect on the GI integrity of rats compared to standard nonsteroidal antiflammatory drugs.
|
The compound was evaluated for its inhibitory activity against COX- 2.
|
None
|
530.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, characterization, and activity of metabolites derived from the cyclooxygenase-2 inhibitor rofecoxib (MK-0966, Vioxx).
Year : 2000
Volume : 10
Issue : 23
First Page : 2683
Last Page : 2686
Authors : Nicoll-Griffith DA, Yergey JA, Trimble LA, Silva JM, Li C, Chauret N, Gauthier JY, Grimm E, Léger S, Roy P, Thérien M, Wang Z, Prasit P, Zamboni R, Young RN, Brideau C, Chan CC, Mancini J, Riendeau D.
Abstract : Metabolites of the COX-2 inhibitor rofecoxib (MK-0966, Vioxx) were prepared by synthetic or biosynthetic methods. Metabolites include products of oxidation, glucuronidation, reduction and hydrolytic ring opening. Based on an in vitro whole blood assay, none of the known human metabolites of rofecoxib inhibits COX-1 nor contributes significantly to the inhibition of COX-2.
|
In vitro inhibition of cyclooxygenase-1 via inhibition of TXB2 generation in the presence of 1 uM arachidonic acid in human platelets at concentration of 10 uM
|
None
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of cyclooxygenase-2 selectivity into ketoprofen.
Year : 2002
Volume : 12
Issue : 4
First Page : 533
Last Page : 537
Authors : Palomer A, Pascual J, Cabré M, Borràs L, González G, Aparici M, Carabaza A, Cabré F, García ML, Mauleón D.
Abstract : We have recently described how to achieve COX-2 selectivity from the non-selective inhibitor indomethacin (1) using a combination of a pharmacophore and computer 3-D models based on the known X-ray crystal structures of cyclooxygenases. In the present study we have focused on the design of COX-2 selective analogues of the NSAID ketoprofen (2). The design is similarly based on the combined use of the previous pharmacophore together with traditional medicinal chemistry techniques motivated by the comparative modeling of the 3-D structures of 2 docked into the COX active sites. The analysis includes use of the program GRID to detect isoenzyme differences near the active site region and is aimed at suggesting modifications of the basic benzophenone frame of the lead compound 2. The resulting series of compounds bearing this central framework is exemplified by the potent and selective COX-2 inhibitor 17 (LM-1669).
|
In vitro inhibition of PGE-2 generation by LPS-stimulated monocytes isolated from human blood.
|
None
|
280.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of cyclooxygenase-2 selectivity into ketoprofen.
Year : 2002
Volume : 12
Issue : 4
First Page : 533
Last Page : 537
Authors : Palomer A, Pascual J, Cabré M, Borràs L, González G, Aparici M, Carabaza A, Cabré F, García ML, Mauleón D.
Abstract : We have recently described how to achieve COX-2 selectivity from the non-selective inhibitor indomethacin (1) using a combination of a pharmacophore and computer 3-D models based on the known X-ray crystal structures of cyclooxygenases. In the present study we have focused on the design of COX-2 selective analogues of the NSAID ketoprofen (2). The design is similarly based on the combined use of the previous pharmacophore together with traditional medicinal chemistry techniques motivated by the comparative modeling of the 3-D structures of 2 docked into the COX active sites. The analysis includes use of the program GRID to detect isoenzyme differences near the active site region and is aimed at suggesting modifications of the basic benzophenone frame of the lead compound 2. The resulting series of compounds bearing this central framework is exemplified by the potent and selective COX-2 inhibitor 17 (LM-1669).
|
In vitro inhibitory potency against human COX-2 (HWB COX-2) by whole blood assay
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A new structural variation on the methanesulfonylphenyl class of selective cyclooxygenase-2 inhibitors.
Year : 1999
Volume : 9
Issue : 22
First Page : 3181
Last Page : 3186
Authors : Li CS, Black WC, Brideau C, Chan CC, Charleson S, Cromlish WA, Claveau D, Gauthier JY, Gordon R, Greig G, Grimm E, Guay J, Lau CK, Riendeau D, Thérien M, Visco DM, Wong E, Xu L, Prasit P.
Abstract : By inserting an oxygen link between the 3-fluorophenyl and the lactone ring of 5,5-dimethyl-3-(3fluorophenyl)-4-(4-methanesulfonylphenyl)-2 (5H)-furanone 1 (DFU), analogs with enhanced in vitro COX-2 inhibitory potency as well as in vivo potency in models of inflammation were obtained.
|
In vitro inhibitory potency against human COX-2 in stably transfected chinese hamster ovary (CHO) cells
|
None
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A new structural variation on the methanesulfonylphenyl class of selective cyclooxygenase-2 inhibitors.
Year : 1999
Volume : 9
Issue : 22
First Page : 3181
Last Page : 3186
Authors : Li CS, Black WC, Brideau C, Chan CC, Charleson S, Cromlish WA, Claveau D, Gauthier JY, Gordon R, Greig G, Grimm E, Guay J, Lau CK, Riendeau D, Thérien M, Visco DM, Wong E, Xu L, Prasit P.
Abstract : By inserting an oxygen link between the 3-fluorophenyl and the lactone ring of 5,5-dimethyl-3-(3fluorophenyl)-4-(4-methanesulfonylphenyl)-2 (5H)-furanone 1 (DFU), analogs with enhanced in vitro COX-2 inhibitory potency as well as in vivo potency in models of inflammation were obtained.
|
Inhibitory potency against PGE-2 production in the human whole blood (HWB COX-2) assay
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 3-heteroaryloxy-4-phenyl-2(5H)-furanones as selective COX-2 inhibitors.
Year : 1999
Volume : 9
Issue : 22
First Page : 3187
Last Page : 3192
Authors : Lau CK, Brideau C, Chan CC, Charleson S, Cromlish WA, Ethier D, Gauthier JY, Gordon R, Guay J, Kargman S, Li CS, Prasit P, Riendeau D, Thérien M, Visco DM, Xu L.
Abstract : A series of 3-heteroaryloxy4-phenyl-2-5H)-furanones were prepared and evaluated for their potency and selectivity as COX-2 inhibitors. This led to the identification of L-778,736 as a potent, orally active and selective inhibitor of the COX-2 enzyme.
|
Inhibition of PGE-2 production in CHO cells expressing human COX-2.
|
None
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 3-heteroaryloxy-4-phenyl-2(5H)-furanones as selective COX-2 inhibitors.
Year : 1999
Volume : 9
Issue : 22
First Page : 3187
Last Page : 3192
Authors : Lau CK, Brideau C, Chan CC, Charleson S, Cromlish WA, Ethier D, Gauthier JY, Gordon R, Guay J, Kargman S, Li CS, Prasit P, Riendeau D, Thérien M, Visco DM, Xu L.
Abstract : A series of 3-heteroaryloxy4-phenyl-2-5H)-furanones were prepared and evaluated for their potency and selectivity as COX-2 inhibitors. This led to the identification of L-778,736 as a potent, orally active and selective inhibitor of the COX-2 enzyme.
|
Tested in vitro for inhibition of cyclooxygenase-2 in human blood assay
|
None
|
830.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design of cyclooxygenase-2 selectivity into ketoprofen.
Year : 2002
Volume : 12
Issue : 4
First Page : 533
Last Page : 537
Authors : Palomer A, Pascual J, Cabré M, Borràs L, González G, Aparici M, Carabaza A, Cabré F, García ML, Mauleón D.
Abstract : We have recently described how to achieve COX-2 selectivity from the non-selective inhibitor indomethacin (1) using a combination of a pharmacophore and computer 3-D models based on the known X-ray crystal structures of cyclooxygenases. In the present study we have focused on the design of COX-2 selective analogues of the NSAID ketoprofen (2). The design is similarly based on the combined use of the previous pharmacophore together with traditional medicinal chemistry techniques motivated by the comparative modeling of the 3-D structures of 2 docked into the COX active sites. The analysis includes use of the program GRID to detect isoenzyme differences near the active site region and is aimed at suggesting modifications of the basic benzophenone frame of the lead compound 2. The resulting series of compounds bearing this central framework is exemplified by the potent and selective COX-2 inhibitor 17 (LM-1669).
|
Evaluation for percent inhibition of prostaglandin G/H synthase 2 in human whole blood (HWB) at a concentration of 10 um
|
None
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
Year : 2004
Volume : 47
Issue : 9
First Page : 2180
Last Page : 2193
Authors : Ranatunge RR, Augustyniak M, Bandarage UK, Earl RA, Ellis JL, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schroeder JD, Shumway MJ, Tam SW, Trocha AM, Young DV.
Abstract : The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
|
Evaluation for percent inhibition of prostaglandin G/H synthase 2 in human whole blood (HWB) at a concentration of 1 um
|
None
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
Year : 2004
Volume : 47
Issue : 9
First Page : 2180
Last Page : 2193
Authors : Ranatunge RR, Augustyniak M, Bandarage UK, Earl RA, Ellis JL, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schroeder JD, Shumway MJ, Tam SW, Trocha AM, Young DV.
Abstract : The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
|
Evaluation for percent inhibition of recombinant prostaglandin G/H synthase 2 in human whole blood (HWB) at a concentration of 10 um
|
None
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
Year : 2004
Volume : 47
Issue : 9
First Page : 2180
Last Page : 2193
Authors : Ranatunge RR, Augustyniak M, Bandarage UK, Earl RA, Ellis JL, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schroeder JD, Shumway MJ, Tam SW, Trocha AM, Young DV.
Abstract : The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
|
Evaluation for percent inhibition of recombinant prostaglandin G/H synthase 2 in human whole blood (HWB) at a concentration of 1 um
|
None
|
45.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
Year : 2004
Volume : 47
Issue : 9
First Page : 2180
Last Page : 2193
Authors : Ranatunge RR, Augustyniak M, Bandarage UK, Earl RA, Ellis JL, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schroeder JD, Shumway MJ, Tam SW, Trocha AM, Young DV.
Abstract : The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
|
In vitro average percent Inhibition of Prostaglandin G/H synthase 2 (COX-2) at a concentration of 1 uM in human whole blood by human whole blood assay
|
None
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors.
Year : 2003
Volume : 46
Issue : 25
First Page : 5484
Last Page : 5504
Authors : Khanapure SP, Garvey DS, Young DV, Ezawa M, Earl RA, Gaston RD, Fang X, Murty M, Martino A, Shumway M, Trocha M, Marek P, Tam SW, Janero DR, Letts LG.
Abstract : A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC(50) for 22c = 1 microM and COX-1 IC(50) for 22c = 20 microM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 microM in an in vitro HWB assay.
|
In vitro average percent Inhibition of Prostaglandin G/H synthase 2 (COX-2) at a concentration of 10 uM in human whole blood by human whole blood assay
|
None
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors.
Year : 2003
Volume : 46
Issue : 25
First Page : 5484
Last Page : 5504
Authors : Khanapure SP, Garvey DS, Young DV, Ezawa M, Earl RA, Gaston RD, Fang X, Murty M, Martino A, Shumway M, Trocha M, Marek P, Tam SW, Janero DR, Letts LG.
Abstract : A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC(50) for 22c = 1 microM and COX-1 IC(50) for 22c = 20 microM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 microM in an in vitro HWB assay.
|
Inhibition of Prostaglandin G/H synthase 2 (COX-2) in human whole blood at 10 uM
|
None
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.
Year : 2003
Volume : 46
Issue : 16
First Page : 3463
Last Page : 3475
Authors : Almansa C, Alfón J, de Arriba AF, Cavalcanti FL, Escamilla I, Gómez LA, Miralles A, Soliva R, Bartrolí J, Carceller E, Merlos M, García-Rafanell J.
Abstract : The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.
|
In vitro inhibition of human Prostaglandin G/H synthase 2 (expressed in sf9 insect cells using baculovirus) enzyme at a concentration of 10 M
|
None
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and cyclooxygenase-2 inhibiting property of 1,5-diarylpyrazoles with substituted benzenesulfonamide moiety as pharmacophore: Preparation of sodium salt for injectable formulation.
Year : 2003
Volume : 46
Issue : 19
First Page : 3975
Last Page : 3984
Authors : Pal M, Madan M, Padakanti S, Pattabiraman VR, Kalleda S, Vanguri A, Mullangi R, Mamidi NV, Casturi SR, Malde A, Gopalakrishnan B, Yeleswarapu KR.
Abstract : A series of 1,5-diarylpyrazoles having a substituted benzenesulfonamide moiety as pharmacophore was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Through SAR and molecular modeling, it was found that fluorine substitution on the benzenesulfonamide moiety along with an electron-donating group at the 4-position of the 5-aryl ring yielded selectivity as well as potency for COX-2 inhibition in vitro. Among such compounds 3-fluoro-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide 3 displayed interesting pharmacokinetic properties along with antiinflammatory activity in vivo. Among the sodium salts tested in vivo, 10, the propionyl analogue of 3, showed excellent antiinflammatory activity and therefore represents a new lead structure for the development of injectable COX-2 specific inhibitors.
|
In vitro percent Inhibition of recombinant human prostaglandin G/H synthase 2 (COX-2) at a concentration of 1 uM
|
None
|
40.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors.
Year : 2003
Volume : 46
Issue : 25
First Page : 5484
Last Page : 5504
Authors : Khanapure SP, Garvey DS, Young DV, Ezawa M, Earl RA, Gaston RD, Fang X, Murty M, Martino A, Shumway M, Trocha M, Marek P, Tam SW, Janero DR, Letts LG.
Abstract : A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC(50) for 22c = 1 microM and COX-1 IC(50) for 22c = 20 microM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 microM in an in vitro HWB assay.
|
In vitro percent Inhibition of recombinant human prostaglandin G/H synthase 2 (COX-2) at a concentration of 10 uM
|
None
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors.
Year : 2003
Volume : 46
Issue : 25
First Page : 5484
Last Page : 5504
Authors : Khanapure SP, Garvey DS, Young DV, Ezawa M, Earl RA, Gaston RD, Fang X, Murty M, Martino A, Shumway M, Trocha M, Marek P, Tam SW, Janero DR, Letts LG.
Abstract : A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC(50) for 22c = 1 microM and COX-1 IC(50) for 22c = 20 microM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 microM in an in vitro HWB assay.
|
In vitro percent inhibition of prostaglandin G/H synthase 2 (COX-2) in human whole blood at 1 uM
|
None
|
84.1
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.
Year : 2003
Volume : 46
Issue : 16
First Page : 3463
Last Page : 3475
Authors : Almansa C, Alfón J, de Arriba AF, Cavalcanti FL, Escamilla I, Gómez LA, Miralles A, Soliva R, Bartrolí J, Carceller E, Merlos M, García-Rafanell J.
Abstract : The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.
|
In vitro inhibitory activity against prostaglandin G/H synthase 2 using mouse peritoneal macrophage method
|
None
|
0.06
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : In vitro structure-activity relationship and in vivo studies for a novel class of cyclooxygenase-2 inhibitors: 5-aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives.
Year : 2004
Volume : 47
Issue : 4
First Page : 792
Last Page : 804
Authors : Shin SS, Byun Y, Lim KM, Choi JK, Lee KW, Moh JH, Kim JK, Jeong YS, Kim JY, Choi YH, Koh HJ, Park YH, Oh YI, Noh MS, Chung S.
Abstract : 5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC(50) comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED(50) of 0.1 mg kg(-1) day(-1) was observed against adjuvant-induced arthritis by a preventive model, positioning 20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED(50) of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague-Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.
|
Ability to inhibit Prostaglandin G/H synthase 2 by using freshly harvested mouse peritoneal macrophages
|
None
|
0.06
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2,2-Dimethyl-4,5-diaryl-3(2H)furanone derivatives as selective cyclo-oxygenase-2 inhibitors.
Year : 2001
Volume : 11
Issue : 2
First Page : 165
Last Page : 168
Authors : Shin SS, Noh MS, Byun YJ, Choi JK, Kim JY, Lim KM, Ha JY, Kim JK, Lee CH, Chung S.
Abstract : A series of 2,2-dimethyl-5-[4-(methylsulfonyl)phenyl]-4-phenyl-3(2H)furanones was prepared and evaluated for their ability to inhibit cyclo-oxygenase-2 (COX-2).
|
In vitro inhibitory concentration against rat Prostaglandin G/H synthase 2
|
None
|
760.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Naphthalene derivatives: A new series of selective cyclooxygenase-2 inhibitors.
Year : 2001
Volume : 11
Issue : 20
First Page : 2687
Last Page : 2690
Authors : Feixas J, Jiménez JM, Godessart N, Puig C, Soca L, Crespo MI.
Abstract : A new series of potent and selective cyclooxygenase-2 inhibitors have been prepared. Some of these compounds show good oral anti-inflammatory activity in rats.
|
In vitro inhibition against ovine Prostaglandin G/H synthase 2
|
Ovis aries
|
427.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 6-Alkyl, alkoxy, or alkylthio-substituted 3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: a novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors.
Year : 2003
Volume : 13
Issue : 13
First Page : 2205
Last Page : 2209
Authors : Rao PN, Amini M, Li H, Habeeb AG, Knaus EE.
Abstract : A novel class of 3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones possessing a central six-membered lactone (pyran-2-one) ring system, in conjunction with C-6 alkyl (Me, Et or i-Pr), alkoxy (OMe, OEt or O-i-Pr), and alkylthio (SMe, SEt or S-i-Pr) substituents, were designed for evaluation as selective COX-2 inhibitors.
|
In vitro inhibitory activity against prostaglandin G/H synthase 2 (COX-2)
|
None
|
430.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of 6-substituted-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: a novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors.
Year : 2003
Volume : 46
Issue : 23
First Page : 4872
Last Page : 4882
Authors : Praveen Rao PN, Amini M, Li H, Habeeb AG, Knaus EE.
Abstract : A group of 6-alkyl (alkoxy or alkylthio)-4-aryl-3-(4-methanesulfonylphenyl)pyran-2-ones (14a-v), possessing either a H or F substituent at the para-position of the C-4 phenyl ring, were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo antiinflammatory-analgesic activities. Although 6-ethylthio-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14s) exhibited a very high in vitro COX-2 inhibitory potency (IC(50) = 0.0032 muM) and COX-2 selectivity (SI > 120 000), 14s exhibited moderate antiinflammatory activity compared to celecoxib in a carrageenan-induced rat paw edema assay. In contrast, the less potent (IC(50) = 0.10 muM), and less selective (SI = 2880) COX-2 inhibitor 6-ethoxy-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14i) exhibited good antiinflammatory activity where a 1 mg/kg oral dose reduced inflammation 32 and 67% at 3 and 5 h postdrug administration relative to the reference drug celecoxib where a 50 mg/kg oral dose reduced inflammation by 79 and 58% at the respective 3 and 5 h time periods. Molecular modeling studies, where 14i was docked in the active site of both COX-1 and COX-2, reveals that the C-6 ethoxy substituent orients the pyran-2-one ring to position the SO(2)Me pharmacophore in the vicinity of the secondary pocket in COX-2. The absence of this COX-2 secondary pocket in the COX-1 binding site is due to the presence of the bulky Ile(523) in COX-1 such that access to the amino acid residues (Ile(517), Phe(518), Gln(192), and His(90)), which line the COX-2 secondary pocket with which the SO(2)Me pharmacophore could interact, is hindered. The six-membered pyran-2-one ring system is a suitable central template to design selective COX-2 inhibitors.
|
In vitro inhibitory activity against prostaglandin G/H synthase 2 from ovine
|
Ovis aries
|
430.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design of acyclic triaryl olefins: a new class of potent and selective cyclooxygenase-2 (COX-2) inhibitors.
Year : 2004
Volume : 14
Issue : 8
First Page : 1953
Last Page : 1956
Authors : Uddin MJ, Rao PN, Knaus EE.
Abstract : A new class of acyclic 1,1-diphenyl-2-(4-methylsulfonylphenyl)-2-alkyl-1-ethenes were synthesized, via a short two-step McMurry olefination reaction and then oxidation of the thiomethyl intermediate using Oxone, in 62-76% yield. The title compounds possess identical C-1 phenyl substituents which precludes the possibility of (Z)- and (E)-stereoisomers. 1,1-Diphenyl-2-(4-methylsulfonylphenyl)hex-1-ene exhibited highly potent (IC(50)=0.014 microM) and selective COX-2 (Selectivity Index >7142) inhibitory activity.
|
In vitro inhibitory activity against prostaglandin G/H synthase 2 from ovine
|
Ovis aries
|
430.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfonamido, azidosulfonyl and N-acetylsulfonamido analogues of rofecoxib: 4-[4-(N-acetylsulfonamido)phenyl]-3-(4-methanesulfonylphenyl)-2(5H)furanone is a potent and selective cyclooxygenase-2 inhibitor.
Year : 2004
Volume : 14
Issue : 8
First Page : 1957
Last Page : 1960
Authors : Zarghi A, Praveen Rao PN, Knaus EE.
Abstract : 4-[4-(N-Acetylsulfonamido)phenyl]-3-(4-methanesulfonylphenyl)-2(5H)furanone, possessing a N-acetylsulfonamido pharmacophore, has been identified as a potent and selective COX-2 inhibitor that has the potential to acetylate the COX-2 isozyme.
|
Inhibitory concentration against Prostaglandin G/H synthase 2
|
None
|
196.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of celecoxib and rofecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere.
Year : 2001
Volume : 44
Issue : 18
First Page : 3039
Last Page : 3042
Authors : Habeeb AG, Praveen Rao PN, Knaus EE.
Abstract : Celecoxib (13) and rofecoxib (17) analogues, in which the respective SO2NH2 and SO2Me hydrogen-bonding pharmacophores were replaced by a dipolar azido bioisosteric substituent, were investigated. Molecular modeling (docking) studies showed that the azido substituent of these two analogues (13, 17) was inserted deep into the secondary pocket of the human COX-2 binding site where it undergoes electrostatic interaction with Arg(513). The azido analogue of rofecoxib (17), the most potent and selective inhibitor of COX-2 (COX-1 IC(50) = 159.7 microM; COX-2 IC(50) = 0.196 microM; COX-2 selectivity index = 812), exhibited good oral antiinflammatory and analgesic activities.
|
Inhibitory of human Prostaglandin G/H synthase 2 expressed in CHO cells.
|
None
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Diaryl-5-hydroxyfuranones: highly selective inhibitors of cyclooxygenase-2 with aqueous solubility.
Year : 2003
Volume : 13
Issue : 6
First Page : 1195
Last Page : 1198
Authors : Black WC, Brideau C, Chan CC, Charleson S, Cromlish W, Gordon R, Grimm EL, Hughes G, Leger S, Li CS, Riendeau D, Thérien M, Wang Z, Xu LJ, Prasit P.
Abstract : The introduction of a hydroxyl group into the 5-position of the diaryl furanone system provides highly selective inhibitors of cyclooxygenase-2. These molecules can be converted into their sodium salts which are water soluble, facilitating intravenous formulation. These salts show excellent potency in rat models of pain, fever and inflammation.
|
Percentage inhibition of prostaglandin G/H synthase 1 in human whole blood (HWB) at a concentration of 100 um
|
None
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
Year : 2004
Volume : 47
Issue : 9
First Page : 2180
Last Page : 2193
Authors : Ranatunge RR, Augustyniak M, Bandarage UK, Earl RA, Ellis JL, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schroeder JD, Shumway MJ, Tam SW, Trocha AM, Young DV.
Abstract : The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
|
Compound was evaluated for percent inhibition of recombinant prostaglandin G/H synthase 1 in human whole blood (HWB) at a concentration of 100 um
|
None
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
Year : 2004
Volume : 47
Issue : 9
First Page : 2180
Last Page : 2193
Authors : Ranatunge RR, Augustyniak M, Bandarage UK, Earl RA, Ellis JL, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schroeder JD, Shumway MJ, Tam SW, Trocha AM, Young DV.
Abstract : The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
|
In vitro average percent Inhibition of Prostaglandin G/H synthase 1 (COX-1) at a concentration of 100 uM in human whole blood by human whole blood assay
|
None
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors.
Year : 2003
Volume : 46
Issue : 25
First Page : 5484
Last Page : 5504
Authors : Khanapure SP, Garvey DS, Young DV, Ezawa M, Earl RA, Gaston RD, Fang X, Murty M, Martino A, Shumway M, Trocha M, Marek P, Tam SW, Janero DR, Letts LG.
Abstract : A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC(50) for 22c = 1 microM and COX-1 IC(50) for 22c = 20 microM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 microM in an in vitro HWB assay.
|
In vitro percent Inhibition of recombinant human prostaglandin G/H synthase 1 (COX-1) at a concentration of 100 uM
|
None
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors.
Year : 2003
Volume : 46
Issue : 25
First Page : 5484
Last Page : 5504
Authors : Khanapure SP, Garvey DS, Young DV, Ezawa M, Earl RA, Gaston RD, Fang X, Murty M, Martino A, Shumway M, Trocha M, Marek P, Tam SW, Janero DR, Letts LG.
Abstract : A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC(50) for 22c = 1 microM and COX-1 IC(50) for 22c = 20 microM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 microM in an in vitro HWB assay.
|
In vitro inhibitory activity against prostaglandin G/H synthase 1 using mouse peritoneal macrophage method
|
None
|
100.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : In vitro structure-activity relationship and in vivo studies for a novel class of cyclooxygenase-2 inhibitors: 5-aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives.
Year : 2004
Volume : 47
Issue : 4
First Page : 792
Last Page : 804
Authors : Shin SS, Byun Y, Lim KM, Choi JK, Lee KW, Moh JH, Kim JK, Jeong YS, Kim JY, Choi YH, Koh HJ, Park YH, Oh YI, Noh MS, Chung S.
Abstract : 5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC(50) comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED(50) of 0.1 mg kg(-1) day(-1) was observed against adjuvant-induced arthritis by a preventive model, positioning 20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED(50) of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague-Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.
|
Ability to inhibit Prostaglandin G/H synthase 1 by using freshly harvested mouse peritoneal macrophages
|
None
|
100.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2,2-Dimethyl-4,5-diaryl-3(2H)furanone derivatives as selective cyclo-oxygenase-2 inhibitors.
Year : 2001
Volume : 11
Issue : 2
First Page : 165
Last Page : 168
Authors : Shin SS, Noh MS, Byun YJ, Choi JK, Kim JY, Lim KM, Ha JY, Kim JK, Lee CH, Chung S.
Abstract : A series of 2,2-dimethyl-5-[4-(methylsulfonyl)phenyl]-4-phenyl-3(2H)furanones was prepared and evaluated for their ability to inhibit cyclo-oxygenase-2 (COX-2).
|
In vitro inhibition of Prostaglandin G/H synthase 1 (from ram seminal vesicles) at a concentration of 10 M
|
Ovis aries
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and cyclooxygenase-2 inhibiting property of 1,5-diarylpyrazoles with substituted benzenesulfonamide moiety as pharmacophore: Preparation of sodium salt for injectable formulation.
Year : 2003
Volume : 46
Issue : 19
First Page : 3975
Last Page : 3984
Authors : Pal M, Madan M, Padakanti S, Pattabiraman VR, Kalleda S, Vanguri A, Mullangi R, Mamidi NV, Casturi SR, Malde A, Gopalakrishnan B, Yeleswarapu KR.
Abstract : A series of 1,5-diarylpyrazoles having a substituted benzenesulfonamide moiety as pharmacophore was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Through SAR and molecular modeling, it was found that fluorine substitution on the benzenesulfonamide moiety along with an electron-donating group at the 4-position of the 5-aryl ring yielded selectivity as well as potency for COX-2 inhibition in vitro. Among such compounds 3-fluoro-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide 3 displayed interesting pharmacokinetic properties along with antiinflammatory activity in vivo. Among the sodium salts tested in vivo, 10, the propionyl analogue of 3, showed excellent antiinflammatory activity and therefore represents a new lead structure for the development of injectable COX-2 specific inhibitors.
|
Inhibitory concentration against Prostaglandin G/H synthase 2
|
None
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of celecoxib and rofecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere.
Year : 2001
Volume : 44
Issue : 18
First Page : 3039
Last Page : 3042
Authors : Habeeb AG, Praveen Rao PN, Knaus EE.
Abstract : Celecoxib (13) and rofecoxib (17) analogues, in which the respective SO2NH2 and SO2Me hydrogen-bonding pharmacophores were replaced by a dipolar azido bioisosteric substituent, were investigated. Molecular modeling (docking) studies showed that the azido substituent of these two analogues (13, 17) was inserted deep into the secondary pocket of the human COX-2 binding site where it undergoes electrostatic interaction with Arg(513). The azido analogue of rofecoxib (17), the most potent and selective inhibitor of COX-2 (COX-1 IC(50) = 159.7 microM; COX-2 IC(50) = 0.196 microM; COX-2 selectivity index = 812), exhibited good oral antiinflammatory and analgesic activities.
|
Inhibitory activity against Prostaglandin G/H synthase 2 in human whole blood assay as LPS induced PGE-2 generation.
|
None
|
57.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological evaluation of benzimidazole/benzothiazole and benzoxazole derivatives as cyclooxygenase inhibitors.
Year : 2003
Volume : 13
Issue : 4
First Page : 657
Last Page : 660
Authors : Paramashivappa R, Phani Kumar P, Subba Rao PV, Srinivasa Rao A.
Abstract : We have synthesised a series of 2-[[2-alkoxy-6-pentadecylphenyl)methyl]thio]-1H-benzimidazoles/benzothiazoles and benzoxazoles from anacardic acid and investigated their ability to inhibit human cyclooxygenase-2 enzyme (COX-2). The active compounds were screened for cyclooxygenase-1 (COX-1) inhibition. Compound 13 is 384-fold and 19 is more than 470-fold selective towards COX-2 compared to COX-1. Thus, this class of compounds may serve as excellent candidates for selective COX-2 inhibition.
|
Compound was evaluated for inhibition concentration of prostaglandin G/H synthase 2 in human blood
|
None
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles.
Year : 2004
Volume : 47
Issue : 9
First Page : 2180
Last Page : 2193
Authors : Ranatunge RR, Augustyniak M, Bandarage UK, Earl RA, Ellis JL, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schroeder JD, Shumway MJ, Tam SW, Trocha AM, Young DV.
Abstract : The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.
|
Compound was tested for the inhibition of human Prostaglandin G/H synthase 2 (COX-2) in human whole blood
|
None
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors.
Year : 2003
Volume : 46
Issue : 25
First Page : 5484
Last Page : 5504
Authors : Khanapure SP, Garvey DS, Young DV, Ezawa M, Earl RA, Gaston RD, Fang X, Murty M, Martino A, Shumway M, Trocha M, Marek P, Tam SW, Janero DR, Letts LG.
Abstract : A novel series of benzo-1,3-dioxolane metharyl derivatives was synthesized and evaluated for cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) inhibition in human whole blood (HWB). In the present study, structure-activity relationships (SAR) in the metharyl analogues were investigated. The spacer group and substitutions in the spacer group were found to be quite important for potent COX-2 inhibition. Compounds in which a methylene group (8a-c), carbonyl group (12a-c), or methylidene group (7a-c) connected cycloalkyl groups to the central benzo-1,3-dioxolane template were found to be potent and selective COX-2 inhibitors. Aryl-substituted compounds linked to the central ring by either a methylene or a carbonyl spacer resulted in potent, highly selective COX-2 inhibitors. In this series of substituted-(2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene compounds, SAR studies demonstrated that substitution at the 3-position of the aryl group optimized COX-2 selectivity and potency, whereas substitution at the 4-position attenuated COX-2 inhibition. Mono- or difluoro substitution at meta position(s), as in 22c and 22h, was advantageous for both in vitro COX-2 potency and selectivity (e.g., COX-2 IC(50) for 22c = 1 microM and COX-1 IC(50) for 22c = 20 microM in HWB assay). Several novel compounds in the (2H-benzo[3,4-d]1,3-dioxolan-5-yl))-1-(methylsulfonyl)benzene series, as shown in structures 7c, 8a, 12a, 21c, 22c, 22e, and 22h, selectively inhibited COX-2 activity by 40-50% at a test concentration of 1 microM in an in vitro HWB assay.
|
In vitro inhibitory activity against human Prostaglandin G/H synthase 2 (COX-2) in 143982 cells
|
None
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.
Year : 2003
Volume : 46
Issue : 16
First Page : 3463
Last Page : 3475
Authors : Almansa C, Alfón J, de Arriba AF, Cavalcanti FL, Escamilla I, Gómez LA, Miralles A, Soliva R, Bartrolí J, Carceller E, Merlos M, García-Rafanell J.
Abstract : The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.
|
In vitro inhibitory activity against human whole blood Prostaglandin G/H synthase 2
|
Homo sapiens
|
500.0
nM
|
|
In vitro inhibitory activity against human whole blood Prostaglandin G/H synthase 2
|
Homo sapiens
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The discovery of rofecoxib, [MK 966, Vioxx, 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2-inhibitor.
Year : 1999
Volume : 9
Issue : 13
First Page : 1773
Last Page : 1778
Authors : Prasit P, Wang Z, Brideau C, Chan CC, Charleson S, Cromlish W, Ethier D, Evans JF, Ford-Hutchinson AW, Gauthier JY, Gordon R, Guay J, Gresser M, Kargman S, Kennedy B, Leblanc Y, Léger S, Mancini J, O'Neill GP, Ouellet M, Percival MD, Perrier H, Riendeau D, Rodger I, Zamboni R.
Abstract : The development of a COX-2 inhibitor rofecoxib (MK 966, Vioxx) is described. It is essentially equipotent to indomethacin both in vitro and in vivo but without the ulcerogenic side effect due to COX-1 inhibition.
|
In vitro inhibitory activity against human whole cells (CHO) Prostaglandin G/H synthase 2
|
None
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The discovery of rofecoxib, [MK 966, Vioxx, 4-(4'-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2-inhibitor.
Year : 1999
Volume : 9
Issue : 13
First Page : 1773
Last Page : 1778
Authors : Prasit P, Wang Z, Brideau C, Chan CC, Charleson S, Cromlish W, Ethier D, Evans JF, Ford-Hutchinson AW, Gauthier JY, Gordon R, Guay J, Gresser M, Kargman S, Kennedy B, Leblanc Y, Léger S, Mancini J, O'Neill GP, Ouellet M, Percival MD, Perrier H, Riendeau D, Rodger I, Zamboni R.
Abstract : The development of a COX-2 inhibitor rofecoxib (MK 966, Vioxx) is described. It is essentially equipotent to indomethacin both in vitro and in vivo but without the ulcerogenic side effect due to COX-1 inhibition.
|
In vitro inhibitory activity against recombinant human Prostaglandin G/H synthase 2
|
None
|
329.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Conformationally restricted 3,4-diarylfuranones (2,3a,4,5-tetrahydronaphthofuranones) as selective cyclooxygenase-2 inhibitors.
Year : 2003
Volume : 13
Issue : 10
First Page : 1639
Last Page : 1643
Authors : Pal M, Rao Veeramaneni V, Nagabelli M, Rao Kalleda S, Misra P, Rao Casturi S, Rao Yeleswarapu K.
Abstract : A number of naphthofuranones were synthesized and tested for COX-1 and COX-2 inhibition. Few of them were identified as selective COX-2 inhibitors. Structure-activity relationship studies within the series are discussed.
|
In vitro inhibitory concentration of compound required to inhibit Prostaglandin G/H synthase 2 enzyme was determined
|
None
|
427.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Isomeric acetoxy analogues of rofecoxib: a novel class of highly potent and selective cyclooxygenase-2 inhibitors.
Year : 2002
Volume : 12
Issue : 19
First Page : 2753
Last Page : 2756
Authors : Rahim MA, Rao PN, Knaus EE.
Abstract : A group of isomers possessing a 2-, 3-, or 4-acetoxy moiety on the 3-phenyl substituent of rofecoxib were synthesized that exhibit highly potent, and selective, COX-2 inhibitory activity that have the potential to acetylate the COX-2 isozyme.
|
In vitro percent inhibition of Prostaglandin G/H synthase 2 (COX-2) in human whole blood was determined
|
None
|
280.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.
Year : 2003
Volume : 46
Issue : 16
First Page : 3463
Last Page : 3475
Authors : Almansa C, Alfón J, de Arriba AF, Cavalcanti FL, Escamilla I, Gómez LA, Miralles A, Soliva R, Bartrolí J, Carceller E, Merlos M, García-Rafanell J.
Abstract : The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.
|
Inhibition concentration against cyclooxygenase-2 (COX-2) in human whole blood
|
None
|
760.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 2-phenylpyran-4-ones: a new class of orally active cyclooxygenase-2 inhibitors.
Year : 2004
Volume : 47
Issue : 15
First Page : 3874
Last Page : 3886
Authors : Caturla F, Jiménez JM, Godessart N, Amat M, Cárdenas A, Soca L, Beleta J, Ryder H, Crespo MI.
Abstract : A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.
|
Inhibition of PGE-2 generation in LPS-stimulated human monocytes (Prostaglandin G/H synthase 2 cell assay)
|
None
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of novel cyclooxygenase-2 selective inhibitors using pharmacophore models.
Year : 2002
Volume : 45
Issue : 7
First Page : 1402
Last Page : 1411
Authors : Palomer A, Cabré F, Pascual J, Campos J, Trujillo MA, Entrena A, Gallo MA, García L, Mauleón D, Espinosa A.
Abstract : In the present study we have investigated whether pharmacophore models may account for the activity and selectivity of the known cyclooxygenase-2 (COX-2) selective inhibitors of the phenylsulfonyl tricyclic series, i.e., Celecoxib (1) and Rofecoxib (3), and whether transferring this structural information onto the frame of a nonsteroidal antiinflammatory drug (NSAID), known to tightly bind the enzyme active site, may be useful for designing novel COX-2 selective inhibitors. With this aim we have developed a pharmacophore based on the geometric disposition of chemical features in the most favorable conformation of the COX-2 selective inhibitors SC-558 (2; analogue of Celecoxib (1)) and Rofecoxib (3) and the more restrained compounds 4 (DFU) and 5. The pharmacophore model contains a sulfonyl S atom, an aromatic ring (ring plane A) with a fixed position of the normal to the plane, and an additional aromatic ring (ring plane B), both rings forming a dihedral angle of 290 degrees +/- 10 degrees. The final disposition of the pharmacophoric groups parallels the geometry of the ligand SC-558 (2) in the known crystal structure of the COX-2 complex. Moreover, the nonconserved residue 523 is known to be important for COX-2 selective inhibition; thus, the crystallographic information was used to position an excluded volume in the pharmacophore, accounting for the space limits imposed by this nonconserved residue. The geometry of the final five-feature pharmacophore was found to be consistent with the crystal structure of the nonselective NSAID indomethacin (6) in the COX-2 complex. This result was used to design indomethacin analogues 8 and 9 that exhibited consistent structure-activity relationships leading to the potent and selective COX-2 inhibitor 8a. Compound 8a (LM-1685) was selected as a promising candidate for further pharmacological evaluation.
|
Inhibition of Prostaglandin G/H synthase 2 in human whole blood
|
Homo sapiens
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : SAR in the alkoxy lactone series: the discovery of DFP, a potent and orally active COX-2 inhibitor.
Year : 1999
Volume : 9
Issue : 15
First Page : 2207
Last Page : 2212
Authors : Leblanc Y, Roy P, Boyce S, Brideau C, Chan CC, Charleson S, Gordon R, Grimm E, Guay J, Léger S, Li CS, Riendeau D, Visco D, Wang Z, Webb J, Xu LJ, Prasit P.
Abstract : Extensive SAR has been established in the alkoxy lactone series and this has lead to the discovery of DFP (5,5-dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanon e), a potent COX-2 inhibitor exhibiting in vivo efficacy in all models studied.
|
Inhibition of human Prostaglandin G/H synthase 2
|
Homo sapiens
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522(1).
Year : 2002
Volume : 45
Issue : 7
First Page : 1511
Last Page : 1517
Authors : Hashimoto H, Imamura K, Haruta J, Wakitani K.
Abstract : A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities. In contrast, introduction of a fluorine atom preserved COX-2 potency and notably increased COX1/COX-2 selectivity. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [9d, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.
|
Inhibitory concentration was measured against Prostaglandin G/H synthase 2 in human whole blood
|
None
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4-Diaryl-5-hydroxyfuranones: highly selective inhibitors of cyclooxygenase-2 with aqueous solubility.
Year : 2003
Volume : 13
Issue : 6
First Page : 1195
Last Page : 1198
Authors : Black WC, Brideau C, Chan CC, Charleson S, Cromlish W, Gordon R, Grimm EL, Hughes G, Leger S, Li CS, Riendeau D, Thérien M, Wang Z, Xu LJ, Prasit P.
Abstract : The introduction of a hydroxyl group into the 5-position of the diaryl furanone system provides highly selective inhibitors of cyclooxygenase-2. These molecules can be converted into their sodium salts which are water soluble, facilitating intravenous formulation. These salts show excellent potency in rat models of pain, fever and inflammation.
|
Inhibitory potency against cyclooxygenase-2 in human whole blood assay
|
None
|
530.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Evaluation of loxoprofen and its alcohol metabolites for potency and selectivity of inhibition of cyclooxygenase-2.
Year : 2004
Volume : 14
Issue : 5
First Page : 1201
Last Page : 1203
Authors : Riendeau D, Salem M, Styhler A, Ouellet M, Mancini JA, Li CS.
Abstract : Loxoprofen, its trans-alcohol and cis-alcohol metabolites were evaluated for selectivity of inhibition of COX-2 over COX-1. The (2S,1'R,2'S)-trans-alcohol derivative was found to be the most active metabolite and to be a potent and nonselective inhibitor of COX-2 and COX-1 in both enzyme and human whole blood assays.
|
The compound was evaluated for prostaglandin E2 inhibition using recombinant Prostaglandin G/H synthase 2
|
None
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of a new methoxytetrahydropyran derivative as dual cyclooxygenase-2/5-lipoxygenase inhibitor.
Year : 2002
Volume : 12
Issue : 5
First Page : 779
Last Page : 782
Authors : Barbey S, Goossens L, Taverne T, Cornet J, Choesmel V, Rouaud C, Gimeno G, Yannic-Arnoult S, Michaux C, Charlier C, Houssin R, Hénichart JP.
Abstract : Dual COX-2/5-LO inhibitors are described as potential new therapeutic agents for inflammatory diseases. A surprisingly potent effect of a 5-LO pharmacophoric group on the COX-2 inhibition is presented as well as pharmacological in vitro and in vivo results.
|
In vivo inhibition of contralateral paw swelling after oral treatment for 28 days (1 mg/kg od) was determined by adjuvabt arthritis in rat
|
Rattus norvegicus
|
87.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.
Year : 2003
Volume : 46
Issue : 16
First Page : 3463
Last Page : 3475
Authors : Almansa C, Alfón J, de Arriba AF, Cavalcanti FL, Escamilla I, Gómez LA, Miralles A, Soliva R, Bartrolí J, Carceller E, Merlos M, García-Rafanell J.
Abstract : The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.
|
In vivo inhibition of hyperalgesia in rat at 3 mg/kg
|
Rattus norvegicus
|
60.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 2-phenylpyran-4-ones: a new class of orally active cyclooxygenase-2 inhibitors.
Year : 2004
Volume : 47
Issue : 15
First Page : 3874
Last Page : 3886
Authors : Caturla F, Jiménez JM, Godessart N, Amat M, Cárdenas A, Soca L, Beleta J, Ryder H, Crespo MI.
Abstract : A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.
|
Antiinflammatory activity in vivo by carrageenan paw edema assay in rat at a dose of 3 mg/kg
|
Rattus norvegicus
|
41.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Naphthalene derivatives: A new series of selective cyclooxygenase-2 inhibitors.
Year : 2001
Volume : 11
Issue : 20
First Page : 2687
Last Page : 2690
Authors : Feixas J, Jiménez JM, Godessart N, Puig C, Soca L, Crespo MI.
Abstract : A new series of potent and selective cyclooxygenase-2 inhibitors have been prepared. Some of these compounds show good oral anti-inflammatory activity in rats.
|
Anti-inflammatory activity in vivo by carrageenan paw edema assay in rat at a dose of 30 mg/kg
|
Rattus norvegicus
|
40.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Naphthalene derivatives: A new series of selective cyclooxygenase-2 inhibitors.
Year : 2001
Volume : 11
Issue : 20
First Page : 2687
Last Page : 2690
Authors : Feixas J, Jiménez JM, Godessart N, Puig C, Soca L, Crespo MI.
Abstract : A new series of potent and selective cyclooxygenase-2 inhibitors have been prepared. Some of these compounds show good oral anti-inflammatory activity in rats.
|
Evaluated in vivo for antiinflammatory activity at 30 mg/kg oral dose in the carrageenan-induced rat paw edema (male Wistar rat)
|
Rattus norvegicus
|
37.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and cyclooxygenase-2 inhibiting property of 1,5-diarylpyrazoles with substituted benzenesulfonamide moiety as pharmacophore: Preparation of sodium salt for injectable formulation.
Year : 2003
Volume : 46
Issue : 19
First Page : 3975
Last Page : 3984
Authors : Pal M, Madan M, Padakanti S, Pattabiraman VR, Kalleda S, Vanguri A, Mullangi R, Mamidi NV, Casturi SR, Malde A, Gopalakrishnan B, Yeleswarapu KR.
Abstract : A series of 1,5-diarylpyrazoles having a substituted benzenesulfonamide moiety as pharmacophore was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Through SAR and molecular modeling, it was found that fluorine substitution on the benzenesulfonamide moiety along with an electron-donating group at the 4-position of the 5-aryl ring yielded selectivity as well as potency for COX-2 inhibition in vitro. Among such compounds 3-fluoro-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide 3 displayed interesting pharmacokinetic properties along with antiinflammatory activity in vivo. Among the sodium salts tested in vivo, 10, the propionyl analogue of 3, showed excellent antiinflammatory activity and therefore represents a new lead structure for the development of injectable COX-2 specific inhibitors.
|
In vivo analgesic activity of compound was determined by inflammatory hyperalgesia model at 3 mg/kg perorally in rat
|
Rattus norvegicus
|
83.4
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.
Year : 2003
Volume : 46
Issue : 16
First Page : 3463
Last Page : 3475
Authors : Almansa C, Alfón J, de Arriba AF, Cavalcanti FL, Escamilla I, Gómez LA, Miralles A, Soliva R, Bartrolí J, Carceller E, Merlos M, García-Rafanell J.
Abstract : The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.
|
In vivo anti-inflammatory activity by air pouch model at 1 mg/kg perorally in rat.
|
Rattus norvegicus
|
95.3
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.
Year : 2003
Volume : 46
Issue : 16
First Page : 3463
Last Page : 3475
Authors : Almansa C, Alfón J, de Arriba AF, Cavalcanti FL, Escamilla I, Gómez LA, Miralles A, Soliva R, Bartrolí J, Carceller E, Merlos M, García-Rafanell J.
Abstract : The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.
|
In vivo anti-inflammatory activity determined by rat carrageenan paw edema method at 10 mg/kg perorally
|
Rattus norvegicus
|
33.3
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.
Year : 2003
Volume : 46
Issue : 16
First Page : 3463
Last Page : 3475
Authors : Almansa C, Alfón J, de Arriba AF, Cavalcanti FL, Escamilla I, Gómez LA, Miralles A, Soliva R, Bartrolí J, Carceller E, Merlos M, García-Rafanell J.
Abstract : The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.
|
Inhibition of ovine Prostaglandin G/H synthase 2
|
Ovis aries
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and structure-activity relationship studies of 3,4,6-triphenylpyran-2-ones as selective cyclooxygenase-2 inhibitors.
Year : 2004
Volume : 47
Issue : 16
First Page : 3972
Last Page : 3990
Authors : Rao PN, Uddin MJ, Knaus EE.
Abstract : A group of regioisomeric 3,4,6-triphenylpyran-2-ones with a MeSO(2) pharmacophore at the para-position of either a C-3 phenyl or a C-4 phenyl substituent on the central six-membered pyran-2-one ring were prepared and evaluated in vitro for their abilities to inhibit the isozymes COX-1 and COX-2. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position of the C-6 phenyl ring attached to the central pyranone, showed that 6-(4-methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was the most potent and selective COX-2 inhibitor (COX-2 IC(50) = 0.02 microM; COX-1 IC(50) > 100 microM) with a high COX-2 selectivity index (SI > 5000) relative to the reference drugs celecoxib (COX-2 IC(50) = 0.07 microM; SI = 474) and rofecoxib (COX-2 IC(50) = 0.50 microM; SI > 200). 6-(4-Methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was a more potent oral antiinflammatory agent (ID(50) = 5.6 mg/kg) than celecoxib (ID(50) = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. In a 4% NaCl-induced abdominal constriction assay, a 5 mg/kg oral dose of 12e exhibited good analgesic activity at different time intervals producing 37.5 and 69% inhibition of writhing at 30 and 60 min, respectively. In contrast, the corresponding 6-(4-methoxyphenyl)-4-(4-methanesulfonylphenyl)-3-phenylpyran-2-one regiosiomer (12o) was a less potent and selective COX-2 inhibitor (COX-2 IC(50) = 0.45 microM; SI = 70). A molecular modeling study for 12e indicated that the p-OMe substituent on the C-6 phenyl ring interacts with the COX-2 binding site amino acids Ile(345), Val(349), Leu(359), Leu(531), and Met(535) and that the OMe substituent may be responsible for proper orientation of the C-3 p-SO(2)Me-phenyl ring within the COX-2 secondary pocket (Gln(192), Arg(513), and Phe(518)). These results show that the COX-2 selectivity and potency of 3,4,6-triphenylpyranone regioisomers can be modulated by appropriate placement of the p-SO(2)Me pharmacophore on either the C-3 or C-4 phenyl moiety. In addition, electronic properties at the para-position of a C-6 phenyl substituent on the central pyranone ring govern COX-2 inhibitory potency and selectivity by controlling the orientation of the p-SO(2)Me pharmacophore within the COX-2 secondary pocket.
|
In vitro inhibitory concentration against ovine Cyclooxygenase-2
|
Ovis aries
|
500.0
nM
|
|
In vitro inhibitory concentration against ovine Cyclooxygenase-2
|
Ovis aries
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of (E)-1,1,2-triarylethenes: novel inhibitors of the cyclooxygenase-2 (COX-2) isozyme.
Year : 2005
Volume : 15
Issue : 2
First Page : 439
Last Page : 442
Authors : Uddin MJ, Rao PN, McDonald R, Knaus EE.
Abstract : A novel class of acyclic 1,1,2-triaryl (E)-ethenes was designed that were synthesized via an (E)-selective Takeda olefination reaction. Among the group of compounds evaluated, (E)-2-(4-fluorophenyl)-1-(4-methylsulfonylphenyl)-1-phenylethene (10c) emerged as the most potent (COX-2 IC(50)=0.0316 microM), and selective (selectivity index>3164), COX-2 inhibitor.
|
Inhibition of human cyclooxygenase-2 expressed in COS cells
|
Homo sapiens
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of 2,3-diaryl-pyrazolo[1,5-b]pyridazines as potent and selective cyclooxygenase-2 inhibitors.
Year : 2004
Volume : 14
Issue : 21
First Page : 5445
Last Page : 5448
Authors : Beswick P, Bingham S, Bountra C, Brown T, Browning K, Campbell I, Chessell I, Clayton N, Collins S, Corfield J, Guntrip S, Haslam C, Lambeth P, Lucas F, Mathews N, Murkit G, Naylor A, Pegg N, Pickup E, Player H, Price H, Stevens A, Stratton S, Wiseman J.
Abstract : GW406381 (8), currently undergoing clinical evaluation for the treatment of inflammatory pain is a member of a novel series of 2,3-diaryl-pyrazolo[1,5-b]pyridazine based cyclooxygenase-2 (COX-2) inhibitors, which have been shown to be highly potent and selective. Several examples of the series, in addition to possessing favourable pharmacokinetic profiles and analgesic activity in vivo, have also demonstrated relatively high brain penetration in the rat compared with the clinically available compounds, which may ultimately prove beneficial in the treatment of pain.
|
In vitro inhibition of ovine prostaglandin G/H synthase 2
|
Ovis aries
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : A new class of acyclic 2-alkyl-1,1,2-triaryl (Z)-olefins as selective cyclooxygenase-2 inhibitors.
Year : 2004
Volume : 47
Issue : 24
First Page : 6108
Last Page : 6111
Authors : Uddin MJ, Praveen Rao PN, McDonald R, Knaus EE.
Abstract : A new class of acyclic (Z)-2-alkyl-1,2-diphenyl-1-(4-methanesulfonylphenyl)ethenes (7) was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure-activity studies identified (Z)-1,2-diphenyl-1-(4-methanesulfonylphenyl)oct-1-ene (7d) as a potent COX-2 inhibitor (IC(50) = 0.42 microM) with a high COX-2 selectivity index (SI > 234). In a carrageenan-induced rat paw edema assay, (Z)-7d exhibited excellent antiinflammatory activity (ID(50) = 1.1 mg/kg). The molecular modeling and structure-activity data acquired indicate that (Z)-olefins having cis C-1 4-methanesulfonylphenyl and C-2 unsubstituted phenyl (or 4-acetoxyphenyl) substituents in conjunction with a C-1 phenyl ring and a C-2 alkyl substituent of appropriate length constitute a suitable template for the design of a novel class of acyclic (Z)-2-alkyl-1,1,2-triaryleth-1-ene COX-2 inhibitors.
|
In vitro inhibitory concentration against ovine Prostaglandin G/H synthase 2
|
Ovis aries
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A new class of acyclic 2-alkyl-1,2-diaryl (E)-olefins as selective cyclooxygenase-2 (COX-2) inhibitors.
Year : 2004
Volume : 14
Issue : 19
First Page : 4911
Last Page : 4914
Authors : Uddin MJ, Rao PN, Rahim MA, McDonald R, Knaus EE.
Abstract : A new class of (E)-2-alkyl-2-(4-methanesulfonylphenyl)-1-phenylethenes were designed for evaluation as selective cyclooxygense-2 (COX-2) inhibitors. The target olefins were synthesized, via a Takeda olefination reaction, followed by oxidation of the respective thiomethyl olefinic intermediate. In vitro COX-1/COX-2 inhibition studies identified (E)-2-(4-methanesulfonylphenyl)-1-phenyloct-1-ene (8d) as a potent (IC(50)=0.77 microM) and selective (Selectivity Index>130) COX-2 inhibitor.
|
In vitro inhibition of Prostaglandin G/H synthase 2 in human whole blood
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-(2-Methoxytetrahydrofuran-2-yl)pyrazoles: a novel class of potent, selective cyclooxygenase-2 (COX-2) inhibitors.
Year : 2004
Volume : 14
Issue : 24
First Page : 6049
Last Page : 6052
Authors : Ranatunge RR, Earl RA, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schwalb DJ, Young DV, Zemtseva IS.
Abstract : A series of 3-(2-methoxytetrahydrofuran-2-yl)pyrazoles (4-10) was synthesized. The compounds were evaluated for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound, 5-(4-methanesulfonylphenyl)-3-(2-methoxytetrahydrofuran-2-yl)-1-p-tolyl-1H-pyrazole 5 showed potent and selective COX-2 inhibition (IC50 for COX-1: >100 microM and COX-2: 1.2 microM).
|
In vitro inhibitory activity against Prostaglandin G/H synthase 2 in murine J774 cells
|
Mus musculus
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : 1,5-Diarylpyrrole-3-acetic acids and esters as novel classes of potent and highly selective cyclooxygenase-2 inhibitors.
Year : 2005
Volume : 48
Issue : 9
First Page : 3428
Last Page : 3432
Authors : Biava M, Porretta GC, Cappelli A, Vomero S, Manetti F, Botta M, Sautebin L, Rossi A, Makovec F, Anzini M.
Abstract : A small set of substituted 1,5-diarylpyrrole-3-acetic and -glyoxylic acid derivatives have been synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity data have been rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site.
|
In vitro inhibitory concentration against Prostaglandin G/H synthase 2 (COX-2) in human whole blood
|
Homo sapiens
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ketone as a potent and orally active cyclooxygenase-2 selective inhibitor: synthesis and biological evaluation.
Year : 2005
Volume : 48
Issue : 11
First Page : 3930
Last Page : 3934
Authors : Khanapure SP, Augustyniak ME, Earl RA, Garvey DS, Letts LG, Martino AM, Murty MG, Schwalb DJ, Shumway MJ, Trocha AM, Young DV, Zemtseva IS, Janero DR.
Abstract : Incorporation of a spacer group between the central scaffold and the aryl ring resulted in a new cyclooxygenase-2 (COX-2) selective inhibitor core structure, 3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ketone (20), with COX-2 IC50 = 0.25 microM and COX-1 IC50 = 14 microM (human whole blood assay). Compound 20 was orally active in the rat air pouch model of inflammation, inhibiting white blood cell infiltration and COX-2-derived PG production. Our data support the identification of a novel COX-2 selective inhibitor core structure exemplified by 20.
|
Percentage inhibition of Prostaglandin G/H synthase 2 in murine J774 cells at 1 uM
|
Mus musculus
|
84.1
%
|
|
Journal : J. Med. Chem.
Title : 1,5-Diarylpyrrole-3-acetic acids and esters as novel classes of potent and highly selective cyclooxygenase-2 inhibitors.
Year : 2005
Volume : 48
Issue : 9
First Page : 3428
Last Page : 3432
Authors : Biava M, Porretta GC, Cappelli A, Vomero S, Manetti F, Botta M, Sautebin L, Rossi A, Makovec F, Anzini M.
Abstract : A small set of substituted 1,5-diarylpyrrole-3-acetic and -glyoxylic acid derivatives have been synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity data have been rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site.
|
Percentage inhibition of Prostaglandin G/H synthase 2 in murine J774 cells at 10 uM
|
Mus musculus
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : 1,5-Diarylpyrrole-3-acetic acids and esters as novel classes of potent and highly selective cyclooxygenase-2 inhibitors.
Year : 2005
Volume : 48
Issue : 9
First Page : 3428
Last Page : 3432
Authors : Biava M, Porretta GC, Cappelli A, Vomero S, Manetti F, Botta M, Sautebin L, Rossi A, Makovec F, Anzini M.
Abstract : A small set of substituted 1,5-diarylpyrrole-3-acetic and -glyoxylic acid derivatives have been synthesized, and their cyclooxygenase (COX-1 and COX-2) inhibiting properties have been evaluated. Some compounds proved to be highly selective COX-2 inhibitors, and their affinity data have been rationalized through docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site.
|
In vitro inhibition of Prostaglandin G/H synthase 2 in human whole blood at 1 uM
|
Homo sapiens
|
75.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-(2-Methoxytetrahydrofuran-2-yl)pyrazoles: a novel class of potent, selective cyclooxygenase-2 (COX-2) inhibitors.
Year : 2004
Volume : 14
Issue : 24
First Page : 6049
Last Page : 6052
Authors : Ranatunge RR, Earl RA, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schwalb DJ, Young DV, Zemtseva IS.
Abstract : A series of 3-(2-methoxytetrahydrofuran-2-yl)pyrazoles (4-10) was synthesized. The compounds were evaluated for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound, 5-(4-methanesulfonylphenyl)-3-(2-methoxytetrahydrofuran-2-yl)-1-p-tolyl-1H-pyrazole 5 showed potent and selective COX-2 inhibition (IC50 for COX-1: >100 microM and COX-2: 1.2 microM).
|
In vitro inhibition of Prostaglandin G/H synthase 2 in human whole blood at 10 uM
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-(2-Methoxytetrahydrofuran-2-yl)pyrazoles: a novel class of potent, selective cyclooxygenase-2 (COX-2) inhibitors.
Year : 2004
Volume : 14
Issue : 24
First Page : 6049
Last Page : 6052
Authors : Ranatunge RR, Earl RA, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schwalb DJ, Young DV, Zemtseva IS.
Abstract : A series of 3-(2-methoxytetrahydrofuran-2-yl)pyrazoles (4-10) was synthesized. The compounds were evaluated for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound, 5-(4-methanesulfonylphenyl)-3-(2-methoxytetrahydrofuran-2-yl)-1-p-tolyl-1H-pyrazole 5 showed potent and selective COX-2 inhibition (IC50 for COX-1: >100 microM and COX-2: 1.2 microM).
|
In vitro inhibition of Prostaglandin G/H synthase 1 in human whole blood at 100 uM
|
Homo sapiens
|
75.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3-(2-Methoxytetrahydrofuran-2-yl)pyrazoles: a novel class of potent, selective cyclooxygenase-2 (COX-2) inhibitors.
Year : 2004
Volume : 14
Issue : 24
First Page : 6049
Last Page : 6052
Authors : Ranatunge RR, Earl RA, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Schwalb DJ, Young DV, Zemtseva IS.
Abstract : A series of 3-(2-methoxytetrahydrofuran-2-yl)pyrazoles (4-10) was synthesized. The compounds were evaluated for their ability to inhibit cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in human whole blood (HWB). The compound, 5-(4-methanesulfonylphenyl)-3-(2-methoxytetrahydrofuran-2-yl)-1-p-tolyl-1H-pyrazole 5 showed potent and selective COX-2 inhibition (IC50 for COX-1: >100 microM and COX-2: 1.2 microM).
|
Inhibitory concentration against COX-2; (valus obtained by Kato et al.)
|
Homo sapiens
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Extraction and visualization of potential pharmacophore points using support vector machines: application to ligand-based virtual screening for COX-2 inhibitors.
Year : 2005
Volume : 48
Issue : 22
First Page : 6997
Last Page : 7004
Authors : Franke L, Byvatov E, Werz O, Steinhilber D, Schneider P, Schneider G.
Abstract : Support vector machines (SVM) were trained to predict cyclooxygenase 2 (COX-2) and thrombin inhibitors. The classifiers were obtained using sets of known COX-2 and thrombin inhibitors as "positive examples" and a large collection of screening compounds as "negative examples". Molecules were encoded by topological pharmacophore-point triangles. In retrospective virtual screening, 50-90% of the known active compounds were listed within the first 0.1% of the ranked database. To check the validity of the constructed classifiers, we developed a method for feature extraction and visualization using SVM. As a result, potential pharmacophore points were weighted according to their importance for COX-2 and thrombin inhibition. Known thrombin and COX-2 pharmacophore points were correctly recognized by the machine learning system. In a prospective virtual screening study, several potential COX-2 inhibitors were predicted and tested in a cellular activity assay. A benzimidazole derivative exhibited significant inhibitory activity with an IC(50) of 0.2 microM, which is better than Celecoxib in our assay. It was demonstrated that the SVM machine-learning method can be used in virtual screening and be analyzed in a human-interpretable way that results in a set of rules for designing novel molecules.
|
In vitro inhibitory activity against ovine cyclooxygenase 2
|
Ovis aries
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 1,3-diphenylprop-2-yn-1-ones as dual inhibitors of cyclooxygenases and lipoxygenases.
Year : 2005
Volume : 15
Issue : 21
First Page : 4842
Last Page : 4845
Authors : Rao PN, Chen QH, Knaus EE.
Abstract : A new class of 1,3-diphenylprop-2-yn-1-ones possessing a p-MeSO2 COX-2 phamacophore on the C-3 phenyl ring was designed for evaluation as dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LOX). Among the group of compounds evaluated, 1-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)prop-2-yn-1-one (11j) exhibited excellent COX-2 inhibitory potency (COX-2 IC50 = 0.1 microM) and selectivity (SI = 300), whereas 1-(4-cyanophenyl)-3-(4-methanesulfonylphenyl)prop-2-yn-1-one (11d) exhibited an optimal combination of COX and LOX inhibition (COX-2 IC50 = 1.0 microM; COX-2 SI = 31.5; 5-LOX IC50 = 1.0 microM; 15-LOX IC50 = 3.2 microM).
|
Inhibitory concentration against COX-2 upon incubation for 15 minutes at 37 degree C
|
Homo sapiens
|
15.0
nM
|
|
Journal : J. Med. Chem.
Title : Extraction and visualization of potential pharmacophore points using support vector machines: application to ligand-based virtual screening for COX-2 inhibitors.
Year : 2005
Volume : 48
Issue : 22
First Page : 6997
Last Page : 7004
Authors : Franke L, Byvatov E, Werz O, Steinhilber D, Schneider P, Schneider G.
Abstract : Support vector machines (SVM) were trained to predict cyclooxygenase 2 (COX-2) and thrombin inhibitors. The classifiers were obtained using sets of known COX-2 and thrombin inhibitors as "positive examples" and a large collection of screening compounds as "negative examples". Molecules were encoded by topological pharmacophore-point triangles. In retrospective virtual screening, 50-90% of the known active compounds were listed within the first 0.1% of the ranked database. To check the validity of the constructed classifiers, we developed a method for feature extraction and visualization using SVM. As a result, potential pharmacophore points were weighted according to their importance for COX-2 and thrombin inhibition. Known thrombin and COX-2 pharmacophore points were correctly recognized by the machine learning system. In a prospective virtual screening study, several potential COX-2 inhibitors were predicted and tested in a cellular activity assay. A benzimidazole derivative exhibited significant inhibitory activity with an IC(50) of 0.2 microM, which is better than Celecoxib in our assay. It was demonstrated that the SVM machine-learning method can be used in virtual screening and be analyzed in a human-interpretable way that results in a set of rules for designing novel molecules.
|
Inhibitory activity against ovine COX2
|
Ovis aries
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and lipoxygenases.
Year : 2006
Volume : 49
Issue : 5
First Page : 1668
Last Page : 1683
Authors : Rao PN, Chen QH, Knaus EE.
Abstract : A group of 1,3-diarylprop-2-yn-1-ones (13, 17, 23, 26 and 27) possessing a C-3 p-SO2Me COX-2 pharmacophore were designed, synthesized and evaluated as potential dual inhibitors of cyclooxygenase-1/2 (COX-1/2) and 5/15-lipoxygenases (5/15-LOX) that exhibit vivo antiinflammatory and analgesic activities. Among this class of compounds, 3-(4-methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-one (13h) was identified as a potent and selective inhibitor of COX-2 (COX-2 IC50 = 0.1 microM; SI = 300), being 5-fold more potent than rofecoxib (COX-2 IC50 = 0.5 microM; SI > 200). In a rat carrageenan-induced paw edema assay 13h exhibited moderate antiinflammatory activity (26% inhibition of inflammation) at 3 h after administration of a 30 mg/kg oral dose. A related dual COX-1/2 and 5/15-LOX inhibitor 3-(4-methanesulfonylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-one (13g, COX-1 IC50 = 31.5 microM; COX-2 IC50 = 1.0 microM; SI = 31.5; 5-LOX IC50 = 1.0 microM; 15-LOX IC50 = 3.2 microM) exhibited more potent antiinflammatory activity (ED50 = 90 mg/kg), being superior to the reference drug aspirin (ED50 = 129 mg/kg). Within this group of compounds 3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e) emerged as having an optimal combination of in vitro COX-1/2 and 5/15-LOX inhibitory effects (COX-1 IC50 = 9.2 microM; COX-2 IC50 = 0.32 microM; SI = 28; 5-LOX IC50 = 0.32 microM; 15-LOX IC50 = 0.36 microM) in conjunction with a good antiinflammatory activity (ED50 = 35 mg/kg) compared to the reference drug celecoxib (ED50 = 10.8 mg/kg) when administered orally. A molecular modeling study where 13e was docked in the COX-2 binding site indicated the C-1 p-i-Pr group was positioned within a hydrophobic pocket (Phe205, Val344, Val349, Phe381 and Leu534), and that this positioning of the i-Pr group facilitated orientation of the C-3 p-SO2Me COX-2 pharmacophore such that it inserted into the COX-2 secondary pocket (His90, Arg513, Ile517 and Val523). A related docking study of 13e in the 15-LOX binding site indicates that the C-3 p-SO2Me COX-2 pharmacophore was positioned in a region closer to the catalytic iron site where it undergoes a hydrogen bonding interaction with His541 and His366, and that the C-1 p-i-Pr substituent is buried deep in a hydrophobic pocket (Ile414, Ile418, Met419 and Ile593) near the base of the 15-LOX binding site.
|
Inhibition of COX2 in human whole blood
|
None
|
760.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Racemic and chiral sulfoxides as potential prodrugs of the COX-2 inhibitors Vioxx and Arcoxia.
Year : 2006
Volume : 16
Issue : 12
First Page : 3209
Last Page : 3212
Authors : Caturla F, Amat M, Reinoso RF, Córdoba M, Warrellow G.
Abstract : The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their potential to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4 were shown to be effectively transformed in vivo into rofecoxib and etoricoxib, respectively, after oral administration in rats. In the case of sulfoxide 2, both a slightly improved pharmacokinetic profile and a better pharmacological activity in an arthritis model were seen when compared with rofecoxib.
|
Inhibition of adjuvant-induced arthritis in Wistar rat at 0.3 mg/kg, po
|
Rattus norvegicus
|
41.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Racemic and chiral sulfoxides as potential prodrugs of the COX-2 inhibitors Vioxx and Arcoxia.
Year : 2006
Volume : 16
Issue : 12
First Page : 3209
Last Page : 3212
Authors : Caturla F, Amat M, Reinoso RF, Córdoba M, Warrellow G.
Abstract : The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their potential to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4 were shown to be effectively transformed in vivo into rofecoxib and etoricoxib, respectively, after oral administration in rats. In the case of sulfoxide 2, both a slightly improved pharmacokinetic profile and a better pharmacological activity in an arthritis model were seen when compared with rofecoxib.
|
Inhibition of yeast-induced pyresis in Wistar rat at 1 mg/kg, po
|
Rattus norvegicus
|
48.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Racemic and chiral sulfoxides as potential prodrugs of the COX-2 inhibitors Vioxx and Arcoxia.
Year : 2006
Volume : 16
Issue : 12
First Page : 3209
Last Page : 3212
Authors : Caturla F, Amat M, Reinoso RF, Córdoba M, Warrellow G.
Abstract : The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their potential to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4 were shown to be effectively transformed in vivo into rofecoxib and etoricoxib, respectively, after oral administration in rats. In the case of sulfoxide 2, both a slightly improved pharmacokinetic profile and a better pharmacological activity in an arthritis model were seen when compared with rofecoxib.
|
Inhibition of COX2 in human whole blood
|
Homo sapiens
|
760.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Racemic and chiral sulfoxides as potential prodrugs of 4-pyrone COX-2 inhibitors.
Year : 2006
Volume : 16
Issue : 13
First Page : 3605
Last Page : 3608
Authors : Caturla F, Amat M, Reinoso RF, Calaf E, Warrellow G.
Abstract : The preparation of the sulfoxide analogues 7, 8, and 9 and their enantiomerically pure forms is discussed as well as their ability to act as prodrugs of the potent and selective sulfone-containing COX-2 inhibitors 1, 2, and 3. Sulfoxide derivatives 7 and 9 were shown to be rapidly transformed in vivo into the corresponding sulfone derivatives 1 and 3, after oral administration to rats.
|
Activity against adjuvant-induced arthritis in po dosed Wistar rat
|
Rattus norvegicus
|
0.3
mg kg-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Racemic and chiral sulfoxides as potential prodrugs of 4-pyrone COX-2 inhibitors.
Year : 2006
Volume : 16
Issue : 13
First Page : 3605
Last Page : 3608
Authors : Caturla F, Amat M, Reinoso RF, Calaf E, Warrellow G.
Abstract : The preparation of the sulfoxide analogues 7, 8, and 9 and their enantiomerically pure forms is discussed as well as their ability to act as prodrugs of the potent and selective sulfone-containing COX-2 inhibitors 1, 2, and 3. Sulfoxide derivatives 7 and 9 were shown to be rapidly transformed in vivo into the corresponding sulfone derivatives 1 and 3, after oral administration to rats.
|
Inhibition of ovine COX2 by enzyme immunoassay
|
Ovis aries
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of methanesulfonamide analogues of rofecoxib: Replacement of methanesulfonyl by methanesulfonamido decreases cyclooxygenase-2 selectivity.
Year : 2007
Volume : 15
Issue : 2
First Page : 1056
Last Page : 1061
Authors : Zarghi A, Praveen Rao PN, Knaus EE.
Abstract : A new group of 3-(4-substituted-phenyl)-4-(4-methylsulfonamidophenyl)-2(5H)furanones in which the methylsulfonyl (MeSO(2)) COX-2 pharmacophore present in rofecoxib was replaced by a methanesulfonamido (MeSO(2)NH) moiety, and where the substituent at the para-position of the C-3 phenyl ring was simultaneously varied (H, F, Cl, Br, Me, OMe), were evaluated to determine the combined effects of steric and electronic substituent properties upon COX-1 and COX-2 inhibitory potency and COX isozyme selectivity. Structure-activity relationship (SAR) studies showed that compounds having a neutral (H), or electronegative halogen (F, Cl, Br), substituent at the para-position of the C-3 phenyl ring inhibited both COX-1 and COX-2 with COX-2 selectivity indexes in the 3.1-39.4 range. In contrast, compounds having an electron-donating Me or OMe substituent were selective inhibitors of COX-2 (COX-1 IC(50)>100 microM). These SAR data indicate the 3-aryl-4-(4-methylsulfonamidophenyl)-2(5H)furanone scaffold provides a suitable template to design COX inhibitors with variable COX-2 selectivity indexes.
|
Inhibition of human recombinant COX2 expressed in insect Sf21 cells by EIA assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : J. Nat. Prod.
Title : Lipoxygenase inhibitory constituents of the fruits of noni (Morinda citrifolia) collected in Tahiti.
Year : 2007
Volume : 70
Issue : 5
First Page : 859
Last Page : 862
Authors : Deng S, Palu 'K, West BJ, Su CX, Zhou BN, Jensen JC.
Abstract : A phytochemical study of the fruits of noni (Morinda citrifolia) collected in Tahiti led to the isolation of two new lignans, (+)-3,4,3',4'-tetrahydroxy-9,7'alpha-epoxylignano-7 alpha,9'-lactone (1) and (+)-3,3'-bisdemethyltanegool (2), as well as seven known compounds, (-)-pinoresinol (3), (-)-3,3'-bisdemethylpinoresinol (4), quercetin (5), kaempferol (6), scopoletin (7), isoscopoletin (8), and vanillin. The structures of 1 and 2 were determined by spectroscopic techniques. Compounds 3, 6, and 8 were isolated for the first time from noni fruit. Compounds 1-8 were shown to inhibit 5- and/or 15-lipoxygenase, with IC50 values ranging from 0.43 to 16.5 microM. Compound 5 exhibited weak inhibitory activity toward cyclooxygenase-2.
|
Inhibition of ovine COX2 by enzyme immuno assay
|
Ovis aries
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel (E)-2-(aryl)-3-(4-methanesulfonylphenyl)acrylic ester prodrugs possessing a diazen-1-ium-1,2-diolate moiety: design, synthesis, cyclooxygenase inhibition, and nitric oxide release studies.
Year : 2007
Volume : 15
Issue : 21
First Page : 6796
Last Page : 6801
Authors : Abdellatif KR, Dong Y, Chen QH, Chowdhury MA, Knaus EE.
Abstract : A novel group of hybrid nitric oxide-releasing anti-inflammatory drugs (11) possessing a 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate, or 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate, nitric oxide (.NO) donor moiety attached via a one-carbon methylene spacer to the carboxylic acid group of (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acids were synthesized. These ester prodrugs (11) all exhibited in vitro inhibitory activity against the cyclooxygenase-2 (COX-2) isozyme (IC(50)=0.94-31.6 microM range). All compounds released .NO upon incubation with phosphate buffer (PBS) at pH 7.4 (3.2-11.3% range). In comparison, the percentage of .NO released was significantly higher (48.6-75.3% range) when these hybrid ester prodrugs were incubated in the presence of rat serum. These incubation studies suggest that both .NO and the parent anti-inflammatory (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acid would be released upon in vivo cleavage by non-specific serum esterases. O(2)-[(E)-2-(4-Acetylaminophenyl)-3-(4-methanesulfonylphenyl)acryloyloxymethyl]-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11f) is a moderately potent (IC(50)=0.94 microM) and selective (SI>104) COX-2 inhibitor that released 73% of the theoretical maximal release of two molecules of .NO/molecule of the parent hybrid ester prodrug upon incubation with rat serum. Hybrid ester .NO-donor prodrugs offer a potential drug design concept for the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular side effects.
|
Inhibition of ovine COX2 at 0.1 uM
|
Ovis aries
|
75.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Toluene-sulfonyl-3-[(3'-hydroxy-5'-substituted)-gamma-butyrolactone]-indoles: synthesis, COX-2 inhibition and anti-cancer activities.
Year : 2008
Volume : 18
Issue : 1
First Page : 85
Last Page : 89
Authors : Singh P, Mittal A, Bhardwaj A, Kaur S, Kumar S.
Abstract : Indoles carrying a cyclic ester (gamma-butyrolactone) at C-3 position have been synthesized by the allylation of 3-indoleglyoxylate followed by iodocyclisation and the nucleophilic replacement of the iodo-group. Screening of these molecules for COX-2 inhibition and anti-cancer activities has identified compounds 10 and 11 as highly potent and selective for COX-2 as well as showing remarkable anti-cancer activities (better than that of indomethacin).
|
Inhibition of ovine COX2 at 0.01 uM
|
Ovis aries
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Toluene-sulfonyl-3-[(3'-hydroxy-5'-substituted)-gamma-butyrolactone]-indoles: synthesis, COX-2 inhibition and anti-cancer activities.
Year : 2008
Volume : 18
Issue : 1
First Page : 85
Last Page : 89
Authors : Singh P, Mittal A, Bhardwaj A, Kaur S, Kumar S.
Abstract : Indoles carrying a cyclic ester (gamma-butyrolactone) at C-3 position have been synthesized by the allylation of 3-indoleglyoxylate followed by iodocyclisation and the nucleophilic replacement of the iodo-group. Screening of these molecules for COX-2 inhibition and anti-cancer activities has identified compounds 10 and 11 as highly potent and selective for COX-2 as well as showing remarkable anti-cancer activities (better than that of indomethacin).
|
Inhibition of ovine COX1 at 10 uM
|
Ovis aries
|
75.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Toluene-sulfonyl-3-[(3'-hydroxy-5'-substituted)-gamma-butyrolactone]-indoles: synthesis, COX-2 inhibition and anti-cancer activities.
Year : 2008
Volume : 18
Issue : 1
First Page : 85
Last Page : 89
Authors : Singh P, Mittal A, Bhardwaj A, Kaur S, Kumar S.
Abstract : Indoles carrying a cyclic ester (gamma-butyrolactone) at C-3 position have been synthesized by the allylation of 3-indoleglyoxylate followed by iodocyclisation and the nucleophilic replacement of the iodo-group. Screening of these molecules for COX-2 inhibition and anti-cancer activities has identified compounds 10 and 11 as highly potent and selective for COX-2 as well as showing remarkable anti-cancer activities (better than that of indomethacin).
|
Inhibition of ovine COX2
|
Ovis aries
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Toluene-sulfonyl-3-[(3'-hydroxy-5'-substituted)-gamma-butyrolactone]-indoles: synthesis, COX-2 inhibition and anti-cancer activities.
Year : 2008
Volume : 18
Issue : 1
First Page : 85
Last Page : 89
Authors : Singh P, Mittal A, Bhardwaj A, Kaur S, Kumar S.
Abstract : Indoles carrying a cyclic ester (gamma-butyrolactone) at C-3 position have been synthesized by the allylation of 3-indoleglyoxylate followed by iodocyclisation and the nucleophilic replacement of the iodo-group. Screening of these molecules for COX-2 inhibition and anti-cancer activities has identified compounds 10 and 11 as highly potent and selective for COX-2 as well as showing remarkable anti-cancer activities (better than that of indomethacin).
|
Inhibition of human COX2
|
Homo sapiens
|
292.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as highly potent and specific COX-2 inhibitors.
Year : 2008
Volume : 16
Issue : 5
First Page : 2183
Last Page : 2199
Authors : Orjales A, Mosquera R, López B, Olivera R, Labeaga L, Núñez MT.
Abstract : New series of 2-(4-methylsulfonylphenyl) and 2-(4-sulfamoylphenyl)pyrimidines were synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). COX-1 and COX-2 inhibitory activity of these compounds was determined using purified enzyme (PE) and human whole blood (HWB) assays. Extensive structure-activity relationship (SAR) work was carried out within these series, and a wide number of potent and specific COX-2 inhibitors were identified (HWB COX-2 IC(50)=2.4-0.3nM and 80- to 780-fold more selective than rofecoxib).
|
Inhibition of human COX2 in human whole blood
|
Homo sapiens
|
211.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as highly potent and specific COX-2 inhibitors.
Year : 2008
Volume : 16
Issue : 5
First Page : 2183
Last Page : 2199
Authors : Orjales A, Mosquera R, López B, Olivera R, Labeaga L, Núñez MT.
Abstract : New series of 2-(4-methylsulfonylphenyl) and 2-(4-sulfamoylphenyl)pyrimidines were synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). COX-1 and COX-2 inhibitory activity of these compounds was determined using purified enzyme (PE) and human whole blood (HWB) assays. Extensive structure-activity relationship (SAR) work was carried out within these series, and a wide number of potent and specific COX-2 inhibitors were identified (HWB COX-2 IC(50)=2.4-0.3nM and 80- to 780-fold more selective than rofecoxib).
|
Inhibition of ovine COX2 by enzyme immunoassay
|
Ovis aries
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Diazen-1-ium-1,2-diolated and nitrooxyethyl nitric oxide donor ester prodrugs of anti-inflammatory (E)-2-(aryl)-3-(4-methanesulfonylphenyl)acrylic acids: synthesis, cyclooxygenase inhibition, and nitric oxide release studies.
Year : 2008
Volume : 16
Issue : 6
First Page : 3302
Last Page : 3308
Authors : Abdellatif KR, Chowdhury MA, Dong Y, Chen QH, Knaus EE.
Abstract : A new group of hybrid nitric oxide-releasing anti-inflammatory drugs wherein an O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (11a-d), or 2-nitrooxyethyl (12a-d), (*)NO-donor moiety is attached directly to the carboxylic acid group of (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acids were synthesized. The 2-nitrooxyethyl ester prodrugs (12a-d) all exhibited in vitro inhibitory activity against the cyclooxygenase-2 (COX-2) isozyme (IC(50)=0.07-2.8 microM range). All compounds released a low amount of (*)NO upon incubation with phosphate buffer (PBS) at pH 7.4 (1.0-4.8% range). In comparison, the percentage (*)NO released was significantly higher (76.2-83.0% range) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum, or moderately higher (7.6-10.1% range) when the nitrooxyethyl ester prodrugs were incubated in the presence of L-cysteine. These incubation studies suggest that both (*)NO and the parent anti-inflammatory (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acid would be released upon in vivo cleavage by non-specific serum esterases in the case of the diazen-1-ium-1,2-diolate esters (11a-d), or interaction with systemic thiols in the case of the nitrate esters (12a-d). O(2)-Acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (E)-3-(4-methanesulfonylphenyl)-2-phenylacrylate (11a) released 83% of the theoretical maximal release of 2 molecules of (*)NO/molecule of the parent hybrid ester prodrug upon incubation with rat serum. Hybrid ester anti-inflammatory/(*)NO donor prodrugs offer a potential drug design concept targeted toward the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular effects.
|
Inhibition of ovine COX2 by enzyme immuno assay
|
Ovis aries
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and cyclooxygenase inhibitory activities of linear 1-(methanesulfonylphenyl or benzenesulfonamido)-2-(pyridyl)acetylene regioisomers.
Year : 2008
Volume : 16
Issue : 4
First Page : 1948
Last Page : 1956
Authors : Chowdhury MA, Dong Y, Chen QH, Abdellatif KR, Knaus EE.
Abstract : A group of 1-(aminosulfonylphenyl and methylsulfonylphenyl)-2-(pyridyl)acetylene regioisomers were designed such that a COX-2 SO2NH2 pharmacophore was located at the para-position of the phenyl ring, or a SO2Me pharmacophore was placed at the ortho-, meta- or para-position of the phenyl ring, on an acetylene template (scaffold). The point of attachment of the pyridyl ring to the acetylene linker was simultaneously varied (2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl) to determine the combined effects of positional, steric, and electronic substituent properties upon COX-1 and COX-2 inhibitory potency and COX isozyme selectivity. These target linear 1-(phenyl)-2-(pyridyl)acetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction. Structure-activity relationship (SAR) data (IC50 values) acquired by determination of the in vitro ability of the title compounds to inhibit the COX-1 and COX-2 isozymes showed that the position of the COX-2 SO2NH2 or SO2Me pharmacophore on the phenyl ring, and the point of attachment of the pyridyl ring to the acetylene linker, were either individual, or collective, determinants of COX-2 inhibitory potency and selectivity. A number of compounds discovered in this study, particularly 1-(4-aminosulfonylphenyl)-2-(3-methyl-2-pyridyl)acetylene (22), 1-(3-methanesulfonylphenyl)-2-(2-pyridyl)acetylene (27), 1-(3-methanesulfonylphenyl)-2-(4-pyridyl)acetylene (29), 1-(4-methanesulfonylphenyl)-2-(2-pyridyl)acetylene (30), and 1-(4-methanesulfonylphenyl)-2-(3-pyridyl)acetylene (31), exhibit potent (IC50 = 0.04-0.33 microM range) and selective (SI = 18 to >312 range) COX-2 inhibitory activities, that compare favorably with the reference drug celecoxib (COX-2 IC50 = 0.07 microM; COX-2 SI = 473). The sulfonamide (22), and methylsulfonyl (27 and 31), compounds exhibited anti-inflammatory activities (ID50 = 59.9-76.6 mg/kg range) that were intermediate in potency between the reference drugs aspirin (ID50 = 128.7 mg/kg) and celecoxib (ID50 = 10.8 mg/kg).
|
Inhibition of LOX5 from human PBML cells at 10 uM by enzyme immuno assay
|
Homo sapiens
|
11.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines as cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibitors.
Year : 2008
Volume : 16
Issue : 7
First Page : 3907
Last Page : 3916
Authors : Reddy MV, Billa VK, Pallela VR, Mallireddigari MR, Boominathan R, Gabriel JL, Reddy EP.
Abstract : A series of 20 novel 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines were designed, synthesized, and screened in vitro for anti-inflammatory activity. These compounds were designed for evaluation as dual inhibitors of cyclooxygenases (COX-1 and COX-2) and lipoxygenases (LOX-5, LOX-12, and LOX-15) that are responsible for inflammation and pain. All pyrazoline molecules prepared are optically active and compounds that are more potent in COX-2 inhibitory activity (5a and 5f) were resolved by chiral column and each enantiomer was tested for cyclooxygenase inhibitory activity. Molecular modeling and comparison of molecular models of 5a enantiomers with that of celecoxib model shows that 5a (enantiomer-1) and 5a (enantiomer-2) have more hydrogen bonding interactions in the catalytic domain of COX-2 enzyme than celecoxib. Compounds 5a, 5e, and 5f showed moderate to good LOX-5 and LOX-15 inhibitory activity and this is comparable to that of celecoxib and more potent than rofecoxib.
|
Inhibition of LOX12 from human platelets at 10 uM by enzyme immuno assay
|
Homo sapiens
|
-2.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines as cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibitors.
Year : 2008
Volume : 16
Issue : 7
First Page : 3907
Last Page : 3916
Authors : Reddy MV, Billa VK, Pallela VR, Mallireddigari MR, Boominathan R, Gabriel JL, Reddy EP.
Abstract : A series of 20 novel 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines were designed, synthesized, and screened in vitro for anti-inflammatory activity. These compounds were designed for evaluation as dual inhibitors of cyclooxygenases (COX-1 and COX-2) and lipoxygenases (LOX-5, LOX-12, and LOX-15) that are responsible for inflammation and pain. All pyrazoline molecules prepared are optically active and compounds that are more potent in COX-2 inhibitory activity (5a and 5f) were resolved by chiral column and each enantiomer was tested for cyclooxygenase inhibitory activity. Molecular modeling and comparison of molecular models of 5a enantiomers with that of celecoxib model shows that 5a (enantiomer-1) and 5a (enantiomer-2) have more hydrogen bonding interactions in the catalytic domain of COX-2 enzyme than celecoxib. Compounds 5a, 5e, and 5f showed moderate to good LOX-5 and LOX-15 inhibitory activity and this is comparable to that of celecoxib and more potent than rofecoxib.
|
Inhibition of LOX15 from rabbit reticulocytes at 10 uM by enzyme immuno assay
|
Oryctolagus cuniculus
|
6.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and biological evaluation of 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines as cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibitors.
Year : 2008
Volume : 16
Issue : 7
First Page : 3907
Last Page : 3916
Authors : Reddy MV, Billa VK, Pallela VR, Mallireddigari MR, Boominathan R, Gabriel JL, Reddy EP.
Abstract : A series of 20 novel 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines were designed, synthesized, and screened in vitro for anti-inflammatory activity. These compounds were designed for evaluation as dual inhibitors of cyclooxygenases (COX-1 and COX-2) and lipoxygenases (LOX-5, LOX-12, and LOX-15) that are responsible for inflammation and pain. All pyrazoline molecules prepared are optically active and compounds that are more potent in COX-2 inhibitory activity (5a and 5f) were resolved by chiral column and each enantiomer was tested for cyclooxygenase inhibitory activity. Molecular modeling and comparison of molecular models of 5a enantiomers with that of celecoxib model shows that 5a (enantiomer-1) and 5a (enantiomer-2) have more hydrogen bonding interactions in the catalytic domain of COX-2 enzyme than celecoxib. Compounds 5a, 5e, and 5f showed moderate to good LOX-5 and LOX-15 inhibitory activity and this is comparable to that of celecoxib and more potent than rofecoxib.
|
Inhibition of COX2 by scintillation proximity assay
|
None
|
760.0
nM
|
|
Journal : J. Nat. Prod.
Title : Screening of ubiquitous plant constituents for COX-2 inhibition with a scintillation proximity based assay.
Year : 2002
Volume : 65
Issue : 11
First Page : 1517
Last Page : 1521
Authors : Huss U, Ringbom T, Perera P, Bohlin L, Vasänge M.
Abstract : A rapid semi-homogeneous cyclooxygenase-2 (COX-2) enzymatic assay using scintillation proximity assay (SPA) technology was developed, and 49 ubiquitous plant secondary metabolites were screened for inhibition of COX-2-catalyzed prostaglandin E(2) (PGE(2)) biosynthesis. Assay conditions were optimized with respect to reaction time, amount of antibody, radiolabeled PGE(2), and SPA beads, and the kinetic parameter, K(m), was estimated. The assay was validated with two natural triterpenoids, ursolic and oleanolic acid, known to inhibit COX-2, as well as with four synthetic COX inhibitors, NS-398, rofecoxib, indomethacin, and aspirin. Plant metabolites of different biosynthetic origin representing several substance classes, including alkaloids, anthraquinones, flavonoids, phenylpropanes, steroids, and terpenes, were screened for inhibition of COX-2-catalyzed PGE(2) production. Of these 49 plant metabolites, eugenol, pyrogallol, and cinnamaldehyde (with IC(50) values of 129, 144, and 245 microM, respectively) were found to inhibit COX-2. This study showed that a COX-2-catalyzed PGE(2) assay using SPA is suitable for screening natural compounds with respect to COX-2 inhibition.
|
Inhibition of COX2 at 1 uM
|
None
|
75.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : 2,3,5-Substituted tetrahydrofurans: COX-2 inhibitory activities of 5-hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols.
Year : 2008
Volume : 43
Issue : 12
First Page : 2792
Last Page : 2799
Authors : Singh P, Mittal A, Kaur S, Kumar S.
Abstract : 5-Hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols have been investigated for their COX-1 and COX-2 inhibitory activities. Compounds 17, 18 and 20 have been identified as showing appreciable COX-2 inhibition and selectivity. The group present at C-5 of tetrahydrofuran and the substituents at the two phenyl rings, through their interactions with active site amino acid residues, significantly affect the activities of these molecules. The quantitative structure-activity relationship studies indicate the role of logP, TPSA, molecular connectivity and valence connectivity towards the activities of these molecules.
|
Inhibition of COX2 at 10 uM
|
None
|
100.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : 2,3,5-Substituted tetrahydrofurans: COX-2 inhibitory activities of 5-hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols.
Year : 2008
Volume : 43
Issue : 12
First Page : 2792
Last Page : 2799
Authors : Singh P, Mittal A, Kaur S, Kumar S.
Abstract : 5-Hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols have been investigated for their COX-1 and COX-2 inhibitory activities. Compounds 17, 18 and 20 have been identified as showing appreciable COX-2 inhibition and selectivity. The group present at C-5 of tetrahydrofuran and the substituents at the two phenyl rings, through their interactions with active site amino acid residues, significantly affect the activities of these molecules. The quantitative structure-activity relationship studies indicate the role of logP, TPSA, molecular connectivity and valence connectivity towards the activities of these molecules.
|
Inhibition of COX1 at 1 uM
|
None
|
75.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : 2,3,5-Substituted tetrahydrofurans: COX-2 inhibitory activities of 5-hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols.
Year : 2008
Volume : 43
Issue : 12
First Page : 2792
Last Page : 2799
Authors : Singh P, Mittal A, Kaur S, Kumar S.
Abstract : 5-Hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols have been investigated for their COX-1 and COX-2 inhibitory activities. Compounds 17, 18 and 20 have been identified as showing appreciable COX-2 inhibition and selectivity. The group present at C-5 of tetrahydrofuran and the substituents at the two phenyl rings, through their interactions with active site amino acid residues, significantly affect the activities of these molecules. The quantitative structure-activity relationship studies indicate the role of logP, TPSA, molecular connectivity and valence connectivity towards the activities of these molecules.
|
Inhibition of COX2
|
None
|
300.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 2,3,5-Substituted tetrahydrofurans: COX-2 inhibitory activities of 5-hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols.
Year : 2008
Volume : 43
Issue : 12
First Page : 2792
Last Page : 2799
Authors : Singh P, Mittal A, Kaur S, Kumar S.
Abstract : 5-Hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols have been investigated for their COX-1 and COX-2 inhibitory activities. Compounds 17, 18 and 20 have been identified as showing appreciable COX-2 inhibition and selectivity. The group present at C-5 of tetrahydrofuran and the substituents at the two phenyl rings, through their interactions with active site amino acid residues, significantly affect the activities of these molecules. The quantitative structure-activity relationship studies indicate the role of logP, TPSA, molecular connectivity and valence connectivity towards the activities of these molecules.
|
Anticancer activity against human PC3 cells at 1 uM
|
Homo sapiens
|
15.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : 2,3,5-Substituted tetrahydrofurans: COX-2 inhibitory activities of 5-hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols.
Year : 2008
Volume : 43
Issue : 12
First Page : 2792
Last Page : 2799
Authors : Singh P, Mittal A, Kaur S, Kumar S.
Abstract : 5-Hydroxymethyl-/carboxyl-2,3-diaryl-tetrahydro-furan-3-ols have been investigated for their COX-1 and COX-2 inhibitory activities. Compounds 17, 18 and 20 have been identified as showing appreciable COX-2 inhibition and selectivity. The group present at C-5 of tetrahydrofuran and the substituents at the two phenyl rings, through their interactions with active site amino acid residues, significantly affect the activities of these molecules. The quantitative structure-activity relationship studies indicate the role of logP, TPSA, molecular connectivity and valence connectivity towards the activities of these molecules.
|
Inhibition of human recombinant COX2 expressed in Sf21 cells assessed as effect on prostaglandin E2 production by ELISA
|
Homo sapiens
|
74.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of dithiolethiones as novel cyclooxygenase inhibitors.
Year : 2009
Volume : 19
Issue : 2
First Page : 459
Last Page : 461
Authors : Zanatta SD, Manallack DT, Jarrott B, Williams SJ.
Abstract : 3H-1,2-Dithiole-3-thiones substituted with a 3,5-di-tert-butyl-4-hydroxyphenyl (DTBHP) or a 3,5-di-tert-butyl-4-methoxyphenyl group at the C5 position were prepared and their ability to inhibit the cyclooxygenase isoenzymes, COX-1 and COX-2 was evaluated. Both compounds were potent inhibitors of COX-2 (relative to rofecoxib), and while the phenol was a weak inhibitor of COX-1, the methyl ether gave no measurable inhibition. Docking studies of the two compounds into the COX-1 and -2 active sites showed that the methyl ether could only fit in the COX-2 active site whereas the phenol could be docked into both COX-1 and -2. This study reports a new mode for inhibitor binding to COX-1 and -2 and a novel structural scaffold for the development of COX-2 selective inhibitors.
|
Inhibition of ovine COX1 at 100 uM by enzyme immunoassay relative to control
|
Ovis aries
|
13.66
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of 4,5-diphenyloxazolone derivatives on route towards selective COX-2 inhibitors.
Year : 2009
Volume : 44
Issue : 5
First Page : 1830
Last Page : 1837
Authors : Dündar Y, Unlü S, Banoğlu E, Entrena A, Costantino G, Nuñez MT, Labeaga L, Sahin MF, Noyanalpan N.
Abstract : A series of 3-unsubstituted/substituted-4,5-diphenyl-2-oxo-3H-1,3-oxazole derivatives were prepared as selective cyclooxygenase-2 (COX-2) inhibitors. Among the synthesized compounds, 4-(4-phenyl-3-methyl-2-oxo-3H-1,3-oxazol-5-yl)benzensulfonamide (compound 6) showed selective COX-2 inhibition with a selectivity index of >50 (IC(50)COX-1=>100 microm, IC(50)COX-2=2 microm) in purified enzyme (PE) assay. Compound 6 also exhibited selective COX-2 inhibition in human whole blood assay. Molecular docking studies showed that 6 can be docked into the COX-2 binding site thus providing the molecular basis for its activity.
|
Inhibition of ovine COX2 at 1 uM by enzyme immunoassay relative to control
|
Ovis aries
|
66.78
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of 4,5-diphenyloxazolone derivatives on route towards selective COX-2 inhibitors.
Year : 2009
Volume : 44
Issue : 5
First Page : 1830
Last Page : 1837
Authors : Dündar Y, Unlü S, Banoğlu E, Entrena A, Costantino G, Nuñez MT, Labeaga L, Sahin MF, Noyanalpan N.
Abstract : A series of 3-unsubstituted/substituted-4,5-diphenyl-2-oxo-3H-1,3-oxazole derivatives were prepared as selective cyclooxygenase-2 (COX-2) inhibitors. Among the synthesized compounds, 4-(4-phenyl-3-methyl-2-oxo-3H-1,3-oxazol-5-yl)benzensulfonamide (compound 6) showed selective COX-2 inhibition with a selectivity index of >50 (IC(50)COX-1=>100 microm, IC(50)COX-2=2 microm) in purified enzyme (PE) assay. Compound 6 also exhibited selective COX-2 inhibition in human whole blood assay. Molecular docking studies showed that 6 can be docked into the COX-2 binding site thus providing the molecular basis for its activity.
|
Inhibition of ovine COX2 by enzyme immunoassay
|
Ovis aries
|
398.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of 4,5-diphenyloxazolone derivatives on route towards selective COX-2 inhibitors.
Year : 2009
Volume : 44
Issue : 5
First Page : 1830
Last Page : 1837
Authors : Dündar Y, Unlü S, Banoğlu E, Entrena A, Costantino G, Nuñez MT, Labeaga L, Sahin MF, Noyanalpan N.
Abstract : A series of 3-unsubstituted/substituted-4,5-diphenyl-2-oxo-3H-1,3-oxazole derivatives were prepared as selective cyclooxygenase-2 (COX-2) inhibitors. Among the synthesized compounds, 4-(4-phenyl-3-methyl-2-oxo-3H-1,3-oxazol-5-yl)benzensulfonamide (compound 6) showed selective COX-2 inhibition with a selectivity index of >50 (IC(50)COX-1=>100 microm, IC(50)COX-2=2 microm) in purified enzyme (PE) assay. Compound 6 also exhibited selective COX-2 inhibition in human whole blood assay. Molecular docking studies showed that 6 can be docked into the COX-2 binding site thus providing the molecular basis for its activity.
|
Inhibition of COX2
|
None
|
760.0
nM
|
|
Journal : J. Nat. Prod.
Title : Expanding the ChemGPS chemical space with natural products.
Year : 2005
Volume : 68
Issue : 7
First Page : 985
Last Page : 991
Authors : Larsson J, Gottfries J, Bohlin L, Backlund A.
Abstract : Recently various attempts have been made to increase the efficacy and precision of chemical libraries used in high-throughput screening (HTS) drug discovery approaches. One such approach is ChemGPS, which provides a defined chemical space for prescreening evaluation of chemical compound properties or virtual dereplication. In the present study, ChemGPS has been applied to a set of natural products shown to exhibit cyclooxygenase-1 and/or -2 (COX-1/2) inhibition. With the purpose of defining chemical properties and linking these to the observed mode of enzyme inhibition, this resulted in two lines of reasoning. On one hand several specific features of these compounds have been identified and discussed. Overall COX inhibition was frequently correlated with the presence of at least one ring in the structure, fragments exhibiting structural rigidity, and a relatively large molecular size. The concept "size" includes several parameters, e.g., molecular volume, weight, and number of bonds. On the other hand, and possibly even more important, was the unexpected finding that the natural products studied to a large extent fell outside the defined ChemGPS chemical space. Therefore, we also propose an expanded space for natural products: ChemGPS-NP.
|
Inhibition of human COX2 expressed in african green monkey COS cells assessed as inhibition of arachidonic acid-stimulated PGE2 production treated 1 hr before arachidonic acid challenge by enzyme immunoassay
|
Homo sapiens
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors.
Year : 2009
Volume : 19
Issue : 15
First Page : 4504
Last Page : 4508
Authors : Swarbrick ME, Beswick PJ, Gleave RJ, Green RH, Bingham S, Bountra C, Carter MC, Chambers LJ, Chessell IP, Clayton NM, Collins SD, Corfield JA, Hartley CD, Kleanthous S, Lambeth PF, Lucas FS, Mathews N, Naylor A, Page LW, Payne JJ, Pegg NA, Price HS, Skidmore J, Stevens AJ, Stocker R, Stratton SC, Stuart AJ, Wiseman JO.
Abstract : A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
|
Inhibition of human COX2 expressed in baculovirus-infected SF9 cells assessed as inhibition of arachidonic acid-stimulated PGE2 production treated 1 hr before arachidonic acid challenge by enzyme immunoassay
|
Homo sapiens
|
107.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors.
Year : 2009
Volume : 19
Issue : 15
First Page : 4504
Last Page : 4508
Authors : Swarbrick ME, Beswick PJ, Gleave RJ, Green RH, Bingham S, Bountra C, Carter MC, Chambers LJ, Chessell IP, Clayton NM, Collins SD, Corfield JA, Hartley CD, Kleanthous S, Lambeth PF, Lucas FS, Mathews N, Naylor A, Page LW, Payne JJ, Pegg NA, Price HS, Skidmore J, Stevens AJ, Stocker R, Stratton SC, Stuart AJ, Wiseman JO.
Abstract : A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
|
Inhibition of COX2 in human whole blood assessed as inhibition of lipopolysaccharide-stimulated PGE2 production after 24 hrs by enzyme immunoassay
|
Homo sapiens
|
260.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidinyl] amines and ethers as potent and selective cyclooxygenase-2 inhibitors.
Year : 2009
Volume : 19
Issue : 15
First Page : 4504
Last Page : 4508
Authors : Swarbrick ME, Beswick PJ, Gleave RJ, Green RH, Bingham S, Bountra C, Carter MC, Chambers LJ, Chessell IP, Clayton NM, Collins SD, Corfield JA, Hartley CD, Kleanthous S, Lambeth PF, Lucas FS, Mathews N, Naylor A, Page LW, Payne JJ, Pegg NA, Price HS, Skidmore J, Stevens AJ, Stocker R, Stratton SC, Stuart AJ, Wiseman JO.
Abstract : A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
|
Inhibition of ovine COX2 assessed as inhibition of PGF2a formation after 20 mins by Ellman's method
|
Ovis aries
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Mono-, di-, and triaryl substituted tetrahydropyrans as cyclooxygenase-2 and tumor growth inhibitors. Synthesis and biological evaluation.
Year : 2010
Volume : 53
Issue : 9
First Page : 3707
Last Page : 3717
Authors : Singh P, Bhardwaj A.
Abstract : Rationally designed tetrahydropyrans (THPs) carrying one, two, or three aryl rings and other substituents were synthesized by the allylation of beta-hydroxy ketones followed by iodocyclization. It has been observed that compounds with one aryl ring on THP are moderate inhibitors of cyclooxygenase-1 (COX-1) (IC(50) = 0.3 microM) and cyclooxygenase-2 (IC(50) = 0.17 microM) with poor selectivity index (SI = 2-3) for COX-2. The presence of two aryl rings enhanced their inhibitory activities for COX-2 (IC(50) = 0.9-5.5 nM). Selectivity for COX-2 over COX-1 also increased (SI = 50-1900), while triaryl substituted THPs, along with high inhibition (IC(50) = 0.57-4.0 nM), also exhibited excellent selectivity for COX-2 over COX-1 (SI = 3200-44000). Similar to the experimental results of increased COX-2 inhibition and selectivity with the increase in the size of the molecule, their docking in the active sites of COX-1 and COX-2 also showed same trend. Seven compounds from the category of di- and triaryl substituted THPs exhibited average GI(50) over all the human tumor cell lines in the range 1.6-3.2 microM and showed in vitro therapeutic indices of 8-17.
|
Inhibition of sheep COX2 at 10 uM by enzyme immunoassay
|
Ovis aries
|
59.34
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation, and docking studies of novel heterocyclic diaryl compounds as selective COX-2 inhibitors.
Year : 2010
Volume : 18
Issue : 17
First Page : 6367
Last Page : 6376
Authors : Eren G, Unlü S, Nuñez MT, Labeaga L, Ledo F, Entrena A, Banoğlu E, Costantino G, Sahin MF.
Abstract : Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC(50)=0.061 microM and COX-2 IC(50)=0.325 microM; selectivity index (SI)=0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC(50)=0.011 microM and 0.398 microM, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC(50)=1 microM, COX-2 IC(50)=0.011 microM; SI= approximately 92). Molecular docking studies of compounds 6b and 11b-d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors.
|
Inhibition of sheep COX1 at 10 uM by enzyme immunoassay
|
Ovis aries
|
13.66
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation, and docking studies of novel heterocyclic diaryl compounds as selective COX-2 inhibitors.
Year : 2010
Volume : 18
Issue : 17
First Page : 6367
Last Page : 6376
Authors : Eren G, Unlü S, Nuñez MT, Labeaga L, Ledo F, Entrena A, Banoğlu E, Costantino G, Sahin MF.
Abstract : Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC(50)=0.061 microM and COX-2 IC(50)=0.325 microM; selectivity index (SI)=0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC(50)=0.011 microM and 0.398 microM, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC(50)=1 microM, COX-2 IC(50)=0.011 microM; SI= approximately 92). Molecular docking studies of compounds 6b and 11b-d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors.
|
Inhibition of sheep COX2 by enzyme immunoassay
|
Ovis aries
|
398.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation, and docking studies of novel heterocyclic diaryl compounds as selective COX-2 inhibitors.
Year : 2010
Volume : 18
Issue : 17
First Page : 6367
Last Page : 6376
Authors : Eren G, Unlü S, Nuñez MT, Labeaga L, Ledo F, Entrena A, Banoğlu E, Costantino G, Sahin MF.
Abstract : Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC(50)=0.061 microM and COX-2 IC(50)=0.325 microM; selectivity index (SI)=0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC(50)=0.011 microM and 0.398 microM, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC(50)=1 microM, COX-2 IC(50)=0.011 microM; SI= approximately 92). Molecular docking studies of compounds 6b and 11b-d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors.
|
Inhibition of sheep COX2 by spectrophotometry
|
Ovis aries
|
780.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis, anti-inflammatory activity, and in vitro antitumor effect of a novel class of cyclooxygenase inhibitors: 4-(aryloyl)phenyl methyl sulfones.
Year : 2010
Volume : 53
Issue : 18
First Page : 6560
Last Page : 6571
Authors : Harrak Y, Casula G, Basset J, Rosell G, Plescia S, Raffa D, Cusimano MG, Pouplana R, Pujol MD.
Abstract : Following our previous research on anti-inflammatory drugs (NSAIDs), we report on the design and synthesis of 4-(aryloyl)phenyl methyl sulfones. These substances were characterized for their capacity to inhibit cyclooxygenase (COX-1 and COX-2) isoenzymes. Molecular modeling studies showed that the methylsulfone group of these compounds was inserted deep in the pocket of the human COX-2 binding site, in an orientation that precludes hydrogen bonding with Arg120, Ser353, and Tyr355 through their oxygen atoms. The N-arylindole 33 was the most potent inhibitor of COX-2 and also the most selective (COX-1/COX-2 IC(50) ratio was 262). The indole derivative 33 was further tested in vivo for its anti-inflammatory activity in rats. This compound showed greater inhibitory activity than ibuprofen. Other compounds (20, 26, 9, and 30) showed strong activity against carrageenan-induced inflammation. The latter compounds showed a weak capacity to inhibit the proliferation of human cell lines K562, NCI-H460, and HT-29 in vitro.
|
Inhibition of mPGES1 mediated PGE2 production in LPS stimulated human whole blood by EIA
|
None
|
530.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biarylimidazoles as inhibitors of microsomal prostaglandin E2 synthase-1.
Year : 2010
Volume : 20
Issue : 23
First Page : 6978
Last Page : 6982
Authors : Wu TY, Juteau H, Ducharme Y, Friesen RW, Guiral S, Dufresne L, Poirier H, Salem M, Riendeau D, Mancini J, Brideau C.
Abstract : Microsomal prostaglandin E(2) synthase (mPGES-1) represents a potential target for novel analgesic and anti-inflammatory agents. High-throughput screening identified several leads of mPGES-1 inhibitors which were further optimized for potency and selectivity. A series of inhibitors bearing a biaryl imidazole scaffold exhibits excellent inhibition of PGE(2) production in enzymatic and cell-based assays. The synthesis of these molecules and their activities will be discussed.
|
Inhibition of ovine COX-1 at 100 uM after 2 mins by fluorescence assay
|
Ovis aries
|
17.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase.
Year : 2011
Volume : 54
Issue : 8
First Page : 3037
Last Page : 3050
Authors : Hwang SH, Wagner KM, Morisseau C, Liu JY, Dong H, Wecksler AT, Hammock BD.
Abstract : A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea were designed, synthesized, and evaluated as novel COX-2/sEH dual inhibitors in vitro using recombinant enzyme assays and in vivo using a lipopolysaccharide (LPS) induced model of pain in rats. The best inhibition potencies and selectivity for sEH and COX-2 over COX-1 were obtained with compounds (21b, 21i, and 21j) in which both the 1,5-diaryl-pyrazole group and the urea group are linked with a three-methylene group. Compound 21i showed the best pharmacokinetic profiles in both mice and rats (higher AUC and longer half-life). Following subcutaneous administration at 10 mg/kg, compound 21i exhibited antiallodynic activity that is more effective than the same dose of either a COX-2 inhibitor (celecoxib) or a sEH inhibitor (t-AUCB) alone, as well as coadministration of both inhibitors. Thus, these novel dual inhibitors exhibited enhanced in vivo antiallodynic activity in a nociceptive behavioral assay.
|
Inhibition of human recombinant COX2 by enzyme immuno assay
|
Homo sapiens
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A diazen-1-ium-1,2-diolated nitric oxide donor ester prodrug of 3-(4-hydroxymethylphenyl)-4-(4-methanesulfonylphenyl)-5H-furan-2-one: synthesis, biological evaluation and nitric oxide release studies.
Year : 2011
Volume : 21
Issue : 13
First Page : 3951
Last Page : 3956
Authors : Abdellatif KR, Huang Z, Chowdhury MA, Kaufman S, Knaus EE.
Abstract : A novel hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrug (NONO-coxib 14) wherein an O(2)-acetoxymethyl 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate (O(2)-acetoxymethyl PROLI/NO) NO-donor moiety was covalently coupled to the CH(2)OH group of 3-(4-hydroxymethylphenyl)-4-(4-methylsulfonylphenyl)-5H-furan-2-one (12), was synthesized. The prodrug 14 released a low amount of NO (4.2%) upon incubation with phosphate buffer (PBS) at pH 7.4 which was significantly higher (34.8% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) upon incubation in the presence of rat serum. These incubation studies suggest that both NO and the parent compound 12 would be released from the prodrug 14 upon in vivo cleavage by non-specific serum esterases. The prodrug ester 14 is a selective COX-2 inhibitor that exhibited AI activity (ED(50)=72.2mmol/kg po) between that of the reference drugs celecoxib (ED(50)=30.9μmol/kg po) and ibuprofen (ED(50)=327μmol/kg po). The NO donor compound 14 exhibited enhanced inhibition of phenylephrine-induced vasoconstriction of isolated mesenteric arteries compared with that observed under control conditions. These studies indicate hybrid ester AI/NO donor prodrugs (NONO-coxibs) constitutes a plausible drug design concept targeted toward the development of selective COX-2 inhibitory AI drugs that are devoid of adverse cardiovascular effects.
|
Inhibition of acetylcholine-induced relaxation in Long Evans rat phenylephrine pre-constricted mesenteric arteries
|
Rattus norvegicus
|
88.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A diazen-1-ium-1,2-diolated nitric oxide donor ester prodrug of 3-(4-hydroxymethylphenyl)-4-(4-methanesulfonylphenyl)-5H-furan-2-one: synthesis, biological evaluation and nitric oxide release studies.
Year : 2011
Volume : 21
Issue : 13
First Page : 3951
Last Page : 3956
Authors : Abdellatif KR, Huang Z, Chowdhury MA, Kaufman S, Knaus EE.
Abstract : A novel hybrid nitric oxide-releasing anti-inflammatory (AI) ester prodrug (NONO-coxib 14) wherein an O(2)-acetoxymethyl 1-(2-carboxypyrrolidin-1-yl)diazen-1-ium-1,2-diolate (O(2)-acetoxymethyl PROLI/NO) NO-donor moiety was covalently coupled to the CH(2)OH group of 3-(4-hydroxymethylphenyl)-4-(4-methylsulfonylphenyl)-5H-furan-2-one (12), was synthesized. The prodrug 14 released a low amount of NO (4.2%) upon incubation with phosphate buffer (PBS) at pH 7.4 which was significantly higher (34.8% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) upon incubation in the presence of rat serum. These incubation studies suggest that both NO and the parent compound 12 would be released from the prodrug 14 upon in vivo cleavage by non-specific serum esterases. The prodrug ester 14 is a selective COX-2 inhibitor that exhibited AI activity (ED(50)=72.2mmol/kg po) between that of the reference drugs celecoxib (ED(50)=30.9μmol/kg po) and ibuprofen (ED(50)=327μmol/kg po). The NO donor compound 14 exhibited enhanced inhibition of phenylephrine-induced vasoconstriction of isolated mesenteric arteries compared with that observed under control conditions. These studies indicate hybrid ester AI/NO donor prodrugs (NONO-coxibs) constitutes a plausible drug design concept targeted toward the development of selective COX-2 inhibitory AI drugs that are devoid of adverse cardiovascular effects.
|
Inhibition of human platelets COX1 assessed as PGE2 production using arachidonic acid as substrate at 10 uM preincubated for 15 mins measured after 15 mins by EIA
|
Homo sapiens
|
-13.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioactive sulfoximines: syntheses and properties of Vioxx analogs.
Year : 2011
Volume : 21
Issue : 16
First Page : 4888
Last Page : 4890
Authors : Park SJ, Buschmann H, Bolm C.
Abstract : The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).
|
Inhibition of human recombinant COX2 expressed in Sf21 cells assessed as PGE2 production using arachidonic acid as substrate at 10 uM preincubated for 15 mins measured after 5 mins by EIA
|
Homo sapiens
|
26.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioactive sulfoximines: syntheses and properties of Vioxx analogs.
Year : 2011
Volume : 21
Issue : 16
First Page : 4888
Last Page : 4890
Authors : Park SJ, Buschmann H, Bolm C.
Abstract : The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).
|
Inhibition of human recombinant COX2 expressed in Sf21 cells assessed as PGE2 production using arachidonic acid as substrate preincubated for 15 mins measured after 5 mins by EIA
|
Homo sapiens
|
156.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioactive sulfoximines: syntheses and properties of Vioxx analogs.
Year : 2011
Volume : 21
Issue : 16
First Page : 4888
Last Page : 4890
Authors : Park SJ, Buschmann H, Bolm C.
Abstract : The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).
|
Inhibition of human ERG expressed in HEK293 cells assessed as inhibition of tail current at holding potential of -70 mV at 1 uM after 10 mins by whole-cell patch clamp method
|
Homo sapiens
|
6.8
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioactive sulfoximines: syntheses and properties of Vioxx analogs.
Year : 2011
Volume : 21
Issue : 16
First Page : 4888
Last Page : 4890
Authors : Park SJ, Buschmann H, Bolm C.
Abstract : The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).
|
Inhibition of human ERG expressed in HEK293 cells assessed as inhibition of tail current at holding potential of -70 mV at 3.16 uM after 10 mins by whole-cell patch clamp method
|
Homo sapiens
|
8.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioactive sulfoximines: syntheses and properties of Vioxx analogs.
Year : 2011
Volume : 21
Issue : 16
First Page : 4888
Last Page : 4890
Authors : Park SJ, Buschmann H, Bolm C.
Abstract : The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).
|
Inhibition of human ERG expressed in HEK293 cells assessed as inhibition of tail current at holding potential of -70 mV at 10 uM after 10 mins by whole-cell patch clamp method
|
Homo sapiens
|
10.4
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioactive sulfoximines: syntheses and properties of Vioxx analogs.
Year : 2011
Volume : 21
Issue : 16
First Page : 4888
Last Page : 4890
Authors : Park SJ, Buschmann H, Bolm C.
Abstract : The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).
|
Inhibition of human ERG expressed in HEK293 cells assessed as inhibition of tail current at holding potential of -70 mV at 31.6 uM after 10 mins by whole-cell patch clamp method
|
Homo sapiens
|
19.1
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioactive sulfoximines: syntheses and properties of Vioxx analogs.
Year : 2011
Volume : 21
Issue : 16
First Page : 4888
Last Page : 4890
Authors : Park SJ, Buschmann H, Bolm C.
Abstract : The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).
|
Inhibition of human ERG expressed in HEK293 cells assessed as inhibition of tail current at holding potential of -70 mV at 100 uM after 10 mins by whole-cell patch clamp method
|
Homo sapiens
|
27.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioactive sulfoximines: syntheses and properties of Vioxx analogs.
Year : 2011
Volume : 21
Issue : 16
First Page : 4888
Last Page : 4890
Authors : Park SJ, Buschmann H, Bolm C.
Abstract : The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).
|
Inhibition of human ERG expressed in HEK293 cells assessed as inhibition of tail current at holding potential of -70 mV at 3.16 uM after 10 mins by whole-cell patch clamp method relative to control
|
Homo sapiens
|
-10.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bioactive sulfoximines: syntheses and properties of Vioxx analogs.
Year : 2011
Volume : 21
Issue : 16
First Page : 4888
Last Page : 4890
Authors : Park SJ, Buschmann H, Bolm C.
Abstract : The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).
|
DRUGMATRIX: Cyclooxygenase COX-2 enzyme inhibition (substrate: Arachidonic acid)
|
None
|
679.0
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 COX2 expressed in Sf21 cells assessed as conversion of arachidonic acid to PGE2 preincubated for 15 mins measured after 5 mins by enzyme immunoassay
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluation of benzo[1.3.2]dithiazolium ylide 1,1-dioxide derivatives as potential dual cyclooxygenase-2/5-lipoxygenase inhibitors.
Year : 2011
Volume : 19
Issue : 21
First Page : 6316
Last Page : 6328
Authors : Tan CM, Chen GS, Chen CS, Chang PT, Chern JW.
Abstract : 3-(4-Bromophenyl)-6-nitrobenzo[1.3.2]dithiazolium ylide 1,1-dioxide (5) was discovered as a new prototype for dual inhibitors of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). Thus, the structure-activity relationships of benzo[1.3.2]dithiazolium ylide 1,1-dioxide skeleton were carried out. The 6-NO(2) group played an essential role in the inhibitory activity. In addition, moderate-sized lipophilic substituents at the para-position of the 3-aryl moiety were required for dual COX-2/5-LOX inhibitory activity. Among the identified potent dual inhibitors, 3-(4-tbutylphenyl) derivative 30c (IC(50) values of 0.27 μM and 0.30 μM against COX-2 and 5-LOX, respectively) and 3-(4-biphenyl) derivative 30f (IC(50) values of 0.50 μM and 0.15μM against COX-2 and 5-LOX, respectively) were the most potent dual COX-2/5-LOX inhibitors. Intraperitoneal administration of 30c at 100mg/kg demonstrated potent acute anti-inflammatory activity. As a result, benzo[1.3.2]dithiazolium ylide 1,1-dioxide represented a novel scaffold for the exploitation in developing dual COX-2/5-LOX inhibitors.
|
Antiinflammatory activity in Wistar rat assessed as inhibition of carrageenan-induced paw edema at 30 mg/kg after 2 hrs
|
Rattus norvegicus
|
81.01
%
|
|
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 rat assessed as inhibition of carrageenan-induced paw oedema at 30 mg/kg, po dosed 30 mins after carrageenan challenge measured after 5 hrs by plethysmograph analysis relative to control
|
Rattus norvegicus
|
81.8
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, evaluation and docking studies on 3-alkoxy-4-methanesulfonamido acetophenone derivatives as non ulcerogenic anti-inflammatory agents.
Year : 2012
Volume : 49
First Page : 397
Last Page : 405
Authors : Bali A, Ohri R, Deb PK.
Abstract : A series of 3-alkoxy-4-methanesulfonamido acetophenone derivatives were synthesized and evaluated for their anti-inflammatory activity in carrageenan-induced rat paw edema model. The synthesized compounds were also investigated for their gastric ulcerogenic potential. The compounds 4a, 4c and 4d showed comparable anti-inflammatory activity to rofecoxib and indomethacin, the standard drugs taken in both studies and were also non ulcerogenic at the test doses. In silico (docking studies) were done to investigate the hypothetical binding mode of the target compounds to the cyclooxygenase isoenzyme (COX-2). A binding model has been proposed based on the docking studies. Selected physicochemical properties were calculated for theoretical ADME profiling of the compounds and excellent compliance was shown with Lipinski's rules.
|
Inhibition of COX2
|
Homo sapiens
|
340.0
nM
|
|
Journal : J. Med. Chem.
Title : Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold.
Year : 2012
Volume : 55
Issue : 5
First Page : 2287
Last Page : 2300
Authors : Liedtke AJ, Crews BC, Daniel CM, Blobaum AL, Kingsley PJ, Ghebreselasie K, Marnett LJ.
Abstract : Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.
|
Inhibition of human recombinant COX2 expressed in Sf21 cells using arachidonic acid as substrate preincubated for 15 mins before arachidonic acid addition measured after 5 mins
|
Homo sapiens
|
170.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses and biological activities of sulfoximine-based acyclic triaryl olefins.
Year : 2012
Volume : 22
Issue : 13
First Page : 4307
Last Page : 4309
Authors : Chen XY, Park SJ, Buschmann H, De Rosa M, Bolm C.
Abstract : Sulfoximine-based acyclic triaryl olefins 8 and 9 have been prepared and initial studies have been performed to determine their biological profiles. In contrast to their sulfonyl-substituted analog 2 sulfoximines 8 and 9 show low COX inhibitory activity. All compounds affect the estrogen receptors. While sulfone 2 interacts exclusively with ER β, sulfoximines 8 and 9 reveal almost equal blocking potencies for both estrogen receptors, ER α and ER β. In the tested series, triaryl olefin 9a shows the highest inhibitory activities with 91% and 80%, respectively (at 10 μM).
|
Anti-inflammatory activity in Rattus norvegicus Wistar (rat) assessed as inhibition of carrageenan-induced paw edema at 30 mg/kg, po administered 30 min post carrageenan challenge measured at 5 hr relative to control
|
Rattus norvegicus
|
82.8
%
|
|
Journal : Med Chem Res
Title : Alkoxyphenyl methanesulfonamides: synthesis, anti-inflammatory effect, and docking studies
Year : 2012
Volume : 21
Issue : 10
First Page : 3053
Last Page : 3062
Authors : Bali A, Dhillon SK, Balakumar C
|
Inhibition of Capra hircus (goat) brain DPP-3 using Arg-Arg-4mbetaNA as substrate assessed as liberation of 4mbetaNA from substrate
|
Capra hircus
|
71.0
%
|
|
Journal : Med Chem Res
Title : Goat brain enkephalin degrading enzyme: interaction with analgesic and antihypertensive drugs
Year : 2011
Volume : 20
Issue : 8
First Page : 1294
Last Page : 1297
Authors : Dhanda S, Singh J, Singh H
|
Inhibition of human recombinant COX2
|
Homo sapiens
|
480.0
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.
|
Analgesic activity in medial meniscal transection rat osteoarthritis pain model assessed as inhibition of change in hind paw weight distribution at 10 mg/kg, po administered on day 28 post medial meniscal transection surgery measured after 3 hrs relative to vehicle-treated control
|
Rattus norvegicus
|
79.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: optimization studies and demonstration of in vivo efficacy.
Year : 2013
Volume : 23
Issue : 11
First Page : 3443
Last Page : 3447
Authors : Plummer MS, Cornicelli J, Roark H, Skalitzky DJ, Stankovic CJ, Bove S, Pandit J, Goodman A, Hicks J, Shahripour A, Beidler D, Lu XK, Sanchez B, Whitehead C, Sarver R, Braden T, Gowan R, Shen XQ, Welch K, Ogden A, Sadagopan N, Baum H, Miller H, Banotai C, Spessard C, Lightle S.
Abstract : Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose.
|
Analgesic activity in medial meniscal transection rat osteoarthritis pain model assessed as inhibition of change in hind paw weight distribution at 10 mg/kg, sc administered on day 28 post medial meniscal transection surgery measured after 3 hrs relative to vehicle-treated control
|
Rattus norvegicus
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: optimization studies and demonstration of in vivo efficacy.
Year : 2013
Volume : 23
Issue : 11
First Page : 3443
Last Page : 3447
Authors : Plummer MS, Cornicelli J, Roark H, Skalitzky DJ, Stankovic CJ, Bove S, Pandit J, Goodman A, Hicks J, Shahripour A, Beidler D, Lu XK, Sanchez B, Whitehead C, Sarver R, Braden T, Gowan R, Shen XQ, Welch K, Ogden A, Sadagopan N, Baum H, Miller H, Banotai C, Spessard C, Lightle S.
Abstract : Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose.
|
Inhibition of ovine COX-2 assessed as using arachidonic acid as substrate at 0.1 uM preincubated for 5 mins prior to substrate addition measured after 2 hrs by enzyme immunoassay relative to control
|
Ovis aries
|
22.15
%
|
|
Journal : Eur. J. Med. Chem.
Title : Stereoselective synthesis and anti-proliferative effects on prostate cancer evaluation of 5-substituted-3,4-diphenylfuran-2-ones.
Year : 2013
Volume : 65
First Page : 323
Last Page : 336
Authors : Liu GZ, Xu HW, Wang P, Lin ZT, Duan YC, Zheng JX, Liu HM.
Abstract : Series of 5-substituted-3,4-diphenylfuran-2-ones were stereoselectively prepared. Their potential anti-proliferative effects on prostate cancer and some of their cyclooxygenases (COXs) inhibitory activities were evaluated. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position and ortho-position of the C-3 phenyl ring and 5-substituted modification of the central furanone, showed that 3-(2-chloro-phenyl)-4-(4-methanesulfonyl-phenyl)-5-(1-methoxy-ethyl)-5H-furan-2-one (13p) was the most potent compound and could effectively reduce the proliferation of prostate cancer cells (PC3 cell IC50 = 20 μM; PC3 PCDNA cell IC50 = 5 μM; PC3 SKP2 cell IC50 = 5 μM; DU145 cell IC50 = 25 μM). The cell cycle analysis for 13p in DU145 indicated that 13p may induce G1 phase arrest.
|
Inhibition of ovine COX-2 assessed as using arachidonic acid as substrate preincubated for 5 mins prior to substrate addition measured after 2 hrs by enzyme immunoassay
|
Ovis aries
|
500.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Stereoselective synthesis and anti-proliferative effects on prostate cancer evaluation of 5-substituted-3,4-diphenylfuran-2-ones.
Year : 2013
Volume : 65
First Page : 323
Last Page : 336
Authors : Liu GZ, Xu HW, Wang P, Lin ZT, Duan YC, Zheng JX, Liu HM.
Abstract : Series of 5-substituted-3,4-diphenylfuran-2-ones were stereoselectively prepared. Their potential anti-proliferative effects on prostate cancer and some of their cyclooxygenases (COXs) inhibitory activities were evaluated. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position and ortho-position of the C-3 phenyl ring and 5-substituted modification of the central furanone, showed that 3-(2-chloro-phenyl)-4-(4-methanesulfonyl-phenyl)-5-(1-methoxy-ethyl)-5H-furan-2-one (13p) was the most potent compound and could effectively reduce the proliferation of prostate cancer cells (PC3 cell IC50 = 20 μM; PC3 PCDNA cell IC50 = 5 μM; PC3 SKP2 cell IC50 = 5 μM; DU145 cell IC50 = 25 μM). The cell cycle analysis for 13p in DU145 indicated that 13p may induce G1 phase arrest.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
134.43
%
|
|
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
|
84.03
%
|
|
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 human recombinant COX-2 by enzyme immunoassay
|
Homo sapiens
|
360.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity.
Year : 2014
Volume : 22
Issue : 8
First Page : 2529
Last Page : 2534
Authors : Yamakawa N, Suzuki K, Yamashita Y, Katsu T, Hanaya K, Shoji M, Sugai T, Mizushima T.
Abstract : Non-steroidal anti-inflammatory drugs (NSAIDs) achieve their anti-inflammatory effect by inhibiting cyclooxygenase activity. We previously suggested that in addition to cyclooxygenase-inhibition at the gastric mucosa, NSAID-induced gastric mucosal cell death is required for the formation of NSAID-induced gastric lesions in vivo. We showed that celecoxib exhibited the most potent membrane permeabilizing activity among the NSAIDs tested. In contrast, we have found that the NSAID rofecoxib has very weak membrane permeabilizing activity. To understand the membrane permeabilizing activity of coxibs in terms of their structure-activity relationship, we separated the structures of celecoxib and rofecoxib into three parts, synthesized hybrid compounds by substitution of each of the parts, and examined the membrane permeabilizing activities of these hybrids. The results suggest that the sulfonamidophenyl subgroup of celecoxib or the methanesulfonylphenyl subgroup of rofecoxib is important for their potent or weak membrane permeabilizing activity, respectively. These findings provide important information for design and synthesis of new coxibs with lower membrane permeabilizing activity.
|
Inhibition of mouse COX-2 assessed as inhibition of [14C]arachidonic acid to radiolabeled prostaglandins preincubated for 15 mins by TLC-based assay
|
Mus musculus
|
60.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Design of Fluorine-Containing 3,4-Diarylfuran-2(5H)-ones as Selective COX-1 Inhibitors.
Year : 2014
Volume : 5
Issue : 11
First Page : 1254
Last Page : 1258
Authors : Uddin MJ, Elleman AV, Ghebreselasie K, Daniel CK, Crews BC, Nance KD, Huda T, Marnett LJ.
Abstract : We report the design and synthesis of fluorine-containing cyclooxygenase-1 (COX-1)-selective inhibitors to serve as prototypes for the development of a COX-1-targeted imaging agent. Deletion of the SO2CH3 group of rofecoxib switches the compound from a COX-2- to a COX-1-selective inhibitor, providing a 3,4-diarylfuran-2(5H)-one scaffold for structure-activity relationship studies of COX-1 inhibition. A wide range of fluorine-containing 3,4-diarylfuran-2(5H)-ones were designed, synthesized, and tested for their ability to selectively inhibit COX-1 in purified protein and human cancer cell assays. Compounds containing a fluoro-substituent on the C-3 phenyl ring and a methoxy-substituent on the C-4 phenyl ring of the 3,4-diarylfuran-2(5H)-one scaffold were the best COX-1-selective agents of those evaluated, exhibiting IC50s in the submicromolar range. These compounds provide the foundation for development of an agent to facilitate radiologic imaging of ovarian cancer expressing elevated levels of COX-1.
|
Inhibition of ovine COX1 assessed as reduction in PGF2alpha production at 100 uM by ELISA
|
Ovis aries
|
25.0
%
|
|
Journal : Eur J Med Chem
Title : Hydroxytriazole derivatives as potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors discovered by bioisosteric scaffold hopping approach.
Year : 2017
Volume : 139
First Page : 936
Last Page : 946
Authors : Pippione AC, Giraudo A, Bonanni D, Carnovale IM, Marini E, Cena C, Costale A, Zonari D, Pors K, Sadiq M, Boschi D, Oliaro-Bosso S, Lolli ML.
Abstract : The aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in π-π staking interaction with Trp227 (partial overlapping) and in a T-shape π-π staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
8.94
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-7.03
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
8.3
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
27.92
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
21.66
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
2.84
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-2.65
%
|
|
|
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
|
2.55
%
|
|
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.
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Inhibition of COX-2 in human whole blood
|
Homo sapiens
|
500.0
nM
|
|
Journal : Eur J Med Chem
Title : Medicinal chemistry of vicinal diaryl scaffold: A mini review.
Year : 2019
Volume : 162
First Page : 1
Last Page : 17
Authors : Ramajayam R.
Abstract : The privileged structures have been widely used as a valuable template in new drug discovery. 1,2-Diaryl or vicinal diaryl is a simple scaffold found in many drugs and naturally occurring compounds. From synthetic point of view, the vicinal diaryl derivatives are easily accessible due to their facile and expedient syntheses. These scaffolds have shown numerous interesting pharmacological activities against various diseases with lot of clinical potentials. This review aims to highlight the evidence of vicinal diaryl motif as a privileged scaffold in COX-2 inhibitors and CA-4 analogs.
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Inhibition of COX2 (unknown origin)
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur J Med Chem
Title : Cyclic enaminone as new chemotype for selective cyclooxygenase-2 inhibitory, anti-inflammatory, and analgesic activities.
Year : 2019
Volume : 182
First Page : 111601
Last Page : 111601
Authors : Kumar R, Saha N, Purohit P, Garg SK, Seth K, Meena VS, Dubey S, Dave K, Goyal R, Sharma SS, Banerjee UC, Chakraborti AK.
Abstract : The cyclic enaminone moiety has been identified as a new scaffold for selective inhibition of cyclooxygenase-2 with anti-inflammatory and analgesic activities. The designed cyclic enaminones have been synthesized conveniently through the development of a new catalyst-free methodology and evaluated for cyclooxygenase (COX-1 and COX-2) inhibitory activities. Three compounds 7d, 8, and 9 predominantly inhibited COX-2 with selectivity index of 74.09, 19.45 and 108.68, respectively, and were assessed for in vivo anti-inflammatory activity in carrageenan induced rat paw edema assay. The anti-inflammatory activity of 7d was comparable to that of celecoxib at a dose of 12.5 mg/kg. However, the compounds 8 and 9 were more/equally effective as anti-inflammatory agent compared to celecoxib at the doses of 12.5 mg/kg and 25 mg/kg and also exhibited anti-inflammatory activity comparable to that of diclofenac. The therapeutic potential of the most active compound 9 was further assessed by performing in vivo thermal and mechanical hyperalgesia tests using various models that revealed its analgesic activity. The in vivo non-ulcerogenicity of 9 revealed the gastrointestinal safety as compared to the non-selective COX inhibitor indomethacin. The in vitro antioxidant activity and in vivo experiments on heart rate and blood pressure provided the cardiovascular safety profile of 9. The molecular docking studies rationalize the COX-2 selectivity of the newly found anti-inflammatory compounds 7d, 8, and 9.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
18.5
%
|
|
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.
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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
|
-0.04
%
|
|
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
|
-0.04
%
|
|
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.
