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.

4,5-Diphenyl-4-isoxazolines (13a-k) possessing a variety of substituents (H, F, MeS, MeSO2) at the para position of one of the phenyl rings were synthesized for evaluation as analgesic and selective cyclooxygenase-2 (COX-2) inhibitory antiinflammatory (AI) agents. Although the 4,5-phenyl-4-isoxazolines (13a-d,f), which do not have a C-3 Me substituent, exhibited potent analgesic and AI activities, those compounds evaluated (13a, 13b, 13h, and 13k) were not selective inhibitors of COX-2. In contrast, 2,3-dimethyl-5-(4-methylsulfonylphenyl)-4-phenyl-4-isoxazoline (13j) exhibited excellent analgesic and AI activities, and it was a potent and selective COX-2 inhibitor (COX-1, IC(50) = 258 microM; COX-2, IC(50) = 0.004 microM). A related compound 13k having a F substituent at the para position of the 4-phenyl ring was also a selective (SI = 3162) but less potent (IC(50) = 0.0316 microM) inhibitor of COX-2 than 13j. A molecular modeling (docking study) for 13j showed that the S atom of the MeSO2 substituent is positioned about 6.46 A inside the entrance to the COX-2 secondary pocket (Val(523)) and that a C-3 Me (13j, 13k) central isoxazoline ring substituent is crucial to selective inhibition of COX-2 for this class of compounds.

A group of 4,5-diphenylisoxazoles (11ap), 3,4-diphenyl-5-trifluoromethylisoxazoles (15, 21), and 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) possessing a variety of substituents (H, F, MeS, MeSO, MeSO 2 ) at the para-position of one of the phenyl rings were synthesized for evaluation as analgesic, and selective COX-2 inhibitory antiinflammatory (AI), agents. Although the 4,5-diphenylisoxazole group of compounds (11ap) exhibited potent analgesic and AI activities, those compounds evaluated (11a, 11b, 11m) were more selective inhibitors of COX-1 than COX-2, with the exception of 4-(4-methylsulphonylphenyl)-5-phenylisoxazole (11n) that showed a modest COX-2 selectivity index (SI) of 2.1. In contrast, 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (15), which retained good analgesic and AI activities, was a highly potent and selective COX-2 inhibitor (COX-1 IC 50 > 500 µM; COX-2 IC 50 < 0.001 µM) with a COX-2 SI of > 500,000, relative to the reference drug celecoxib (COX-1 IC 50 = 22.9 µM; COX-2 IC 50 = 0.0567 µM) with a COX-2 SI of 404. The 3-phenyl-4-(4-methylsulphonylphenyl) regioisomer (21) was a less potent inhibitor (COX-1 IC 50 = 252 µM; COX-2 IC 50 = 0.2236 µM) with a COX-2 SI of 1122, relative to the regioisomer (15). The related compound 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) exhibited similar (to 21) potency and COX-2 selectivity (COX-1 IC 50 > 200 µM; COX-2 IC 50 = 0.226 µM) with an SI of 752. A molecular modeling (docking) study for the most potent, and selective, COX-2 inhibitor (15) in the active site of the human COX-2 enzyme showed the C-5 CF 3 substituent is positioned 3.37 Å from the phenolic OH of Tyr 355 , and 6.91 Å from the Ser 530 OH. The S-atom of the MeSO 2 substituent is positioned deep (7.40 Å from the entrance) inside the COX-2 secondary pocket (Val 523 ). These studies indicate a C-5 CF 3 (15, 21), or C-3 NHSO 2 Me (23), central isoxazole ring substituent is crucial to selective inhibition of COX-2 for this class of compounds. Drug Dev. Res. 51:273-286, 2000.

A group of 2,3-diphenylcycloprop-2-enes having a variety of substituents at the paraposition of the C-2 phenyl ring (H, F), and C-3 phenyl ring (H, F, SMe, SOMe, SO 2 Me), in conjunction with either a C-1 carbonyl, oxime, oxime acetate, benzoyl hydrazone, or hydrogen substituent were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase-2 (COX-2) inhibitors. This group of cycloprop-2-ene compounds exhibited significant analgesic activity, since 4% NaCl-induced abdominal constriction was reduced by 43-90% at 30 min, and 41-100% at 60 min, after drug administration relative to the reference drugs aspirin and celecoxib (58% and 32% inhibition at 30 min after drug administration) for a 50 mg/kg intraperitoneal dose. AI activities, determined using the carrageenan-induced rat paw edema assay, showed that this class of cycloprop-2-ene compounds exhibited AI activities in the inactive-to-modest activity range (0-26% inhibition) for a 50 mg/kg oral dose. The AI potency order for a group of 2,3-diphenylcycloprop-2-enes with respect to the C-1 substituent was oxime4hydrogen4carbonyl4benzoyl hydrazone. 2,3-Diphenylcycloprop-2-en-1-one oxime (20) was the most active AI agent, inducing a 26% reduction in inflammation, relative to the reference drugs ibuprofen and celecoxib, which showed 52% and 58% reductions in inflammation, at 5 h after drug administration. In vitro COX-1 and COX-2 inhibition studies showed that 2,3-diphenylcycloprop-2-en-1-one oxime (20) is a selective COX-2 inhibitor (COX-1 IC 50 4100 mM; COX-2 IC 50 ¼ 2.94 mM; COX-2 selectivity index434). A molecular modeling study that docked the oxime (20) in the active site of the human COX-2 isozyme showed that it binds in the vicinity of the mouth of the COX-2 binding site with the O-atom of the oxime (==N-OH) moiety separated from the NH 2 group of Arg 120 by about 3.65 Å . This orientation of the oxime compound (20) in the COX-2 binding site could be due to a potentially strong ionic interaction between the ==NOH oxime moiety and the guanidinium moiety of Arg 120 . Drug Dev.

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