Design and syntheses of diarylisoxazoles: Novel inhibitors of cyclooxygenase-2 (COX-2) with analgesic-antiinflammatory activity

Abstract

A group of 4,5-diphenylisoxazoles (11a-p), 3,4-diphenyl-5-trifluoromethylisoxazoles (15, 21), and 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) possessing a variety of substituents (H, F, MeS, MeSO, MeSO2) 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 (11a-p) 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 (11 n) 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 IC50 > 500 μM; COX-2 IC50 < 0.001 μM) with a COX-2 SI of > 500,000, relative to the reference drug celecoxib (COX-1 IC50 = 22.9 μM; COX-2 IC50 = 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 IC50 = 252 μM; COX-2 IC50 = 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 IC50 > 200 μM; COX-2 IC50 = 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 CF3 substituent is positioned 3.37Å from the phenolic OH of Tyr355 , and 6.91 Å from the Set530 OH. The S-atom of the MeSO2 substituent is positioned deep (7.40Å from the entrance) inside the COX-2 secondary pocket (Val523). These studies indicate a C-5 CF3 (15, 21), or C-3 NHSO2Me (23), central isoxazole ring substituent is crucial to selective inhibition of COX-2 for this class of compounds. © 2001 Wiley-Liss, Inc.