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

Abstract

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, 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 (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 ( 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 O H of Tyr 355 , and 6.91 Å from the Ser 530 O H. 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. © 2001 Wiley‐Liss, Inc.