Design and syntheses of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates: novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

Abstract

A group of methyl 2-methyl-2-[2-(4-benzoyl-5-phenyl-7-halo-2-azabicyclo[4.1.0]hept-3-ene)]acetates (10-15), and the related acetamide derivative (16), that possess a variety of C-7 substituents (Br, Cl, F, H), were designed for evaluation as analgesic-antiinflammatory agents. The effect of the C-7 substituent(s) and the nature of the acetic acid ester (R 1 = OMe) or acetamide (R 1 = NH 2 ) moiety on analgesic activity was determined using a 4% NaCI-induced abdominal constriction assay. Compounds 10-16 inhibited writhing by 36-82%, relative to the reference drugs aspirin (58% inhibition) and celecoxib (62% inhibition). The nature of the C-7 substituents was a determinant of analgesic activity in the 7,7-dihalo group of compounds where the relative activity profile was 7-Cl 2 > 7-Br 2 > 7-F 2 > 7-Cl,7-F, and for 7-monohalo compounds where the potency order was 7-Br > 7-Cl. Elaboration of the 7,7-dibromo methyl acetate ester (10) to the corresponding acetamide derivative (16) enhanced analgesic activity. The nature of the 7-halo substituent(s) in the 7,7-dihalo group of compounds was a determinant of antiinflammatory activity, determined using the carrageenan-induced rat paw edema assay, where the relative potency order was 7-Br 2 > 7-Cl 2 > 7-F 2 > 7-Cl,7-F. The most potent 7,7-dibromo compound (10) inhibited inflammation by 62%, relative to the reference drug ibuprofen (44%), and 10 inhibited COX-2 (IC 50 = 26.4 μM) and COX-1 (IC 50 = 227 μM) for a COX-2 selectivity index of 8.6. Docking 10 in the active site of human COX-2 showed it binds in the center of the COX-2 binding site with the C-5 phenyl ring oriented toward the acetylation site (Ser 530 ), and the phenyl group of the C-4 benzoyl moiety oriented in the vicinity of the COX-2 secondary binding pocket near Val 523 .