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

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 f or evaluation as analgesic-antiinflammatory agents. The effect of the C-7 s ubstituent(s) and the nature of the acetic acid ester (R-1 = OMe) or acetam ide (R-1 = NH2) moiety on analgesic activity was determined using a 4% NaCl -induced abdominal constriction assay. Compounds 10-16 inhibited writhing b y 36-82%, relative to the reference drugs aspirin (58% inhibition) and cele coxib (62% inhibition). The nature of the C-7 substituents was a determinan t of analgesic activity in the 7,7-dihalo group of compounds where the rela tive activity profile was 7-Cl-2 > 7-Br-2 > 7-F-2 > 7-Cl,7-F, and for 7-mon ohalo compounds where the potency order was 7-Br > 7-Cl. Elaboration of the 7,7-dibromo methyl acetate ester (10) to the corresponding acetamide deriv ative (16) enhanced analgesic activity. The nature of the 7-halo substituen t(s) in the 7,7-dihalo group of compounds was a determinant of antiinflamma tory 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%, re lative to the reference drug ibuprofen (44%), and 10 inhibited COX-2 (IC50 = 26.4 mu M) and COX-1 (IC50 = 227 mu M) for a COX-2 selectivity index of 8 .6. Docking 10 in the active site of human COX-2 showed it binds in the cen ter 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(52 3). Drug Dev. Res. 49:75-84, 2000. (C) 2000 Wiley-Liss, Inc.