Non-prostanoid thromboxane A2 receptor antagonists with a dibenzoxepin ring system. 1

Article abstract of DOI:10.1021/jm00096a016

A series of 11-[[2-[(arylsulfonyl)amino]ethyl]thio]-6,11- dihydrodibenz[b,e]oxepin-2-carboxylic acids and related derivatives were synthesized. The compounds were tested for their antagonizing effects on guinea pig platelet TXA₂/PGH₂ receptors. Structure-activity relationships are discussed. (±)-11-[[2-[(Styrylsulfonyl)amino]ethyl]thio]-6,11- dihydrodibenz[b,e]oxepin-2-carboxylic acid (41) and (±)-11-[[2- [(phenylsulfonyl)amino]ethyl]thio]-6,11-dihydrodibenz[b,e]thiepin-2- carboxylic acid (4af) were the most promising compounds with K(i) values of 6.5 ± 0.29 and 3.7 ± 0.31 nM, respectively, for the TXA₂/PGH₂ receptor. These compounds also significantly inhibited U-46619-induced guinea pig platelet aggregation ex vivo (10 mg/kg po). Compound 41 was resolved into its optically active form. The (-)-isomer was 60-fold more potent than the (+)- isomer in the TXA₂/PGH₂ receptor binding assay. Some compounds tested in this study showed both TXA₂/PGH₂ receptor antagonizing and TXA₂ synthase inhibitory effects.