| Abstract
| - We have previously disclosed the selective ETA receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4‘-(2-oxazolyl)[1,1‘-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2‘-position of 1 led to the identification of several analogueswith improved binding affinity as well as selectivity for the ETA receptor. Following the discoverythat a 3-amino-isoxazole group displays significantly improved metabolic stability in comparisonto its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2‘-substituentleading to 16a (BMS-207940). Compound 16a is an extremely potent (ETAKi = 10 pM) andselective (80000-fold for ETA vs ETB) antagonist. It is also 150-fold more potent and >6-foldmore selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearanceand volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ETpressor responses with 30-fold greater potency than 1. After oral dosing at 3 μmol/kg, 16adisplays enhanced duration relative to 1.
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