Biphenylsulfonamide Endothelin Antagonists:  Structure−Activity Relationships of a Series of Mono- and Disubstituted Analogues and Pharmacology of the Orally Active Endothelin Antagonist 2‘-Amino-N- (3,4-dimethyl-5-isoxazolyl)-4‘-(2-methylpropyl)[1,1‘-biphenyl]-2-sulfonamide (BMS-187308)

Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ET<INF>A</INF>) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4‘-position. Introduction of an amino group at the 2‘-position also led to improved analogues. Combination of the optimal 4‘-isobutyl substituent with the 2‘-amino function afforded an analogue (<BO>20</BO>, BMS-187308) with improved ET<INF>A</INF> binding affinity and functional activity. Compound <BO>20</BO> also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 μmol/kg iv <BO>20</BO> attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.