Biphenylsulfonamide endothelin antagonists: Structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of theorally 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) benzene sulfonamide led to the identification of the biphenylsulfonamides as a nove l series of endothelin-A (ETA) selective antagonists. Appropriate substitut ions on the pendant phenyl ring led to improved binding as well as function al 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'-isob utyl substituent with the 2'-amino function afforded an analogue (20, BMS-1 87308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 mu mol/kg iv 20 attenuated the presser responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of end othelin-1 in nonhuman primates.