Application of structure–metabolism relationships in the identification of a selective endothelin A antagonist, BMS-193884, with favourable pharmacokinetic properties

1. Based on binding affinity, 2′-amino-N-(3,4-dimethyl-5-isoxazolyl)-4′-(2-methylpropyl)[1,1′-biphenyl]-2-sulfonamide (2) was identified as an initial lead in a programme to identify selective endothelin (ET) receptor antagonists. However, the compound was extensively metabolized in preclinical animal species and human in vitro systems due to oxidative biotransformation.2. To optimize this structural class, the site of metabolism of 2 was determined. This allowed for focussed structure–activity and structure–metabolism studies aimed at finding more metabolically stable analogues that maintained potency. New analogues were screened for their ET binding characteristics and their stability in rat and human liver microsomes.3. The use of the microsomal stability screen was tested by the determination of the pharmacokinetic parameters of select analogues. A good correlation was found between reduced rates of rat microsomal metabolism and reduced clearance in the rat.4. N-(3,4-dimethyl-5-isoxazolyl)-4′-(2-oxazo...