Selective ETA antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives

The fifth paper in this series describes the culmination of our investigati ons into the development of a potent and selective ETA receptor antagonist for the treatment of diseases mediated by ET-1. Receptor site mapping of se veral ETA antagonists prepared previously identified a common cationic bind ing site which prompted synthesis of phenoxyphenylacetic acid derivative 13 a, which showed good in vitro activity (IC50 59 nM, rat aortic ETA). Optimi zation of 13a led to the identification of 27b, which exhibited an IC50 of 4 nM. Although this did not translate into the expected in vivo potency, a compound of comparable in vitro activity, 27a (RPR118031A), showed a far be tter pharmacokinetic profile and in vivo potency (75 mu mol/kg) and was dul y proposed and accepted as a development candidate.