Pyrrolidine-3-carboxylic acids as endothelin antagonists. 5. Highly selective, potent, and orally active ETA antagonists

The synthesis and structure-activity relationships (SAR) of a series of pyr rolidine-3-carboxylic acids as endothelin antagonists are described. The da ta shows an increase in selectivity when the methoxy of Atrasentan (ABT-627 ) is replaced with methyl, and the benzodioxole is replaced with dihydroben zofuran. Adding a fluorine further increases the binding activity and provi des a metabolically stable and orally bioavailable ETA-selective antagonist .