AZOLE ENDOTHELIN ANTAGONISTS .1. A RECEPTOR MODEL EXPLAINS AN UNUSUALSTRUCTURE-ACTIVITY PROFILE

The pseudotetrapeptide FR-139317 is a potent and highly selective anta gonist of the endothelin-A (ET(A)) receptor; however, its peptidic nat ure leads to poor oral absorption characteristics which make it an unl ikely drug candidate. In an attempt to improve these properties, we ha ve replaced a portion of the amide bond framework of FR-139317 with a heterocyclic surrogate. The resultant analogs are also ET(A)-selective antagonists, but show a structure-activity profile substantially diff erent from that of the peptidic series, particularly with regard to th e requirements for the side chain group that has been incorporated int o the heterocycle. The nature of the heterocycle itself also has profo und effects on the activity of the compounds. Both of these surprising results can be rationalized through examination of a 3D model of ET l igand-receptor binding that has previously been developed in our labor atories.