ChemInform Abstract: Azole Endothelin Antagonists. Part 1. A Receptor Model Explains an Unusual Structure-Activity Profile.
Abstract
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ChemInform Abstract
Central (4 examples) and terminal (21 examples) dipeptide surrogates, e.g. (I) and (II), resp., of the pseudotetrapeptide FR-139317 (III), a potent and highly selective antagonist of the endothelin-A (ETA) receptor of poor oral absorption characteristics, are prepared. Some of the resultant analogues are also ETA-selective antagonists, but show a structure-activity profile substantially different from that of the peptidic series, particularly with regard to the requirements of the side chain group that has been incorporated into the heterocycle. The nature of the heterocycle has profound effects on the activity of the compounds. The results are rationalized through examination of a 3D model of ET ligand-receptor binding.