Discovery of a series of pyrrolidine-based endothelin receptor antagonistswith enhanced ETA receptor selectivity

Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ETA and ETB receptors. The ETA receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ETB receptor mediates different e ffects in different tissues, including nitric oxide release from endothelia l cells, and vasoconstriction in certain vascular cell types. Selective ant agonists of endothelin receptor subtypes may prove useful in determining th e role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A- 127722 has been disclosed as a potent and ETA-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists wi th altered selectivity (ETA-selective, ETB-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds wit h alkyl groups at the 2-position possessed ETA selectivity improved over A- 127722 (1400-fold selective), with the best of these compounds showing near ly 19,000-fold selectivity. (C) 1999 Elsevier Science Ltd. All rights reser ved.