Selective endothelin A receptor antagonists. 2. Discovery and structure-activity relationships of 5-ketopentanoic acid derivatives

Article abstract of DOI:10.1016/S0223-5234(97)84014-7

The second in this series of papers describes the further progress made in the discovery of a potent and selective endothelin ET(A) receptor antagonist for the potential treatment of diseases in which endothelin has been shown to have a pathophysiological role including hypertension, ischaemic diseases and atherosclerosis. We describe herein the synthesis and structure-activity relationships of a novel series of 5-ketopentanoic acid derivatives exemplified by the lead compound 1 (IC₅₀ 0.72 μM, rat aortic ET(A)R). Optimisation of the in vitro binding of 1 led to the identification of a more potent compound (37) which exhibited an IC₅₀ < 0.1 μM.M with > 300-fold selectivity for the ET(A) receptor over the ET(B) receptor. This compound demonstrated functional antagonism of endothelin-induced vasoconstriction in vitro.