211108-25-7Relevant articles and documents
Selective endothelin a receptor antagonists. 3. Discovery and structure- activity relationships of a series of 4-phenoxybutanoic acid derivatives
Astles, Peter C.,Brealey, Clive,Brown, Thomas J.,Facchini, Vincenzo,Handscombe, Caroline,Harris, Neil V.,McCarthy, Clive,McLay, Iain M.,Porter, Barry,Roach, Alan G.,Sargent, Carol,Smith, Christopher,Walsh, Roger J. A.
, p. 2732 - 2744 (2007/10/03)
The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ET(A)) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ET(A) receptor antagonists. In this paper, we describe how a pharmacophore model for ET(A) receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ET(A) receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2- methylphenyl)butanoic acid (12m). This compound exhibits low-nanomolar binding to the ET(A) receptor and a greater than 1000-fold selectivity over the ET(B) receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.
