194221-57-3Relevant articles and documents
Selective endothelin A receptor antagonists. 2. Discovery and structure-activity relationships of 5-ketopentanoic acid derivatives
Astles,Brown,Harris,Harper,McCarthy,Porter,Smith,Walsh
, p. 515 - 522 (2007/10/03)
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 300-fold selectivity for the ET(A) receptor over the ET(B) receptor. This compound demonstrated functional antagonism of endothelin-induced vasoconstriction in vitro.
