Optimization and in Vivo Evaluations of a Series of Small, Potent, and Specific Renin Inhibitors Containing a Novel Leu-Val Replacement

Article abstract of DOI:10.1021/jm00394a035

Further structure-activity relationships (SAR) for a novel dipeptide series of renin inhibitors are reported.These inhibitors retain the Phe⁸-His⁹ portion of angiotensinogen and employ a unique Leu¹⁰-Val¹¹ replacement (LVR).SAR at the Leu¹⁰ side chain revealed that the LVR derived from cyclohexylalanine provided a nearly 10-fold boost in potency for the final inhibitor.In addition SAR work was carried out to delineate the relationships between binding potency and (1) the size, shape, and charge of the side chain at the His⁹ position; (2) the size and topology of the side chain at the Phe⁸ site; and (3) the size of the Phe⁸ N-protecting group.One of the more potent inhibitors, 12, was shown to provide a substantial antihypertensive effect in a sodium depleted monkey model when administered intravenously.Metabolism work, in Sprague-Dawley rats, provided insights into the susceptibility of 12 to significant hepatic clearance and provided encouraging evidence for intestinal absorption.