Discovery of renin inhibitors containing a simple aspartate binding moiety that imparts reduced P450 inhibition

Abstract

Discovery of potent renin inhibitors which contain a simplified alkylamino Asp-binding group and exhibit improved selectivity for renin over Cyp3A4 is described. Structure-function results in this series are rationalized based on analysis of selected compounds bound to renin, and the contribution of each molecular feature leading to the reduced P450 inhibition is quantified.

Keywords: Biphenyl; Cyp3A4; Hypertension; Renin inhibitors; X-ray crystallography.