Linda S. Payne

Design of Renin Inhibitors Containing Conformationally Restricted Mimetics of the P1-P1′ and P1 through P2′ Sites

The clinical efficacy of converting enzyme inhibitors1 for reducing blood pressure in a large percentage of hypertensive patients has aroused considerable interest in developing agents that interrupt the renin-angiotensin system at other points, for example by blockade of the angiotensin II receptor2 or by inhibition of the aspartic proteinase, renin. Substrate based design of renin inhibitors in which the scissile P1-P1′ dipeptide is replaced with a non-hydrolyzable group, often a mimetic of a tetrahedral transition state for amide bond hydrolysis, has provided a useful approach for obtaining a variety of inhibitor structure types,3 many with Ki’s of better than 10−9 M. A clinically useful renin inhibitor, however, has not yet emerged due to poor pharmacokinetics (i.e., metabolism or rapid clearance) or poor oral absorption, problems often encountered with peptidic drug targets. An example of this is seen with 1, a “tetrapeptide” inhibitor4 that spans the P4 through P3′ sites of the renin substrate and which utilizes the statine analog, ACHPA5, as a P1-P1′ dipeptide replacement (Figure 1). Although 1 is quite potent in vitro, very low levels of drug are found in the blood after oral administration to the rhesus monkey at 50 mg/kg, and the half life after intravenous administration is short (< 1 h). Rapid biliary excretion of intact drug has been demonstrated for a number of other renin inhibitors.6