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

Abstract

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 K_i’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