ORALLY POTENT HUMAN RENIN INHIBITORS DERIVED FROM ANGIOTENSINOGEN TRANSITION-STATE - DESIGN, SYNTHESIS, AND MODE OF INTERACTION

A three-dimensional structure of the complex of human renin and the scissile site P4Pro to P1' Val of angiotensinogen was deduced in order to design potent human renin inhibitors rationally. On the basis of this structure, an orally potent human renin inhibitor (1a) was designed from the angiotensinogen transition state and synthesized. The inhibitor la contains a (2R)-3-(morpholinocarbonyl)-2-(l-naphthylmethyl)propionyl residue (P4-P3) with a retro-inverso amide bond, L-histidine, and a novel amino acid, (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid, named cyclohexylnorstatine (2a). The optically pure cyclohexylnorstatine was efficiently prepared from Boc-L-cyclohexylalaninol (3), and the stereochemistry of la was established by X-ray crystal analysis. The analyses of interaction between la and human renin using modeling techniques indicated that (1) the cyclohexyl group of P1and the naphthyl group of P3were accommodated in large hydrophobic subsites S1and S3, respectively; (2) the imidazole of P2His was hydrogen bonded to the side chain OH of Ser-233 to contribute to the selectivity of renin inhibition; (3) cyclohexylnorstatine isopropyl ester residue was accommodated in S1-S1'. The importance of the stereochemistry in the potent and specific inhibitor was clearly shown. Oral administration to monkeys of this inhibitor resulted in a drop of 10-20 mmHg in mean blood pressure and a reduction of plasma renin activity for a 5-h period. © 1990, American Chemical Society. All rights reserved.