Orally potent human renin inhibitors derived from angiotensinogen transition state: design, synthesis, and mode of interaction

• Published in: Journal of medicinal chemistry 1990-10, Vol.33 (10), p.2707-2714
• Main Authors: Iizuka, Kinji, Kamijo, Tetsuhide, Harada, Hiromu, Akahane, Kenji, Kubota, Tetsuhiro, Umeyama, Hideaki, Ishida, Toshimasa, Kiso, Yoshiaki
• Format: Article
• Language: English
• Subjects: Administration, Oral; Aminobutyrates - chemical synthesis; Aminobutyrates - metabolism; Aminobutyrates - pharmacology; Animals; Binding Sites; Cathepsin D - antagonists & inhibitors; Cattle; Chemistry; Chymotrypsin - antagonists & inhibitors; Computer Graphics; Crystallography; Dipeptides - chemical synthesis; Dipeptides - metabolism; Dipeptides - pharmacology; Exact sciences and technology; Haplorhini; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Humans; In Vitro Techniques; Models, Molecular; Morpholines; Naphthalenes; Organic chemistry; Pepsin A - antagonists & inhibitors; Preparations and properties; Protein Binding; Renin - antagonists & inhibitors; Renin - metabolism; Stereoisomerism; Swine; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00172a005

A three-dimensional structure of the complex of human renin and the scissile site P4 Pro 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 1a contains a (2R)-3-(morpholinocarbonyl)-2-(1-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 1a was established by X-ray crystal analysis. The analyses of interaction between 1a and human renin using modeling techniques indicated that (1) the cyclohexyl group of P1 and the naphthyl group of P3 were accommodated in large hydrophobic subsites S1 and S3, respectively; (2) the imidazole of P2 His 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.