PMID: 2120440Oct 1, 1990Paper

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

Journal of Medicinal Chemistry
K IizukaYoshiaki Kiso

Abstract

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...Continue Reading

Citations

Jan 1, 1993·Archives of Insect Biochemistry and Physiology·E P MaslerJ J Menn
Nov 1, 1991·Medicinal Research Reviews·J P Snyder
Jul 1, 1992·Medicinal Research Reviews·M D Walkinshaw
Aug 10, 2012·Expert Opinion on Drug Discovery·Yoshio Hamada, Yoshiaki Kiso
Jan 20, 2016·Journal of Peptide Science : an Official Publication of the European Peptide Society·Iwona WinieckaDaniel Sokulski
Nov 20, 2015·Biopolymers·Yoshio Hamada, Yoshiaki Kiso
Jan 20, 2007·Biopolymers·Youhei SohmaYoshiaki Kiso
Mar 12, 2005·Journal of Peptide Science : an Official Publication of the European Peptide Society·Youhei SohmaYoshiaki Kiso
Oct 11, 2005·Medicinal Research Reviews·Brigitte Bauvois, Daniel Dauzonne
Sep 4, 2008·Archiv der Pharmazie·Jeffrey-Tri NguyenYoshiaki Kiso
May 15, 1992·Analytical Biochemistry·M C OliveiraL Juliano
Sep 1, 1993·Japanese Journal of Pharmacology·Y EtohN Toda
Jul 27, 2001·Journal of the American Chemical Society·Y AoyagiR M Williams
Jun 26, 2001·The Journal of Organic Chemistry·D AmantiniL Vaccaro
Nov 12, 2021·Accounts of Chemical Research·Haocheng ZhangHanmin Huang

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