Renin Inhibitors. I. Synthesis and Structure-Activity Relationships of Transition-State Inhibitors Containing Homostatine Analogues at the Scissile Bond

Shugo ATSUUMI; Masato NAKANO; Yutaka KOIKE; Seiichi TANAKA; Kenji MATSUYAMA; Makiko NAKANO; Hajime MORISHIMA

doi:10.1248/cpb.40.364

Shugo ATSUUMI, Masato NAKANO, Yutaka KOIKE, Seiichi TANAKA, Kenji MATSUYAMA, Makiko NAKANO, Hajime MORISHIMA

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Keywords: renin inhibitor, antihypertensive agent, homostatine analogue, transition-state analogue, structure-activity relationship

JOURNAL FREE ACCESS

1992 Volume 40 Issue 2 Pages 364-370

DOI https://doi.org/10.1248/cpb.40.364

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Abstract

The synthesis and structure-activity relationships of transition-state renin inhibitors containing the homostatine analogues at the scissile bond are described. These inhibitors incorporate the amino acid side chains corresponding to positions 7-12 (P₄-P₂') of angiotensinogen. Ethyl, 2-hydroxyethyl and 3-hydroxypropyl groups at position 2 of the homostatine analogues (P₁') are more effective for increasing potency than the isopropyl group. A combination of residues at P₁, P₃ and P₄ is important for potency and this result auggests that S₁, S₃ and S₄ form a huge hydrophobic core together in renin.

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