The design of a new group of angiotensin‐converting enzyme inhibitors

Abstract

Using X‐ray and NMR data relating to the conformation of the antihypertensive, angiotensin‐converting enzyme inhibitor, captopril, and structure—activity relationships of analogues, it has been possible to postulate with the aid of computer graphics, the orientation of the three functions, the thiol, the terminal carboxyl and the carbonyl group which are involved in binding to the enzyme. Bicyclic mimetics of captopril, with related arrays of these functions, have been designed and synthesized. Compounds with the closest approximation to the array in captopril are the most active inhibitors of angiotensin converting enzyme, in vitro.

A method for estimating the potency of angiotensin‐converting enzyme inhibitors in man.

“…This finding in man correlates with in vitro results with ACE inhibitors (Ondetti & Cushman, 1982). Our approach thus allows the establishment of potency of the inhibitor (Ki-dose) and to judge the type of antagonism in man in relation to in vitro results (Strittmatter & Snyder, 1986;Hassall et al, 1982 (Ondetti & Cushman, 1982). The high potency of cilazapril in man is in accordance with results from in vitro and in vivo animal experiments (Natoff et al, 1985).…”

“…Application of classic pharmacologic methodology (Arunlakshana & Schild, 1959) should allow one to quantitate the competitive antagonism between A-I and ACE inhibitors seen in in vitro studies (Ondetti & Cushman, 1982;Strittmatter & Snyder, 1986 (Arunlakshana & Schild, 1959;Wellstein et al, 1985). The aim of this study was to apply these principles to establish a dose-response relationship for a new ACE inhibitor, cilazapril (Hassall et al, 1982;Natoff et al, 1985 1.25, 3.75, 10, and 30 mg of cilazapril orally with a 7 day washout period between the test days. On each day two A-I dose-effect curves were derived by a continuous intravenous infusion and dosage was increased at 3 min intervals (0.1 to 18 ,ug min-') as described in detail previously Wellstein et al, 1987).…”

Recent developments in the design of angiotensin‐converting enzyme inhibitors

“…152 Hassel has reported lactam analogs of captopril (Table XXIV) in which a proline surrogate is present. 153,154 In this series, the mercapto substituent and the "proline" carboxylic acid must be trans to one another about the plane of the bicyclic system for maximum activity (cf. 24-8 and 24-9).…”

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“…Earlier modeling studies had investigated the ACE pharmacophore, but based on a small number of compounds (Hassell et al, 1982, Andrews et al, 1985. The first experiment described in the present paper was a blindfold test to see whether progol could rediscover the pharmacophore proposed by Mayer et al, given their particular assumptions (regarding the active 3D conformations and zinc-binding geometry, described in the next subsection).…”