Slow Tight Binding Inhibitors of Angiotensin Converting Enzyme
We have found that apparent Ki values of some, but not all, carboxyalkyl-dipeptide inhibitors of angiotensin converting enzyme decrease as a function of incubation time. The most potent of the ACE inhibitors tested so far is RAC-X-65 (N-[1(S)-carboxy-3-carboxanilidiopropyl]-L-Ala-L-Pro). When RAC-X-65 is not preincubated with human serum ACE (2.4 × 10−11 M), the apparent Ki value is 4.4 × 10−10 M. Preincubation of RAC-X-65 with ACE for 15 min before addition of substrate yields an apparent Ki of 4.1 × 10−11 M. a 90 min preincubation of the inhibitor with ACE yields an apparent Ki of 1.2 × 10−11 M, i. e., the reaction of the inhibitor with enzyme is virtually stoichiometric. The enzyme:inhibitor complex is poorly separated by molecular sieve chromatography or by dilution. That such tightly bound complexes are formed in vivo is suggested by the following results: The intravenous ED50 (anesthetized rats) of RAC-X-65 is 9.43 nmol/kg, and the time for half recovery (t MATHTYPE) of responsiveness to i. v. angiotensin I, 120 ng/kg, following a cumulative dose of 240 nmol/kg of the inhibitor is 165 min. For comparison, the i. v. ED50 of captopril is 105 nmol/kg, and its t MATHTYPE following a cumulative dose of 240 nmol/kg is 16 min. Implied is the possibility that slow tight binding inhibitors of ACE may be used in a 1 pill per day regimen for the treatment of hypertension.
KeywordsCumulative Dose Blood Pressure Response Inhibitor Complex Chlorhexidine Gluconate Monoethyl Ester
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