title: Slow tight binding inhibitors of angiotensin converting enzyme.
abstract: 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 X 10(-11) M), the apparent Ki value is 4.4 X 10(-10) M. Preincubation of RAC-X-65 with ACE for 15 min before addition of substrate yields an apparent Ki of 4.1 X 10(-11) M. a 90 min preincubation of the inhibitor with ACE yields an apparent Ki of 1.2 X 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 (t1/2) 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 t1/2 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.
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C051316:N-(1-carboxy-3-carboxanilidopropyl)alanylproline; D004656:Enalapril; D007703:Peptidyl-Dipeptidase A