Inhibition of angiotensin converting enzyme by CV-3317, a non-sulfhydryl compound.
N-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2- yl)glycine hydrochloride (CV-3317) and its de-esterified products, CV-3317-COOH and CV-3317-(5-OH)-COOH, inhibited rabbit lung angiotensin converting enzyme (ACE) with the IC50s of 1.2 X 10(-7), 4.0 X 10(-8) and 4.9 X 10(-8) M, respectively, angiotensin I (A-I)-induced vasoconstriction of the rat aorta (IC50: 2.6 X 10(-7), 2.6 X 10(-8) and 5.4 X 10(-8) M, respectively), and A-I-induced pressor response of the rat kidney (IC50: 3.9 X 10(-7), 3.5 X 10(-8) and 2.8 X 10(-8) M, respectively). In these 3 experiments, both de-esterified products were 4 to 14 times more potent than captopril. In rats, CV-3317 (0.0138 to 138 mumol/kg, p.o.) inhibited plasma and lung ACEs, and the effects at a dose of 0.46 mumol/kg lasted more than 8 hr. CV-3317 inhibited the A-I-induced pressor action in rats (0.138 to 13.8 mumol/kg, p.o. or 0.046 to 0.138 mumol/kg i.v.) and dogs (0.46 to 4.6 mumol/kg, p.o.) in a dose-related manner. CV-3317 was more potent and longer acting than captopril in these in vivo ACE inhibitions. CV-3317 augmented bradykinin-induced hypotension (dogs) and contraction of the ileum (guinea pigs) less potently than captopril. In spontaneously hypertensive rats (SHR), CV-3317 (3 mg/kg, p.o.) markedly inhibited plasma and tissue (aorta, kidney, lung and brain) ACEs; and when administered daily for 2 weeks, it inhibited the plasma, aorta, kidney and lung ACEs; in particular, it markedly inhibited the aortic ACE. Captopril (30 mg/kg, p.o.) markedly inhibited tissue ACEs and slightly plasma ACE, but its inhibitory effects on tissue ACEs, except for the aorta, were unclear by repeated dosings and its effect on plasma ACE was rather enhanced. Thus, the inhibition of vascular ACE may be particularly important for the antihypertensive effect of the ACE inhibitors, including CV-3317, in SHR.
D000803:Angiotensin I / Q000037:antagonists & inhibitors; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D014661:Vasoconstriction / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D007189:Indans; D007192:Indenes; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D001920:Bradykinin; C047759:delapril