Inhibition of Angiotensin Converting Enzyme by CV-3317, a Non-Sulfhydryl Compound

Inada, Yuji; Terashita, Zen‐ichi; Imura, Yoshimi; Tanabe, Masao; Nishikawa, Kohei; Kikuchi, Shintarō

doi:10.1254/jjp.42.99

Cited by 32 publications

(24 citation statements)

References 18 publications

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“…We have already reported that CV-331 7 is a potent orally effective angiotensin con verting enzyme inhibitor and that the potency of this agent on the inhibitory effect of conversion from A-I to A-II is considered to be more potent and longer lasting than that of captopril (6). In the present study, the antihypertensive activity of CV-3317 was examined in normotensive rats and various hypertensive animal models.…”

Section: Discussionmentioning

confidence: 74%

“…The conscious rats were guillotined 5 hr after the final dose of a 5-week treatment regimen, and samples of blood and lung tissues were removed. The ACE activity of plasma and lung homogenates was measured by a radioenzymatic assay (7), as described in detail in the second paper (6). Plasma renin activity (PRA) and angiotensin I (A-I) concentration were measured by radioimmu noassay with a commercial assay kit (CEA IRE-SORIN, France).…”

Section: Methodsmentioning

confidence: 99%

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Antihypertensive Action of a Non-Sulfhydryl Angiotensin Converting Enzyme Inhibitor (CV-3317) in Various Hypertensive Models

Inada

Tanabe

Shibouta

et al. 1986

Japanese Journal of Pharmacology

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Abstract-The antihypertensive action of N-[N-[(S)-1-ethoxycarbonyl-3-phenyl propyl]-L-alanyl]-N-(indan-2-yl)glycinehydrochloride (CV-3317), a nonsulfhydryl compound characterized as an angiotensin converting enzyme inhibitor in our previous work, was examined in hypertensive animal models.In 2-kidney, 1 clip hypertensive rats and dogs, CV-331 7 (3 and/or 10 mg/kg, p.o.) produced a sustained antihypertensive action of about 15 to 25 mmHg. Daily oral administrations of CV-3317 (1 to 10 mg/kg/day) to spontaneously hypertensive rats (SHR) for 5 weeks produced a sustained antihypertensive action of 20 to 40 mmHg. When CV-3317 (3 mg/kg) was combined with hydrochlorothiazide (10 mg/kg), its anti hypertensive action was intensified in potency and duration.CV-3317 (30 mg/ kg) induced a slight hypotension (5 to 10 mmHg) in normotensive rats, but had no effect on the blood pressure of 1 -kidney, 1 clip hypertensive rats and on that of a low renin type of DOCA/salt hypertensive rat. The antihypertensive activity of CV-3317 was more potent than that of captopril.In pithed SHR, the pressor response induced by an electrical stimulation of the preganglionic sympathetic nerve, but not the pressor response to norepinephrine, was attenuated by both agents (0.3 mg/kg, i.v.). Both agents may exert their antihypertensive action not only primarily by inhibiting the renin-angiotensin system, but also by inhibiting norepinephrine release from the sympathetic nerve terminals indirectly by reducing the formation of vascular angiotensin II.

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Section: Discussionmentioning

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Antihypertensive Action of a Non-Sulfhydryl Angiotensin Converting Enzyme Inhibitor (CV-3317) in Various Hypertensive Models

Inada

Tanabe

Shibouta

et al. 1986

Japanese Journal of Pharmacology

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“…With increasing interest in self-contained renin-angiotensin systems within organs such as blood vessels, kidney, heart, and brain, differences in the actions of ACE inhibitors have begun to become apparent, the most likely basis for which would be differences in the distribution of these drugs into various tissues. Most investigators, however, who have attempted to correlate differences in potency and tissue distribution of ACE inhibitors with important actions in vivo did not investigate a very large or diverse array of inhibitors, or a very extensive group of tissues (Chevillard et al, 1988;Cohen & Kurz, 1982;Inada et al, 1986;Jackson et al, 1987a,b;Norman et al, 1987;Sakaguchi et al, 1988;Unger etal., 1984Unger etal., , 1985Unger etal., , 1986a.…”

Section: Introductionmentioning

confidence: 99%

“…It is now a fairly well-accepted hypothesis that the long-term antihypertensive actions of ACE inhibitors are related to their inhibition of ACE in the walls of blood vessels, which contain all of the components of the renin-angiotensin system (Cohen & Kurz, 1982;Dzau, 1987;Inada et al, 1986;Scholkens et al, 1984;Unger et al, 1984Unger et al, , 1985. Differences among ACE inhibitors have been reported with respect to their abilities to cross the blood-brain barrier Unger et al, 1984Unger et al, , 1985, but these have not yet been correlated with differences in antihypertensive activity or with differences in other centrally-mediated actions that might be due to modification of neuropeptide metabolism.…”

Section: Introductionmentioning

confidence: 99%

Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE).

Dw¹,

Wang²,

Fung³

et al. 1989

Brit J Clinical Pharma

108

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1. Seven drugs (captopril, zofenopril, enalapril, ramipril, lisinopril, fosinopril, and SQ 29,852) were compared in vitro in homogenates of aorta, brain, heart, lung, and kidney and in sera of spontaneously hypertensive rats (SHR) both with respect to potencies of their active moieties as inhibitors of angiotensin‐converting enzyme (ACE), and, where applicable, rates of hydrolysis of their prodrug ester functions. 2. In ex vivo dose‐response and time‐course studies, the inhibitory effects of the seven drugs on tissue ACEs and their relative distributions to SHR tissues were compared following oral administration. 3. The relative potencies of the inhibitory moieties of the drugs (in parentheses) and the normalized ‘equiactive’ oral doses employed for time‐course studies were: SQ 29,852 (1.0), 100 mg kg‐1; captopril (3.5), 30 mg kg‐1; enalapril (12), 20 mg kg‐1; fosinopril (13), 25 mg kg‐1; zofenopril (20), 10 mg kg‐1; lisinopril (24), 10 mg kg‐1; and ramipril (51), 5 mg kg‐1. 4. Following oral administration of the drugs to SHR, the degree and duration of ACE inhibition in aorta and lung correlated with the antihypertensive actions, with ramipril, lisinopril, and zofenopril producing effects of the greatest magnitude and duration. 5. Ramipril and enalapril did not inhibit brain ACE ex vivo; captopril and zofenopril had modest but short‐lasting effects; and fosinopril, lisinopril, and SQ 29,852 had long‐lasting inhibitory actions, which, with the latter two, were delayed in onset. 6. All of the drugs produced significant inhibition of kidney ACE, with ramipril and fosinopril having somewhat weaker effects, perhaps due to biliary routes of excretion. 7. Captopril, fosinopril, and particularly zofenopril inhibited cardiac ACE ex vivo with degrees and durations that were marked compared with those of the other drugs; preliminary studies with isolated hearts suggest a possible relationship between inhibition of cardiac ACE and preservation of cardiac function subsequent to ischaemia.

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“…Inhibition of angiotensin converting enzyme (ACE) in vitro 1.1. Rabbit lung ACE: Angiotensin con verting enzyme (ACE) was prepared from the lung of albino male rabbits, as described (11). For the kinetic study of ACE inhibition, lung ACE was prepared according to Dorer et al (12) but with some modification; the preparation was not purified further after fractionation with ammonium sulfate.…”

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confidence: 99%

Inhibition of Angiotensin Converting Enzyme by (R)-3-[(S)-1-Carboxy-5-(4-Piperidyl)pentyl]amino-4-Oxo-2,3,4,5-Tetrahydro-1,5-Benzothiazepine-5-Acetic Acid (CV-5975), a Non-Sulfhydryl Compound

Inada

Tanabe

Itoh

et al. 1988

Japanese Journal of Pharmacology

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Abstract-CV-5975, (R)-3-[(S)-1 -carboxy-5-(4-piperidyl)pentyl]amino-4-oxo 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid, was found to inhibit rabbit lung angiotensin converting enzyme (ACE) activity with an IC50 of 3.1 X10-9 M and a K; of 2.6X10-9 M, inhibit the angiotensin I (A-I)-induced contraction of the guinea pig ileum with an IC50 of 1.3X10_$ M, and augment the bradykinin (BK) induced contraction of the ileum with an AC50 of 9.2x10-10 M. The activity of CV-5975 was comparable to or slightly more potent than that of enalaprilat.The overall inhibition constant (Ki*), calculated from a steady-state analysis of enzyme reactions, was 4.4x10-12 M for CV-5975; this indicates that the inhibition was about 5 times more potent than that of enalaprilat (2.0x10-" M). In rats, CV 5975 (0.03 and 0.3 mg/kg, i.v. and 3 and 10 mg/kg, p.o.) inhibited the A-I-induced pressor action more potently and for a longer period than did the corresponding doses of enalaprilat and enalapril.CV-5975 and enalapril (3 mg/kg, p.o.) aug mented the BK-induced depressor action to a similar extent.In dogs, CV-5975 (0.3 and 1 mg/kg, p.o.) markedly inhibited the A-I-induced pressor action in a dose related manner, and the duration of this inhibitory activity was longer than with the corresponding doses of enalapril. These data provide evidence for the proposal that CV-5975 is a highly potent and long lasting ACE inhibitor.

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Inhibition of Angiotensin Converting Enzyme by CV-3317, a Non-Sulfhydryl Compound

Cited by 32 publications

References 18 publications

Antihypertensive Action of a Non-Sulfhydryl Angiotensin Converting Enzyme Inhibitor (CV-3317) in Various Hypertensive Models

Antihypertensive Action of a Non-Sulfhydryl Angiotensin Converting Enzyme Inhibitor (CV-3317) in Various Hypertensive Models

Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE).

Inhibition of Angiotensin Converting Enzyme by (R)-3-[(S)-1-Carboxy-5-(4-Piperidyl)pentyl]amino-4-Oxo-2,3,4,5-Tetrahydro-1,5-Benzothiazepine-5-Acetic Acid (CV-5975), a Non-Sulfhydryl Compound

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