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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.

No abstract

Abstract-Theantihypertensive activity of a new angiotensin converting enzyme (ACE) inhibitor, 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 examined in nor motensive rats and various hypertensive animal models. In spontaneously hyper tensive rats, CV-5975 (1 to 10 mg/kg, p.o.) had a dose-related, sustained anti hypertensive action, which was more potent and longer than that of enalapril. The potency and duration of action of CV-5975 was intensified when it was administered repeatedly or combined with hydrochlorothiazide. CV-5975 (1 mg/kg, p.o.) inhibited the ACE activity of plasma and tissues; inhibition on the ACE activity of the aorta, kidney, and brain was marked when CV-5975 was administered repeatedly. In 2-kidney, 1 clip hypertensive rats (1 to 10 mg/kg, p.o.) and dogs (0.3 and 1 mg/kg, p.o.), CV-5975 had a marked, sustained antihypertensive action, which was more marked than that of enalapril. In normotensive rats (10 mg/kg), 1 -kidney, 1 clip hypertensive rats (3 and 10 mg/kg), and hyporeninemic DOCA/salt hyper tensive rats (1 to 10 mg/kg/day), CV-5975 administered orally once or repeatedly reduced blood pressure, whereas enalapril did not. These results indicate that CV-5975 is a potent and long-lasting antihypertensive agent, the action of which is mediated primarily by inhibiting ACE activity and partly by some unknown mechanisms.

Ausgehend von den 2‐Halogeninosinen (I) werden durch Acetylierung, Chlorierung mit dem Vilsmeier‐Reagens und Aminierung über (II) und (III) die 2‐Halogenadenosine (IV) hergestellt.