| Popis: |
Recent clinical data demonstrate that angiotensin converting enzyme (ACE) inhibitors possess promising antihypertensive properties. We now report on the ACE inhibitory activity and antihypertensive action of N-[N-[1-(S)-ethoxycarbonyl-3-pheny1propy1]-L-alany1]-N-(indan-2-y1)-glycine-HCl(CV-3317). CV-3317-COOH, the parent diacid of CV-3317, inhibited rabbit lung ACE by 50% (IC50) at a concentration of 0.04 μM. In rats, inhibition of plasma and lung ACE by CV-3317 occurred at ID50 of 0.02 and 0.08 mg/kg, p.o., respectively. The duration of ACE inhibitory activity by CV-3317 (6.75 mg/kg, p.o.), determined by the time to restore the inhibitory effects by 50% of base-line levels of ACE activity, was about 11 hr for plasma and about 19 hr for lung. In rats, inhibition of the pressor effects of angiotensin I by CV-3317 occurred at an ID50 of 0.97 mg/kg, p.o. for 4 hr-observation periods after administration. In spontaneously hypertensive rats (SHR), CV-3317 at 3 and 10 mg/kg, p.o. lowered blood pressure by 20 to 30 mmHg; this effect lasted for at least 6 hr. Daily administrations of CV-3317 (3 and 10 mg/kg/ day) to the SHR for 5 weeks produced marked, sustained antihypertensive activity of 20 to 40 mmHg with duration of action at least 8 hr. In 2-kidney, 1 clip hypertensive rats and dogs, CV-3317 at 3 and 10 mg/kg, p.o. lowered blood pressure by 20 to 35 mmHg over 6 hr. CV-3317, even at a higher dose of 30 mg/kg, p.o., had no effect on blood pressure of 1-kidney, 1 clip hypertensive rats and low renin types of both DOCA/salt hypertensive rats and nephrectomized SHR. These data demonstrate that CV-3317 is a potent, long-lasting ACE inhibitor and antihypertensive agent. |
