PHARMACOLOGICAL PROPERTIES OF FPL-63547, A NOVEL INHIBITOR OF ANGIOTENSIN-CONVERTING ENZYME

1. FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotensin converting enzyme (ACE) in vitro (IC50 0.51 nM). 2. In conscious normotensive dogs, FPL 63547 (10-300 μg kg-1 i.v.) produced prolonged, dose-related inhibition of plasma ACE activity and angiotensin I pressor responses, without affecting basal blood pressure, heart rate or pressor responses to angiotensin II. 3. In anaesthetized dogs, FPL 63547 diacid (3-300 μg kg-1 i.v. cumulatively) produced dose-related increases in cardiac output accompanied by falls in total peripheral resistance indicative of vasodilatation. Mild stimulation of cardiac rate and contractility was also observed. Enalapril diacid had a similar profile. 4. FPL 63547 was a highly effective antihypertensive agent after oral administration to spontaneously hypertensive rats (SHR) pretreated with a diuretic. It lowered systolic blood pressure (SBP) on acute administration over the range 3 x 10-7 - 10-5 mol kg-1 p.o. (≃0.13-4.5 mg kg-1 p.o.). FPL 63547 was more potent than other ACE inhibitors tested, threshold active doses for lisinopril, enalapril and captopril being 10-6, 10-6 and 3 x 10-5 mol kg-1 p.o., respectively. The antihypertensive effects of FPL 63547, unlike those of enalapril and captopril, were of long duration. 5. The antihypertensive efficacy of FPL 63547 was also observed following chronic oral administration. A dose of 0.5 mg kg-1 day-1 once daily for 23 days produced a sustained reduction of SBP. By the end of the treatment period, SBP was significantly lowered both pre- and post-dose, i.e. effective 24 h control had been achieved. 6. The profile of FPL 63547 is consistent with it being a potent, selective and long-acting ACE inhibitor. As an antihypertensive agent in SHR it compared favourably with other members of this class with respect to potency and duration of action.