Pharmacological properties of FPL 63547, a novel inhibitor of angiotensin-converting enzyme

Br J Pharmacol. 1990 May;100(1):83-9. doi: 10.1111/j.1476-5381.1990.tb12056.x.

Abstract

1. FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotension converting enzyme (ACE) in vitro (IC50 0.51 nM). 2. In conscious normotensive dogs, FPL 63547 (10-300 micrograms 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 micrograms 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. (congruent to 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.

MeSH terms

  • Angiotensin I / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Blood Pressure / drug effects
  • Cardiac Output / drug effects
  • Dogs
  • Dose-Response Relationship, Drug
  • Heart Rate / drug effects
  • Lung / drug effects
  • Lung / enzymology
  • Male
  • Peptidyl-Dipeptidase A / blood
  • Rabbits
  • Rats
  • Rats, Inbred SHR
  • Thiadiazoles / pharmacology*
  • Vasodilation / drug effects

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Thiadiazoles
  • utibapril
  • Angiotensin I
  • Peptidyl-Dipeptidase A