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 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.
Carr
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RD
Fisons plc, Pharmaceutical Division, Research and Development Laboratories, Loughborough.
Higgs
L
L
Killingback
P G
PG
Nicol
A K
AK
O'Connor
S E
SE
Robson
A
A
Wells
E
E
Simpson
W T
WT
D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013830:Thiadiazoles / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D013830:Thiadiazoles; C065021:utibapril; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A