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

Abstract

FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotensin converting enzyme (ACE) in vitro (IC50 0.51 nm). 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. 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. 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 × 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 × 10−5 mol kg−1 p.o., respectively. The antihypertensive effects of FPL 63547, unlike those of enalapril and captopril, were of long duration. 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. 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.

Antihypertensive activity of Rosa rugosa Thunb. flowers: Angiotensin I converting enzyme inhibitor

“…The obtained IC 50 value for captopril was found to be 69.8 nM (15.16 ng/ml). The data obtained is similar to that in literature where IC 50 values for captopril range from 2.27 nM to 0.58 mM (Inada et al, 1986;Carr et al, 1990;Udupa and Rao, 1997;Dyck et al, 2003). When 10 ml of 1.25 mg/ml HHL and 20 ml ACE (0.05 unit/ml) were added to the reaction mixture, the IC 50 value for captopril was 13 nM (Geng et al, 2010).…”

Preferential biliary elimination of FPL 63547, a novel inhibitor of angiotensin‐converting enzyme, in the rat

“…Bile and urine samples were taken for 5 h following dosing but all the compounds tested are long-acting probably as a result of tight binding to ACE, and pharmacological and pharmacokinetic evidence supports their continued presence in the body beyond 5 h. For example, in conscious dogs the inhibition of plasma ACE produced by a single i.v. dose of FPL 63547 peaks at 0.5-1 h and is still evident 24 h after certain doses (Carr et al, 1990). In all probability a proportion of each compound is taken up into tissues sites from which it is released and eliminated at a very slow rate.…”

“…Preparation of enzyme Rabbit lung ACE was affinity purified on lisinopril-Sepharose according to the method of Bull et al (1985), modified as described in the accompanying paper (Carr et al, 1990 By constructing a standard curve of inhibition of ACEmediated hydrolysis (14C-count versus log inhibitory concentration) the concentration of ACE inhibitor in the 'unknown' samples was determined.…”

“…FPL 63547, a novel thiadiazoline, is a potent and long acting ACE inhibitor with antihypertensive properties in spontaneously hypertensive rats (Carr et al, 1990). Mackaness (1985) first suggested that ACE inhibitors may be developed which are suited to biliary transport, thus reducing the clinical problems associated with their use in patients with impaired kidney function.…”

Prejunctional modulation by angiotensins of noradrenaline release from sympathetic neurons in isolated rabbit aorta

“…Captopril and lisinopril are competitive inhibitors of ACE (Carr et al 1990). Neither of these drugs had any effect on the stimulation-evoked 3 H-overflow.…”