Abstract
CV-5975, (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acid, was found to inhibit rabbit lung angiotensin converting enzyme (ACE) activity with an IC50 of 3.1 × 10-9 M and a K1 of 2.6 × 10-9 M, inhibit the angiotensin I (A-I)-induced contraction of the guinea pig ileum with an IC50 of 1.3 × 10-8 M, and augment the bradykinin (BK)-induced contraction of the ileum with an AC50 of 9.2 × 10-10 M. The activity of CV-5975 was comparable to or slightly more potent than that of enalaprilat. The overall inhibition constant (Ki*), calculated from a steady-state analysis of enzyme reactions, was 4.4 × 10-12 M for CV-5975; this indicates that the inhibition was about 5 times more potent than that of enalaprilat (2.0 × 10-11 M). In rats, CV-5975 (0.03 and 0.3 mg/kg, i.v. and 3 and 10 mg/kg, p.o.) inhibited the A-I-induced pressor action more potently and for a longer period than did the corresponding doses of enalaprilat and enalapril. CV-5975 and enalapril (3 mg/kg, p.o.) augmented the BK-induced depressor action to a similar extent. In dogs, CV-5975 (0.3 and 1 mg/kg, p.o.) markedly inhibited the A-I-induced pressor action in a dose related manner, and the duration of this inhibitory activity was longer than with the corresponding doses of enalapril. These data provide evidence for the proposal that CV-5975 is a highly potent and long lasting ACE inhibitor.
