Inhibition of Angiotensin Converting Enzyme by (R)-3-[(S)-1-Carboxy-5-(4-Piperidyl)pentyl]amino-4-Oxo-2,3,4,5-Tetrahydro-1,5-Benzothiazepine-5-Acetic Acid (CV-5975), a Non-Sulfhydryl Compound

Abstract

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 X10-9 M and a K; of 2.6X10-9 M, inhibit the angiotensin I (A-I)-induced contraction of the guinea pig ileum with an IC50 of 1.3X10_$ M, and augment the bradykinin (BK) induced contraction of the ileum with an AC50 of 9.2x10-10 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 4.4x10-12 M for CV-5975; this indicates that the inhibition was about 5 times more potent than that of enalaprilat (2.0x10-" 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.) aug mented 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.

(R)-3-((S)-1-carboxy-5-(4-piperidyl)pentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (CV-5975): A new potent and long-lasting inhibitor of angiotensin converting enzyme.

“…This finding indicates that a basic amino group is essential for longlasting inhibitory activity in vivo. Although the role of the nitrogen atom in prolonging the duration of action is not yet clear, it might be related to the existence of an additional binding site on ACE and/or it may confer increased affinity to ACE (27). The preparation and function of the hypertensin -converting enzyme.…”