Inhibition of angiotensin converting enzyme by (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetra- hydro-1,5-benzothiazepine-6-acetic acid (CV-5975), a non-sulfhydryl compound.
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 x 10(-9) M and a Ki of 2.6 x 10(-9) M, inhibit the angiotensin I (A-I)-induced contraction of the guinea pig ileum with an IC50 of 1.3 x 10(-8) M, and augment the bradykinin (BK)-induced contraction of the ileum with an AC50 of 9.2 x 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 x 10(-12) M for CV-5975; this indicates that the inhibition was about 5 times more potent than that of enalaprilat (2.0 x 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.
Inada
Y
Y
Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Tanabe
M
M
Itoh
K
K
Sugihara
H
H
Nishikawa
K
K
D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D004285:Dogs; D004656:Enalapril / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008168:Lung / Q000201:enzymology; D008297:Male; D011817:Rabbits; D051381:Rats; D013841:Thiazepines / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D013841:Thiazepines; C054055:CV 5975; D004656:Enalapril; D000803:Angiotensin I; D001920:Bradykinin