A new class of angiotensin-converting enzyme inhibitors

Aa, Patchett; Harris, Elbert E.; Ew, Tristram; Mj, Wyvratt; Mt, Wu; Taub, D.; Er, Peterson; Tj, Ikeler; J, ten Broeke; Lg, Payne; Dl, Ondeyka; Ed, Thorsett; Wj, Greenlee; Ns, Lohr; Rd, Hoffsommer; Joshua, H; Wv, Ruyle; Jw, Rothrock; Sd, Aster; Al, Maycock; Fm, Robinson; Hirschmann, Ralph; Cs, Sweet; Eh, Ulm; Dm, Gross; Tc, Vassil; Ca, Stone

doi:10.1038/288280a0

Cited by 710 publications

(280 citation statements)

References 13 publications

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“…Studies of ACE inhibition with rabbit lung homogenates (Table 1) and guinea pig ileum (Table 2) indicated that CV-5975 is a potent ACE inhibitor. The IC50 value of enalaprilat on the lung ACE was compatible with the published values (17,18). CV-5975 aug mented the BK-induced contraction of the guinea pig ileum more potently than did enalaprilat, but inhibited the A-I-induced con traction of the ileum to much the same extent as enalaprilat did (Table 2).…”

Section: Discussionsupporting

confidence: 78%

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

Inada

Tanabe

Itoh

et al. 1988

Japanese Journal of Pharmacology

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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.

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Section: Discussionsupporting

confidence: 78%

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

Inada

Tanabe

Itoh

et al. 1988

Japanese Journal of Pharmacology

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“…Certain inhibitors of angiotensin-converting enzyme (ACE, EC 3.4.15.1) which transforms the decapeptide angiotensin I to the powerful vasoconstrictor octapeptide angiotensin II offer promise as therapeutic agents. Useful antihypertensive properties have been demonstrated, clinically, for the nonapeptide SQ 20 881 and the orally-active inhibitors captopril (SQ 14 225,I) [I] and MK 421 (enalapril II) [2]. The two latter compounds are very active inhibitors of ACE in vitro (table 2).…”

Section: Introductionmentioning

confidence: 99%

“…tulated zinc atom in the enzyme while retaining a close similarity to the dipeptide Ala-Pro. The compound MK 421, which includes an Ala-Pro fragment in the molecule was the outcome of extensive structure-activity studies; it is visualised as a transition stage analogue inhibitor [2].…”

Section: Introductionmentioning

confidence: 99%

The design of a new group of angiotensin‐converting enzyme inhibitors

et al. 1982

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Using X‐ray and NMR data relating to the conformation of the antihypertensive, angiotensin‐converting enzyme inhibitor, captopril, and structure—activity relationships of analogues, it has been possible to postulate with the aid of computer graphics, the orientation of the three functions, the thiol, the terminal carboxyl and the carbonyl group which are involved in binding to the enzyme. Bicyclic mimetics of captopril, with related arrays of these functions, have been designed and synthesized. Compounds with the closest approximation to the array in captopril are the most active inhibitors of angiotensin converting enzyme, in vitro.

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“…Enalapril maleate is a new orally active converting enzyme inhibitorwith no sulfhydryl group in its molecular structure (1,2). Acute and chronic effect of enalapril on blood pressure (BP) has been examined in hyper tensive animals, including spontaneously hypertensive rats (SHR) and renal hyper tensive rats or dogs (3)(4)(5)(6)(7)(8).…”

mentioning

confidence: 99%