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J Med Chem. 2002 Mar 28;45(7):1477-86.

Toward an optimal joint recognition of the S1' subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP).

Author information

1
Département de Pharmacochimie Moléculaire et Structurale, INSERM U266, CNRS UMR 8600, UFR des Sciences Pharmaceutiques et biologiques, 4 Avenue de l'observatoire, 75270 Paris Cedex 06, France.

Abstract

The formation of vasoconstrictors (e.g., angiotensin II and endothelin) and the inactivation of vasodilators (e.g., bradykinin and atrial natriuretic) by membrane-bound zinc metallopeptidases are key mechanisms in the control of blood pressure and fluid homeostasis. The way in which these peptides modulate physiological functions has been intensively studied. With the aim to develop compounds that can jointly block the three metallopeptidases-neutral endopeptidase (NEP, neprilysin), angiotensin-converting enzyme (ACE), and endothelin-converting enzyme (ECE-1)-we studied the common structural specificity of the S1' subsites of these peptidases. Various mercaptoacyl amino acids of the general formula HS-CH2-CH(R1')CO-Trp-OH, possessing more or less constrained R1' side chains, were designed. The mercapto-acyl synthons contain one or two asymmetrical centers. The K(i) values of the separated stereoisomers of the most efficient inhibitors were used to determine the stereochemical preference of each enzyme. A guideline for the joint inhibition of the three peptidases was obtained with the (2R,3R) isomer of compound 13b. Its K(i) values on NEP, ACE, and ECE were 0.7, 43, and 26 nM, respectively.

PMID:
11906289
DOI:
10.1021/jm0005454
[Indexed for MEDLINE]

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