PMID: 11906289Mar 22, 2002Paper

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

Journal of Medicinal Chemistry
Nicolas InguimbertBernard P Roques

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.

References

Jul 1, 1992·Hypertension·Z A AbassiH R Keiser
Feb 12, 2000·Journal of Molecular Biology·C OefnerG E Dale

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Citations

Oct 10, 2002·Bioorganic & Medicinal Chemistry Letters·Fariborz FiroozniaArco Y Jeng
Aug 25, 2004·Proceedings of the National Academy of Sciences of the United States of America·Trairak PisitkunMark A Knepper
Jul 29, 2006·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Nikhil H Gokhale, J A Cowan
Jul 2, 2020·Molecular Pharmacology·Gabrielle C GregoriouElena E Bagley
Mar 11, 2004·The Journal of Peptide Research : Official Journal of the American Peptide Society·N InguimbertB-P Roques

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