Phosphinic Tripeptides as Dual Angiotensin-Converting Enzyme C-Domain and Endothelin-Converting Enzyme-1 Inhibitors

• Published in: Journal of medicinal chemistry 2010-01, Vol.53 (1), p.208-220
• Main Authors: Jullien, Nicolas, Makritis, Anastasios, Georgiadis, Dimitris, Beau, Fabrice, Yiotakis, Athanasios, Dive, Vincent
• Format: Article
• Language: English
• Subjects: Angiotensin-Converting Enzyme Inhibitors - chemical synthesis; Angiotensin-Converting Enzyme Inhibitors - chemistry; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Antihypertensive agents; Aspartic Acid Endopeptidases - antagonists & inhibitors; Biological and medical sciences; Blood Pressure - drug effects; Cardiovascular system; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endothelin-Converting Enzymes; Life Sciences; Matrix Metalloproteinase Inhibitors; Medical sciences; Metalloendopeptidases - antagonists & inhibitors; Molecular Conformation; Neprilysin - antagonists & inhibitors; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Peptidyl-Dipeptidase A - metabolism; Pharmacology. Drug treatments; Rats; Rats, Inbred SHR; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9010803

A new series of phosphinic inhibitors able to interact with both angiotensin-converting enzyme (ACE) C-domain and endothelin-converting enzyme-1 (ECE-1), while sparing neprilysin (NEP), has been developed. The most potent and selective inhibitor in this series (compound 8 F2 ) displays K i values of 0.65 nM, 150 nM, 14 nM and 6.7 μM toward somatic ACE C-domain, ACE N-domain, ECE-1, and NEP, respectively. Remarkably, in this series, the inhibitor’s ability to discriminate between ECE-1 and NEP was observed to depend on the stereochemistry of the residue present in the inhibitor’s P1′ position. After iv administration, compound 8 F2 (10 mg/kg) lowered mean arterial blood pressure by 24 ± 2 mmHg in spontaneously hypertensive rats, as compared with controls. Mixed ACE/ECE-1 inhibitor may lead to a new generation of vasopeptide inhibitors that should reduce the levels of angiotensin-II and endothelin-1, without interfering with bradykinin cleavage.