title: Phosphinic tripeptides as dual angiotensin-converting enzyme C-domain and endothelin-converting enzyme-1 inhibitors.
abstract: 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 microM 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 P(1)' 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.
authors.affiliation: CEA, DSV, Service d'Ingenierie Moleculaire des Proteines (SIMOPRO), Bat 152, CE-Saclay, Gif/Yvette 91191 Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jullien
authors.forename: Anastasios
authors.initials: A
authors.lastname: Makritis
authors.forename: Dimitris
authors.initials: D
authors.lastname: Georgiadis
authors.forename: Fabrice
authors.initials: F
authors.lastname: Beau
authors.forename: Athanasios
authors.initials: A
authors.lastname: Yiotakis
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D000072396:Endothelin-Converting Enzymes; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D007703:Peptidyl-Dipeptidase A; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes