Phosphinic tripeptides as dual angiotensin-converting enzyme C-domain and endothelin-converting enzyme-1 inhibitors
Résumé
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 8F2) 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 8F2 (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. © 2009 American Chemical Society.
Mots clés
angiotensin II
dipeptidyl carboxypeptidase
dipeptidyl carboxypeptidase inhibitor
endothelin 1
endothelin converting enzyme
endothelin converting enzyme inhibitor
isoxazole derivative
membrane metalloendopeptidase
phosphinic acid derivative
animal experiment
animal model
antihypertensive activity
article
concentration response
controlled study
drug potency
drug selectivity
drug synthesis
enzyme inhibition
enzyme inhibitor interaction
hypertension
IC 50
male
mean arterial pressure
nonhuman
rat
reaction analysis
spontaneously hypertensive rat
stereochemistry
Angiotensin-Converting Enzyme Inhibitors
Animals
Aspartic Acid Endopeptidases
Blood Pressure
Dose-Response Relationship
Drug
Drug Evaluation
Preclinical
Matrix Metalloproteinase 13
Metalloendopeptidases
Molecular Conformation
Neprilysin
Oligopeptides
Peptidyl-Dipeptidase A
Rats
Inbred SHR
Stereoisomerism
Structure-Activity Relationship