Phosphinic tripeptides as dual angiotensin-converting enzyme C-domain and endothelin-converting enzyme-1 inhibitors
2010
Jullien, N. | Makritis, A. | Georgiadis, D. | Beau, F. | Yiotakis, A. | Dive, V. | Institut de Radioprotection et de Sûreté Nucléaire (IRSN) | Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS) ; Médicaments et Technologies pour la Santé (MTS) ; Université Paris-Saclay-Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) | University of Athens Medical School [Athens] | Institut de Biologie et de Technologies de Saclay (IBITECS) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay
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Показать больше [+] Меньше [-]Английский. 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.
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