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

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CEA, DSV, Service d’Ingénierie Moléculaire des Protéines (SIMOPRO), Bat 152, CE-Saclay, Gif/Yvette 91191 Cedex, France
Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis Zografou 15771, Athens, Greece
*To whom correspondence should be addressed. Phone: 330169082603. Fax: 330169089071. E-mail: [email protected]
§Present address: Institut de Radioprotection et de Sureté Nucléaire (IRSN), DRPH/SRBE/LRPAT, Bat 05, BP17, Fontenay-aux-roses 92262, France.
Cite this: J. Med. Chem. 2010, 53, 1, 208–220
Publication Date (Web):November 9, 2009
Copyright © 2009 American Chemical Society

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    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 Ki 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.

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    NMR characterization of compounds 5F1, 5F2, 7F1, 7F2, 8F1, and 8F2. This material is available free of charge via the Internet at

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