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Substituted alpha-mercaptoketones, new types of specific neprilysin inhibitors

Abstract : New neprilysin inhibitors containing an alpha-mercaptoketone HSC((RR2)-R-1)CO group, as zinc ligand were designed. Two parameters were explored for potency optimization: the size of the inhibitor which could interact with the S-1, S-1' or S-2' domain of the enzyme and the nature of the substituents R-1, R-2 of the mercaptoketone group. Introduction of a cyclohexyl chain in R-1, R-2 position and a (3-thiophen)benzyl group in position R-3 (compound 12n) yielded to the most potent inhibitor of this series with a Ki value of 2 +/- 0.3 nM. This result suggests that this new inhibitor interacts within the S-1, S-1' domain of NEP allowing a pentacoordination of the catalytic Zn2+ ion by the mercaptoketone moiety. (C) 2017 Elsevier Ltd. All rights reserved.
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https://hal-cnrs.archives-ouvertes.fr/hal-03292700
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Submitted on : Tuesday, July 20, 2021 - 3:23:18 PM
Last modification on : Friday, July 23, 2021 - 3:53:01 AM

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Herve Poras, Remi Patouret, Simon Leiris, Tanja Ouimet, Marie-Claude Fournie-Zaluski, et al.. Substituted alpha-mercaptoketones, new types of specific neprilysin inhibitors. Bioorganic & Medicinal Chemistry Letters, 2017, 27 (16), pp.3883-3890. ⟨10.1016/j.bmcl.2017.06.050⟩. ⟨hal-03292700⟩

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