Substituted α-mercaptoketones, new types of specific neprilysin inhibitors

Hervé Poras; Rémi Patouret; Simon Leiris; Tanja Ouimet; Marie-Claude Fournié-Zaluski; Bernard P Roques

doi:10.1016/j.bmcl.2017.06.050

Substituted α-mercaptoketones, new types of specific neprilysin inhibitors

Bioorg Med Chem Lett. 2017 Aug 15;27(16):3883-3890. doi: 10.1016/j.bmcl.2017.06.050. Epub 2017 Jun 21.

Authors

Hervé Poras¹, Rémi Patouret¹, Simon Leiris¹, Tanja Ouimet¹, Marie-Claude Fournié-Zaluski¹, Bernard P Roques²

Affiliations

¹ Pharmaleads, Paris BioPark, 11 rue Watt, 75013 Paris, France.
² Pharmaleads, Paris BioPark, 11 rue Watt, 75013 Paris, France; Université Paris-Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France. Electronic address: bernard.roques@pharmaleads.com.

PMID: 28676269
DOI: 10.1016/j.bmcl.2017.06.050

Abstract

New neprilysin inhibitors containing an α-mercaptoketone HSC(R¹R²)CO group, as zinc ligand were designed. Two parameters were explored for potency optimization: the size of the inhibitor which could interact with the S₁, S₁' or S₂' domain of the enzyme and the nature of the substituents R¹, R² of the mercaptoketone group. Introduction of a cyclohexyl chain in R¹, R² position and a (3-thiophen)benzyl group in position R³ (compound 12n) yielded to the most potent inhibitor of this series with a Ki value of 2±0.3nM. This result suggests that this new inhibitor interacts within the S₁, S₁' domain of NEP allowing a pentacoordination of the catalytic Zn²⁺ ion by the mercaptoketone moiety.

Keywords: Neprilysin inhibitor; Substituted α-mercaptoketone; Zinc bidentation.

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Ketones / chemical synthesis
Ketones / chemistry
Ketones / pharmacology*
Molecular Structure
Neprilysin / antagonists & inhibitors*
Neprilysin / metabolism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Ketones
Neprilysin