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.


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


  • Enzyme Inhibitors
  • Ketones
  • Neprilysin