Discovery of a new isomannide-based peptidomimetic synthetized by Ugi multicomponent reaction as human tissue kallikrein 1 inhibitor

Bioorg Med Chem Lett. 2017 Jan 15;27(2):314-318. doi: 10.1016/j.bmcl.2016.11.051. Epub 2016 Nov 18.

Abstract

Human kallikrein 1 (KLK1) is the most extensively studied member of this family and plays a major role in inflammation processes. From Ugi multicomponent reactions, isomannide-based peptidomimetic 10 and 13 where synthesized and showed low micromolar values of IC50 for KLK1 The most active compound (10) presented competitive mechanism, with three structural modifications important to interact with active site residues which corroborates its KLK1 inhibition. Finally, the most active compound also showed good ADMET profile, which indicates compound 10 as a potential hit in the search for new KLK1 inhibitors with low side effects.

Keywords: Inhibitors; Kallikreins; Molecular modeling; Peptidomimetics; Ugi reactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Kallikreins / antagonists & inhibitors*
  • Kallikreins / metabolism
  • Models, Molecular
  • Molecular Structure
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology*
  • Structure-Activity Relationship

Substances

  • 1,4-3,6-dianhydromannitol
  • Bridged Bicyclo Compounds, Heterocyclic
  • Enzyme Inhibitors
  • Peptidomimetics
  • KLK10 protein, human
  • Kallikreins