Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas' disease

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4834-4837. doi: 10.1016/j.bmcl.2015.06.066. Epub 2015 Jun 23.

Abstract

Inhibition of the cysteine protease cruzain from Trypanosoma cruzi has been studied pre-clinically as a new chemotherapeutic approach to treat Chagas' disease. Efficacious effects of vinylsulfone-based cruzain inhibitors in animal models support this therapeutic hypothesis. More recently, substrate-activity screening was used to identify nonpeptidic tetrafluorophenoxymethyl ketone inhibitors of cruzain that showed promising efficacy in animal models. Herein we report efforts to further optimize the in vitro potency and in vivo pharmacokinetic properties of this new class of cruzain inhibitors. Through modifications of the P1, P2 and/or P3 positions, new analogs have been identified with reduced lipophilicity, enhanced potency, and improved oral exposure and bioavailability.

Keywords: Chagas’ disease; Cruzain; Lead optimization; Pharmacokinetics; Protease inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Availability
  • Chagas Disease / drug therapy*
  • Chagas Disease / metabolism
  • Cysteine Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrocarbons, Fluorinated / chemical synthesis
  • Hydrocarbons, Fluorinated / chemistry
  • Hydrocarbons, Fluorinated / pharmacokinetics*
  • Hydrocarbons, Fluorinated / pharmacology*
  • Ketones / chemical synthesis
  • Ketones / chemistry
  • Ketones / pharmacokinetics*
  • Ketones / pharmacology*
  • Molecular Structure
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / metabolism
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacokinetics*
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma cruzi / drug effects*

Substances

  • Enzyme Inhibitors
  • Hydrocarbons, Fluorinated
  • Ketones
  • Protozoan Proteins
  • Trypanocidal Agents
  • tetrafluorophenoxymethyl ketone
  • Cysteine Endopeptidases
  • cruzain, Trypanosoma cruzi