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

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.

• Authors: R Jeffrey Neitz, Clifford Bryant, Steven Chen, Jiri Gut, Estefania Hugo Caselli, Servando Ponce, Somenath Chowdhury, Haichao Xu, Michelle R Arkin, Jonathan A Ellman, Adam R Renslo
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 21 Pg. 4834-4837 (Nov 01 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 26144347 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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