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

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

Author information

1
Small Molecule Discovery Center, and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, United States.
2
Department of Chemistry, Yale University, New Haven, CT 06520, United States.
3
Small Molecule Discovery Center, and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, United States. Electronic address: adam.renslo@ucsf.edu.

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

PMID:
26144347
PMCID:
PMC4737481
DOI:
10.1016/j.bmcl.2015.06.066
[Indexed for MEDLINE]
Free PMC Article

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