| Literature DB >> 26144347 |
R Jeffrey Neitz1, Clifford Bryant1, Steven Chen1, Jiri Gut1, Estefania Hugo Caselli1, Servando Ponce1, Somenath Chowdhury2, Haichao Xu2, Michelle R Arkin1, Jonathan A Ellman2, Adam R Renslo3.
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.Entities:
Keywords: Chagas’ disease; Cruzain; Lead optimization; Pharmacokinetics; Protease inhibitors
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Year: 2015 PMID： 26144347 PMCID： PMC4737481 DOI： 10.1016/j.bmcl.2015.06.066
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823