title: 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.affiliation: Small Molecule Discovery Center, and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, United States.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.affiliation: Small Molecule Discovery Center, and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, United States.
authors.forename: Clifford
authors.initials: C
authors.lastname: Bryant
authors.affiliation: Small Molecule Discovery Center, and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Chen
authors.affiliation: Small Molecule Discovery Center, and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, United States.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Small Molecule Discovery Center, and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, United States.
authors.forename: Estefania
authors.initials: E
authors.lastname: Hugo Caselli
authors.affiliation: Small Molecule Discovery Center, and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, United States.
authors.forename: Servando
authors.initials: S
authors.lastname: Ponce
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, United States.
authors.forename: Somenath
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, United States.
authors.forename: Haichao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Small Molecule Discovery Center, and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, United States.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, United States.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ellman
authors.affiliation: 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.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
mesh_terms: D001682:Biological Availability; D014355:Chagas Disease / Q000188:drug therapy* / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015394:Molecular Structure; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D006845:Hydrocarbons, Fluorinated; D007659:Ketones; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; C000608311:tetrafluorophenoxymethyl ketone; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi
keywords: Chagas’ disease; Cruzain; Lead optimization; Pharmacokinetics; Protease inhibitors