title: Structurally simple inhibitors of lanosterol 14alpha-demethylase are efficacious in a rodent model of acute Chagas disease.
abstract: We report structure-activity studies of a large number of dialkyl imidazoles as inhibitors of Trypanosoma cruzi lanosterol-14alpha-demethylase (L14DM). The compounds have a simple structure compared to posaconazole, another L14DM inhibitor that is an anti-Chagas drug candidate. Several compounds display potency for killing T. cruzi amastigotes in vitro with values of EC(50) in the 0.4-10 nM range. Two compounds were selected for efficacy studies in a mouse model of acute Chagas disease. At oral doses of 20-50 mg/kg given after establishment of parasite infection, the compounds reduced parasitemia in the blood to undetectable levels, and analysis of remaining parasites by PCR revealed a lack of parasites in the majority of animals. These dialkyl imidazoles are substantially less expensive to produce than posaconazole and are appropriate for further development toward an anti-Chagas disease clinical candidate.
authors.affiliation: Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Suryadevara
authors.forename: Srinivas
authors.initials: S
authors.lastname: Olepu
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Lockman
authors.forename: Junko
authors.initials: J
authors.lastname: Ohkanda
authors.forename: Mandana
authors.initials: M
authors.lastname: Karimi
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: James M
authors.initials: JM
authors.lastname: Kraus
authors.forename: Jan
authors.initials: J
authors.lastname: Schoepe
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
mesh_terms: D000208:Acute Disease; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D058886:Sterol 14-Demethylase; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase