Structurally Simple Inhibitors of Lanosterol 14r-Demethylase Are Efficacious In a Rodent Model of Acute Chagas Disease

نویسندگان

  • Praveen Kumar Suryadevara
  • Srinivas Olepu
  • Jeffrey W. Lockman
  • Junko Ohkanda
  • Mandana Karimi
  • Christophe L. M. J. Verlinde
  • James M. Kraus
  • Jan Schoepe
  • Wesley C. Van Voorhis
  • Andrew D. Hamilton
  • Frederick S. Buckner
  • Michael H. Gelb
چکیده

We report structure-activity studies of a large number of dialkyl imidazoles as inhibitors of Trypanosoma cruzi lanosterol-14R-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 EC50 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.

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تاریخ انتشار 2009