jm900030h_si_001.pdf (312.42 kB)
Download file

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

Download (312.42 kB)
journal contribution
posted on 25.06.2009, 00:00 authored by 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
We report structure−activity studies of a large number of dialkyl imidazoles as inhibitors of Trypanosoma cruzi lanosterol-14α-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.