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Structurally simple inhibitors of lanosterol 14alpha-demethylase are efficacious in a rodent model of acute Chagas disease.
Title | Structurally simple inhibitors of lanosterol 14alpha-demethylase are efficacious in a rodent model of acute Chagas disease. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Suryadevara, PK, Olepu, S, Lockman, JW, Ohkanda, J, Karimi, M, Verlinde, CLMJ, Kraus, JM, Schoepe, J, Van Voorhis, WC, Hamilton, AD, Buckner, FS, Gelb, MH |
Journal | J Med Chem |
Volume | 52 |
Issue | 12 |
Pagination | 3703-15 |
Date Published | 2009 Jun 25 |
ISSN | 1520-4804 |
Keywords | Acute Disease, Animals, Chagas Disease, Cytochrome P-450 Enzyme System, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Female, Imidazoles, Mice, Mice, Inbred BALB C, Models, Molecular, Molecular Structure, Parasitic Sensitivity Tests, Sterol 14-Demethylase, Structure-Activity Relationship, Trypanosoma cruzi |
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. |
DOI | 10.1021/jm900030h |
Alternate Journal | J. Med. Chem. |
PubMed ID | 19463001 |