Browsing by Author "Shackleford, David M."

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    Antitrypanosomal activity of fexinidazole metabolites, potential new drug candidates for Chagas disease.
    (2014) Bahia, Maria Terezinha; Nascimento, Álvaro Fernando da Silva do; Mazzeti, Ana Lia; Marques, Luiz F.; Gonçalves, Karolina Ribeiro; Mota, Ludmilla Walter Reis; Diniz, Lívia de Figueiredo; Caldas, Ivo Santana; Silva, André Talvani Pedrosa da; Shackleford, David M.; Koltun, Maria; Saunders, Jessica; White, Karen L.; Scandale, Ivan; Charman, Susan A.; Chatelain, Eric
    This study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30% to 40%) and 100 mg/kg/day (100%). In the benznidazole- treated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80%). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole.
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    Pharmacological characterization, structural studies, and in vivo activities of anti-chagas disease lead compounds derived from Tipifarnib.
    (2012) Buckner, Frederick S.; Bahia, Maria Terezinha; Suryadevara, Praveen Kumar; White, Karen L.; Shackleford, David M.; Chennamaneni, Naveen Kumar; Hulverson, Matthew A.; Laydbak, Joy U.; Chatelain, Eric; Scandale, Ivan; Verlinde, Christophe L. M. J.; Charman, Susan A.; Lepesheva, Galina I.; Gelbc, Michael H.
    Chagas disease, caused by the protozoan pathogen Trypanosoma cruzi, remains a challenging infection due to the unavailability of safe and efficacious drugs. Inhibitors of the trypanosome sterol 14 -demethylase enzyme (CYP51), including azole antifungal drugs, are promising candidates for development as anti-Chagas disease drugs. Posaconazole is under clinical investigation for Chagas disease, although the high cost of this drug may limit its widespread use. We have previously reported that the human protein farnesyltransferase (PFT) inhibitor tipifarnib has potent anti-T. cruzi activity by inhibiting the CYP51 enzyme. Furthermore, we have developed analogs that minimize the PFT-inhibitory activity and enhance the CYP51 inhibition. In this paper, we describe the efficacy of the lead tipifarnib analog compared to that of posaconazole in a murine model of T. cruzi infection. The plasma exposure profiles for each compound following a single oral dose in mice and estimated exposure parameters after repeated twice-daily dosing for 20 days are also presented. The lead tipifarnib analog had potent suppressive activity on parasitemia in mice but was unsuccessful at curing mice, whereas posaconazole as well as benznidazole cured 3 of 5 and 4 of 6 mice, respectively. The efficacy results are consistent with posaconazole having substantially higher predicted exposure than that of the tipifarnib analog after repeat twice-daily administration. Further changes to the tipifarnib analogs to reduce plasma clearance are therefore likely to be important. A crystal structure of a trypanosomal CYP51 bound to a tipifarnib analog is reported here and provides new insights to guide structure-based drug design for further optimized compounds.