Pharmacological characterization, structural studies, and in vivo activities of anti-chagas disease lead compounds derived from Tipifarnib.
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2012
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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.
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BUCKNER, F. S. et al. Pharmacological characterization, structural studies, and in vivo activities of anti-chagas disease lead compounds derived from Tipifarnib. Antimicrobial Agents and Chemotherapy, v. 56, p. 4914-4921, 2012. Disponível em: <http://aac.asm.org/content/56/9/4914>. Acesso em: 23 fev. 2017.