Pharmacological Characterization, Structural Studies, and In Vivo Activities of Anti-Chagas Disease Lead Compounds Derived from Tipifarnib

Abstract

g 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.

Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease

“…Several factors could be in play. A majority of studies that previously reported successful clearance of murine T. cruzi infections by posaconazole employed mice in early acute phase, with treatment starting as early as 1 day after the infection (8,9,33,34,37,38). It is possible that T. cruzi parasites in longer-term infections respond differently to treatment with posaconazole than parasites in early acute infections.…”

In Vitro and In Vivo Studies of the Antiparasitic Activity of Sterol 14α-Demethylase (CYP51) Inhibitor VNI against Drug-Resistant Strains of Trypanosoma cruzi

“…Among them, CL-Brener (TcVI), whose complete genome sequencing was reported in 2005 (23), and Tulahuen (also TcVI), whose CYP51 gene we cloned and have been studying (24), are known to be drug sensitive, while there are other strains of the parasite that display medium [e.g., Y (TcII)] or high [e.g., Colombiana (TcI)] resistance to the current clinically available nitroderivative compounds (Bz and Nf) (20,25,26). Interestingly, this drug resistance appears to encompass antifungal azoles, including posaconazole (14,27).…”

Clinical Candidate VT-1161's Antiparasitic Effect In Vitro , Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi

“…In these short-term in vivo experiments, we evaluated the ability of VT-1161 to suppress parasitemia during the acute phase of infection of mice with the Y strain of T. cruzi, because the Y strain is known to be naturally moderately resistant to nitro derivatives, such as benznidazole and nifurtimox (1), and has decreased susceptibility to the CYP51 inhibitors posaconazole (42,43) and VNI (44). Besides, infection of Swiss mice using 10 4 bloodstream forms of the Y strain of T. cruzi reaches peak parasitemia on day 8 (44), which allows the relatively fast selection of potentially promising compounds.…”