Fungal infections are a common occurrence, with an estimated worldwide prevalence of 20% to 25%. Consistent with most of Europe and the United States, a recent retrospective study found that onychomycosis exhibited the most common dermatophyte infection. Especially, the absolute number of onychomycosis cases increased 10-fold over a 40-year period. The most common species causing onychomycosis in Europe and the United States are Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum.

A study from E P Garvey, et al described a fungal CYP51 inhibitor, Oteseconazole (VT-1161). The compound uses a tetrazole to bind the heme iron within the enzyme’s active site. The tetrazole was critical in establishing greater selectivity for fungal CYP51 versus off-target human CYPs . The potency of VT-1161 against Candida albicans CYP51 in a cellular assay was ≤0.5 nM compared to in vitro IC₅₀ values of ∼100 μM or greater against human CYP51 and key xenobiotic-metabolizing CYPs present in human liver microsomes (e.g., CYP2C9).

VT-1161 has also demonstrated potent intrinsic activity against the dermatophyte <i>T. rubrum</i>.

In an initial screen to determine its antifungal activity against dermatophytes, Oteseconazole (VT-1161) was tested in microdilution assays against clinical isolates of the most common causes of human onychomycosis: <i>T. rubrum<i>, <i>T. mentagrophytes</i>, and <i>E. floccosum</i>. The MIC values for VT-1161 against the 11 isolates tested ranged from ≤0.016 μg/ml to 0.5 μg/ml. And the effect exhibits similar to those of the in-assay positive comparator itraconazole (0.03 to 0.5 μg/ml). The MIC₅₀ and MIC₉₀ values for Oteseconazole (VT-1161) were ≤0.016 and 0.03 μg/ml, respectively, while those for itraconazole were 0.06 and 0.25 μg/mL, respectively.

In preparation for efficacy studies in this species, single oral doses of 5 and 25 mg/kg Oteseconazole (VT-1161) in 20% Cremophor EL for guinea pigs, and plasma concentrations tested for up to 48 h. Exposures showed high and approximately dose-proportional. Also, the pharmacokinetic half-life exhibited long (≥48 h). The data shows an accurate value not determined due to the lack of sufficient concentrations at extended time points.

To sum up, Oteseconazole (VT-1161) is an orally active anti-fungal agent, potently binds to and inhibits Candida albicans CYP51 (Kd, <39 nM), shows no obvious effect on human CYP51.

Reference:

VT-1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a guinea pig model. Antimicrob Agents Chemother. 2015 Apr;59(4):1992-7.