Current fungal CYP51 inhibitors (i.e., “azoles” such as fluconazole and voriconazole) are effective antifungal agents, yet potently inhibit a broad range of off-target human cytochrome P450 enzymes leading to safety liabilities (e.g., drug-drug interactions, liver and reproductive toxicities). We report the discovery of a novel, fungal CYP51-selective agent with broad-spectrum activity. Herein, the triazole heme iron binding group of current agents was replaced with novel, less avid heme iron binding groups in concert with homology-model guided, potency-enhancing scaffold modifications. This process generated VT-1598, an orally available inhibitor that demonstrates high potency against a broad range of yeasts, molds, and endemic fungi. Viamet is developing VT-1598 for the treatment of coccidioidomycosis, or Valley Fever, a systemic fungal infection in the SW United States with notable unmet need. In a preclinical model of Valley Fever, VT-1598 was highly effective in treating an infection localized to the CNS. VT-1598 has been granted Qualified Infectious Disease Product (QIDP) and orphan drug designations by the FDA to treat coccidioidomycosis. VT-1598 complements Viamet’s yeast- and dermatophyte-active Phase 2B agent VT-1161 under development for both onychomycosis and recurrent vulvovaginal candidiasis.

Discovery of the potent and selective, broad spectrum fungal CYP51 inhibitor VT-1598

253rd National Meeting (2017)

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