While the orally-active azoles such as voriconazole and itraconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to safety liabilities (e.g., drug-drug interactions, liver toxicity). We disclose rationally-designed, broad-spectrum antifungal agents selective for the target fungal enzyme, CYP51, vis-a-vis related human CYP enzymes (e.g. CYP3A4). Using proprietary methodology, the triazole metal-binding group found in current antifungal agents was replaced with novel, less avid metal-binding groups in concert with potency-enhancing scaffold modifications. This process generated a series of fungal CYP51-selective inhibitors inclusive of the oral antifungal VT-1161, now in Phase 2b clinical trials. This series exhibits exceptional potency against key yeast and dermatophyte strains. The methodology described is potentially applicable to the design of best-in-class metalloenzyme inhibitor therapies for a broad array of diseases.

Design and optimization of potent, selective fungal CYP51 inhibitors

250th National Meeting (2015)

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