<b>Abstract:</b> 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 toxicity). We report a rationally-designed, broad-spectrum antifungal agent that is highly selective for the target enzyme, fungal CYP51, relative to human CYP enzymes (e.g. CYP3A4). Herein, the triazole metal-binding group found in current 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 agent VT-1129, now in Phase 1 clinical trials. This compound exhibits exceptional potency against Cryptococcus species in vitro, and in vivo in a standard mouse model of cryptococcal meningitis. The methodology described is potentially applicable to the design of best-in-class metalloenzyme inhibitor therapies for a broad array of diseases.

Discovery of the potent and selective fungal CYP51 inhibitor VT-1129

251st National Meeting (2016)

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