vt-1161 and Mycoses

While the orally-active azoles such as fluconazole and posaconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug-drug interactions, liver, and reproductive toxicities). Recently we described the rationally-designed, antifungal agent VT-1161 that is more selective for fungal CYP51 than related human CYP enzymes such as CYP3A4. Herein, we describe the use of a homology model of Aspergillus fumigatus to design and optimize a novel series of highly selective, broad spectrum fungal CYP51 inhibitors. This series includes the oral antifungal VT-1598 that exhibits excellent potency against yeast, dermatophyte, and mold fungal pathogens.

Topics: 14-alpha Demethylase Inhibitors; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Cytochrome P450 Family 51; Drug Design; Fungi; Humans; Molecular Docking Simulation; Mycoses; Pyridines; Tetrazoles