Design and optimization of highly-selective,broad spectrum fungal CYP51 inhibitors |
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Authors: | Christopher M. Yates Edward P. Garvey Sammy R. Shaver Robert J. Schotzinger William J. Hoekstra |
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Affiliation: | Viamet Pharmaceuticals Inc., Durham, NC 27703, USA |
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Abstract: | 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. |
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Keywords: | Lanosterol 14 α-demethylase CYP51 Azole Fungal infection Antifungal |
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