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. 2017 Aug 1;27(15):3243-3248.
doi: 10.1016/j.bmcl.2017.06.037. Epub 2017 Jun 15.

Design and optimization of highly-selective, broad spectrum fungal CYP51 inhibitors

Christopher M Yates  1 , Edward P Garvey  2 , Sammy R Shaver  2 , Robert J Schotzinger  2 , William J Hoekstra  2
Affiliations

Design and optimization of highly-selective, broad spectrum fungal CYP51 inhibitors

Christopher M Yates et al. Bioorg Med Chem Lett. .

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.

Keywords: Antifungal; Azole; CYP51; Fungal infection; Lanosterol 14 α-demethylase.

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