title: Design and optimization of highly-selective fungal CYP51 inhibitors.
abstract: 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 various safety issues (e.g., drug-drug interactions, liver toxicity). Herein, we describe rationally-designed, broad-spectrum antifungal agents that are more selective for the target fungal enzyme, CYP51, than related human CYP enzymes such as CYP3A4. Using proprietary methodology, the triazole metal-binding group found in current clinical agents was replaced with novel, less avid metal-binding groups in concert with potency-enhancing molecular scaffold modifications. This process produced a unique series of fungal CYP51-selective inhibitors that included the oral antifungal 7d (VT-1161), now in Phase 2 clinical trials. This series exhibits excellent potency against key yeast and dermatophyte strains. The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases.
authors.affiliation: Viamet Pharmaceuticals Inc., Durham, NC 27703, USA. Electronic address: whoekstra@viamet.com.
authors.forename: William J
authors.initials: WJ
authors.lastname: Hoekstra
authors.affiliation: Viamet Pharmaceuticals Inc., Durham, NC 27703, USA.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Garvey
authors.affiliation: Viamet Pharmaceuticals Inc., Durham, NC 27703, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Moore
authors.affiliation: Viamet Pharmaceuticals Inc., Durham, NC 27703, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Rafferty
authors.affiliation: Viamet Pharmaceuticals Inc., Durham, NC 27703, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Yates
authors.affiliation: Viamet Pharmaceuticals Inc., Durham, NC 27703, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schotzinger
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D058886:Sterol 14-Demethylase / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D058886:Sterol 14-Demethylase
keywords: Azole; CYP51; Fungal infection; Lanosterol demethylase