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ACS Med Chem Lett. 2014 Jan 22;5(4):434-9. doi: 10.1021/ml500010m. eCollection 2014 Apr 10.

R-Configuration of 4-Aminopyridyl-Based Inhibitors of CYP51 Confers Superior Efficacy Against Trypanosoma cruzi.

Author information

1
Department of Chemistry, Scripps Florida , Jupiter, Florida 33458, United States.
2
Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States ; Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States ; Cellular Ultra-Structure Laboratory, Oswaldo Cruz Institute (IOC), FIOCRUZ , Rio de Janeiro, RJ 21040-362, Brazil.
3
Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States ; Center for Discovery and Innovation in Parasitic Diseases and Department of Pathology, University of California San Francisco , San Francisco, California 94158, United States.
4
Department of Molecular Therapeutics, Scripps Florida , Jupiter, Florida 33458, United States.

Abstract

Sterol 14α-demethylase (CYP51) is an important therapeutic target for fungal and parasitic infections due to its key role in the biosynthesis of ergosterol, an essential component of the cell membranes of these pathogenic organisms. We report the development of potent and selective d-tryptophan-derived inhibitors of T. cruzi CYP51. Structural information obtained from the cocrystal structure of CYP51 and (R)-2, which is >1000-fold more potent than its enantiomer (S)-1, was used to guide design of additional analogues. The in vitro efficacy data presented here for (R)-2-(R)-8, together with preliminary in vitro pharmacokinetic data suggest that this new CYP51 inhibitor scaffold series has potential to deliver drug candidates for treatment of T. cruzi infections.

KEYWORDS:

CYP51; R-configuration; T. cruzi; inhibitors

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