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R‑CONFIGURATION OF 4‑AMINOPYRIDYL-BASED INHIBITORS OF CYP51 CONFERS SUPERIOR EFFICACY AGAINST TRYPANOSOMA CRUZI
Choi, Jun Yong et al. | Date Issued: 2014
Author
Choi, Jun Yong
Calvet, Claudia M
Vieira, Debora F
Gunatilleke, Shamila S
Cameron, Michael D
McKerrow, James H
Podust, Larissa M
Roush, William R
Affilliation
Scripps Florida. Department of Chemistry. Florida, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultra-Estrutura Celular. Rio de Janeiro, RJ, Brasil.
University of California San Francisco. Department of Pathology. San Francisco, CA, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.
Scripps Florida. Department of Molecular Therapeutics. Florida, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.
Scripps Florida. Department od Chemistry. Florida, USA.
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
T. cruzi
CYP51
R-configuration
Inhibitors
4‑Aminopyridyl-Based Inhibitors of CYP51
 
DeCS
Trypanosoma cruzi
Publisher
American Chemical Society
Citation
CHOI, Jun Yong et al. R‑Configuration of 4‑Aminopyridyl-Based Inhibitors of CYP51 Confers Superior Efficacy Against Trypanosoma cruzi. ACS Medicinal Chemistry Letters, v. 5, n. 4, p. 434-439, Jan. 2014.
DOI
10.1021/ml500010m
ISSN
1948-5875