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VFV as a New Effective CYP51 Structure-Derived Drug Candidate for Chagas Disease and Visceral Leishmaniasis.
- Source :
-
The Journal of infectious diseases [J Infect Dis] 2015 Nov 01; Vol. 212 (9), pp. 1439-48. Date of Electronic Publication: 2015 Apr 15. - Publication Year :
- 2015
-
Abstract
- Sterol 14α-demethylases (CYP51) are the enzymes essential for sterol biosynthesis. They serve as clinical targets for antifungal azoles and are considered as targets for treatment of human Trypanosomatidae infections. Recently, we have shown that VNI, a potent and selective inhibitor of trypanosomal CYP51 that we identified and structurally characterized in complex with the enzyme, can cure the acute and chronic forms of Chagas disease. The purpose of this work was to apply the CYP51 structure/function for further development of the VNI scaffold. As anticipated, VFV (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide, the derivative designed to fill the deepest portion of the CYP51 substrate-binding cavity, reveals a broader antiprotozoan spectrum of action. It has stronger antiparasitic activity in cellular experiments, cures the experimental Chagas disease with 100% efficacy, and suppresses visceral leishmaniasis by 89% (vs 60% for VNI). Oral bioavailability, low off-target activity, favorable pharmacokinetics and tissue distribution characterize VFV as a promising new drug candidate.<br /> (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Animals
Antiprotozoal Agents pharmacokinetics
Benzamides pharmacokinetics
Biotransformation
Cytochrome P-450 Enzyme Inhibitors pharmacokinetics
Disease Models, Animal
Female
Humans
Imidazoles pharmacology
Inhibitory Concentration 50
Mice
Mice, Inbred BALB C
Microsomes, Liver drug effects
Molecular Structure
Oxadiazoles pharmacokinetics
Rats
Structure-Activity Relationship
Tissue Distribution
Trypanosoma cruzi drug effects
Antiprotozoal Agents pharmacology
Benzamides pharmacology
Chagas Disease drug therapy
Cytochrome P-450 Enzyme Inhibitors pharmacology
Cytochrome P-450 Enzyme System chemistry
Leishmaniasis, Visceral drug therapy
Oxadiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6613
- Volume :
- 212
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of infectious diseases
- Publication Type :
- Academic Journal
- Accession number :
- 25883390
- Full Text :
- https://doi.org/10.1093/infdis/jiv228