期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 16, 页码 6989-7005出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm500448u
关键词
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资金
- NIH RO1 [AI095437]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- FIOCRUZ
- Dr. Miriam & Sheldon G. Adelson Medical Research Foundation (APNRR Proteomics Platform) [A120343]
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]
- NIH [P41 RR001081]
CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection.
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