| 論文名 |
4-Aminopyridyl-based CYP51 inhibitors as anti-Trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency. |
| 著者 |
Claudia M Calvet
Debora F Vieira
Jun Yong Choi
Danielle Kellar
Michael D Cameron
Jair Lage Siqueira-Neto
Jiri Gut
Jonathan B Johnston
Li Lin
Susan Khan
James H McKerrow
William R Roush
Larissa M Podust
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| キーワード |
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| 出版年月 |
1970年1月 |
| 発表先 |
J Med Chem. 2014 Aug 28;57(16):6989-7005. doi: 10.1021/jm500448u. Epub 2014 Aug 19. |
| WEBサイト |
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| 論文概要（和文） |
抗トリパノソーマクルジ薬としての4-アミノピリジルベースのCYP51阻害剤は、薬物動態プロファイルとin Vivo効力が向上します |
| 論文概要（英文） |
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. |
