期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 4, 页码 1010-1021出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm101250y
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资金
- NIH [AG021601, AG031220]
- Sherman Fairchild Foundation
- Lincy Foundation
- Robert Galvin
2-Aminothiazoles are a new class of small molecules with antiprion activity in prion-infected neuroblastoma cell lines (J. Virol. 2010, 84, 3408). We report here structure-activity studies undertaken to improve the potency and physiochemical properties of 2-aminothiazoles, with a particular emphasis on achieving and sustaining high drug concentrations in the brain. The results of this effort include the generation of informative structure-activity relationships (SAR) and the identification of lead compounds that are orally absorbed and achieve high brain concentrations in animals. The new aminothiazole analogue (5-methylpyridin-2-yl)-[4-(3-phenylisoxazol-5-yl)-thiazol-2-yl]-amine (27), for example, exhibited an EC50 of 0.94 mu M in prion-infected neuroblastoma cells (ScN2a-cl3) and reached a concentration of similar to 25 mu M in the brains of mice following three days of oral administration in a rodent liquid diet. The studies described herein suggest 2-aminothiazoles as promising new leads in the search for effective therapeutics for prion diseases.
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