2-Aminothiazoles as Therapeutic Leads for Prion Diseases

详细信息    查看全文

• 作者：Alejandra Gallardo-Godoy ; Joel Gever ; Kimberly L. Fife ; B. Michael Silber ; Stanley B. Prusiner ; Adam R. Renslo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 24, 2011
• 年：2011
• 卷：54
• 期：4
• 页码：1010-1021
• 全文大小：993K
• 年卷期：v.54,no.4(February 24, 2011)
• ISSN：1520-4804

文摘

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鈭抋ctivity 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鈭抋ctivity 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 (<b>27b>), for example, exhibited an ECb>50b> of 0.94 渭M in prion-infected neuroblastoma cells (ScN2a-cl3) and reached a concentration of 25 渭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.