The Small Molecule Discovery Center, San Francisco, California 94158, United States.
J Med Chem. 2011 Feb 24;54(4):1010-21. doi: 10.1021/jm101250y. Epub 2011 Jan 19.
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 EC(50) of 0.94 μM in prion-infected neuroblastoma cells (ScN2a-cl3) and reached a concentration of ∼25 μM 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.
2-氨基噻唑是一类具有朊病毒活性的新小分子，可在朊病毒感染的神经母细胞瘤细胞系中发挥作用（J. Virol. 2010, 84, 3408）。我们在此报告了为提高 2-氨基噻唑的效力和物理化学性质而进行的构效关系研究，特别强调了在大脑中实现和维持高药物浓度。这方面的努力包括生成信息丰富的构效关系（SAR）和鉴定具有口服吸收能力并在动物体内达到高脑浓度的先导化合物。例如，新的氨基噻唑类似物（5-甲基吡啶-2-基）-[4-（3-苯基异恶唑-5-基）-噻唑-2-基]-胺（27）在朊病毒感染的神经母细胞瘤细胞（ScN2a-cl3）中的 EC50 为 0.94 μM，并且在啮齿动物液体饮食中口服给药 3 天后，其在小鼠大脑中的浓度达到约 25 μM。本文所述的研究表明，2-氨基噻唑是寻找朊病毒病有效治疗方法的有前途的新先导化合物。
