Discovery of Novel Potent and Highly Selective Glycogen Synthase Kinase-3尾 (GSK3尾) Inhibitors for Alzheimer鈥檚 Disease: Design, Synthesis, and Characterization of Pyrazines

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• 作者：Stefan Berg ; Margareta Bergh ; Sven Hellberg ; Katharina H枚gdin ; Yvonne Lo-Alfredsson ; Peter S枚derman ; Stefan von Berg ; Tatjana Weigelt ; Mats Orm枚 ; Yafeng Xue ; Julie Tucker ; Jan Neelissen ; Eva Jerning ; Yvonne Nilsson ; Ratan Bhat
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9107-9119
• 全文大小：700K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

Glycogen synthase kinase-3尾, also called tau phosphorylating kinase, is a proline-directed serine/threonine kinase which was originally identified due to its role in glycogen metabolism. Active forms of GSK3尾 localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer鈥檚 disease (AD) brain. By using a high throughput screening (HTS) approach to search for new chemical series and cocrystallization of key analogues to guide the optimization and synthesis of our pyrazine series, we have developed highly potent and selective inhibitors showing cellular efficacy and blood鈥揵rain barrier penetrance. The inhibitors are suitable for in vivo efficacy testing and may serve as a new treatment strategy for Alzheimer鈥檚 disease.