Discovery of novel potent and highly selective glycogen synthase kinase-3β (GSK3β) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines.
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| Abstract |
Glycogen synthase kinase-3β, 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 GSK3β localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer's 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-brain barrier penetrance. The inhibitors are suitable for in vivo efficacy testing and may serve as a new treatment strategy for Alzheimer's disease.
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| Authors | Stefan Berg, Margareta Bergh, Sven Hellberg, Katharina Högdin, Yvonne Lo-Alfredsson, Peter Söderman, Stefan von Berg, Tatjana Weigelt, Mats Ormö, Yafeng Xue, Julie Tucker, Jan Neelissen, Eva Jerning, Yvonne Nilsson, Ratan Bhat |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 21 Pg. 9107-19 (Nov 08 2012) ISSN: 1520-4804 [Electronic] United States |
| PMID | 22489897 (Publication Type: Journal Article) |
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