2. Academic Validation
  3. Discovery of novel potent and highly selective glycogen synthase kinase-3β (GSK3β) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines

Discovery of novel potent and highly selective glycogen synthase kinase-3β (GSK3β) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines

  • J Med Chem. 2012 Nov 8;55(21):9107-19. doi: 10.1021/jm201724m.
Stefan Berg 1,  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
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, AstraZeneca R&D, Innovative Medicines CNS & Pain Södertälje, SE-151 85 Södertälje, Sweden. Stefan.berg@astrazeneca.com
PMID: 22489897 DOI: 10.1021/jm201724m
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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