Download MendeleyDiscovery of novel potent and highly selective glycogen synthase kinase-3 beta (GSK3 beta ) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines.
Berg, S., Bergh, M., Hellberg, S., Hogdin, K., Lo-Alfredsson, Y., Soderman, P., von Berg, S., Weigelt, T., Ormo, M., Xue, Y., Tucker, J., Neelissen, J., Jerning, E., Nilsson, Y., Bhat, R.(2012) J Med Chem 55: 9107-9119
- PubMed: 22489897
- DOI: https://doi.org/10.1021/jm201724m
- Primary Citation of Related Structures:
4ACC, 4ACD, 4ACG, 4ACH, 4ACM - PubMed 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.
Organizational Affiliation:
Department of Medicinal Chemistry, AstraZeneca R&D, Innovative Medicines CNS & Pain Södertälje, SE-151 85 Södertälje, Sweden. [email protected]
