title: Discovery of novel potent and highly selective glycogen synthase kinase-3β (GSK3β) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines.
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.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D, Innovative Medicines CNS & Pain Södertälje, SE-151 85 Södertälje, Sweden. Stefan.berg@astrazeneca.com
authors.forename: Stefan
authors.initials: S
authors.lastname: Berg
authors.forename: Margareta
authors.initials: M
authors.lastname: Bergh
authors.forename: Sven
authors.initials: S
authors.lastname: Hellberg
authors.forename: Katharina
authors.initials: K
authors.lastname: Högdin
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lo-Alfredsson
authors.forename: Peter
authors.initials: P
authors.lastname: Söderman
authors.forename: Stefan
authors.initials: S
authors.lastname: von Berg
authors.forename: Tatjana
authors.initials: T
authors.lastname: Weigelt
authors.forename: Mats
authors.initials: M
authors.lastname: Ormö
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Xue
authors.forename: Julie
authors.initials: J
authors.lastname: Tucker
authors.forename: Jan
authors.initials: J
authors.lastname: Neelissen
authors.forename: Eva
authors.initials: E
authors.lastname: Jerning
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Nilsson
authors.forename: Ratan
authors.initials: R
authors.lastname: Bhat
mesh_terms: D016475:3T3 Cells; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D018938:Caco-2 Cells; D002417:Cattle; D018360:Crystallography, X-Ray; D015195:Drug Design; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010539:Permeability; D010766:Phosphorylation; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D011719:Pyrazines; D013449:Sulfonamides; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3