title: Efficacy of a novel, orally active GSK-3 inhibitor 6-Methyl-N-[3-[[3-(1-methylethoxy)propyl]carbamoyl]-1H-pyrazol-4-yl]pyridine-3-carboxamide in tau transgenic mice.
abstract: Neurofibrillary tangles (NFTs) composed of hyperphosphorylated and aggregated tau are common pathological characteristics in Alzheimer's disease (AD) and other tauopathies. Aberrant tau phosphorylation is an early and pivotal event in the pathogenesis of tauopathies, and since GSK-3 is a key factor implicated in aberrant tau phosphorylation, GSK-3 inhibition is expected to suppress tauopathy disease progression. In the present study, we report the efficacy of a newly discovered small molecule GSK-3 inhibitor, 6-methyl-N-[3-[[3-(1-methylethoxy)propyl]carbamoyl]-1H-pyrazol-4-yl]pyridine-3-carboxamide (compound A), to inhibit tau phosphorylation and to reduce the amount of pathological aggregated tau in JNPL3 mice that overexpress a mutant form of human tau. Compound A is a highly potent and selective inhibitor of GSK-3 with an IC(50) of 2 nM, with at least 230-fold lower potency against 27 other kinases. Oral administration of compound A resulted in a significant reduction of tau phosphorylation at several GSK-3 directed sites. Furthermore, chronic oral administration of compound A markedly reduced aggregated tau in old JNPL3 mice. These results suggest that a novel, orally active GSK-3 inhibitor, compound A, has potency in the prevention of tau pathology.
authors.affiliation: Pharmacology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Uno_Yumiko1@takeda.co.jp
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Uno
authors.forename: Hiroki
authors.initials: H
authors.lastname: Iwashita
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Uchiyama
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kori
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakanishi
mesh_terms: D000284:Administration, Oral; D000375:Aging; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C545866:6-methyl-N-(3-((3-(1-methylethoxy)propyl)carbamoyl)-1H-pyrazol-4-yl)pyridine-3-carboxamide; D004791:Enzyme Inhibitors; C054369:MAPT protein, human; D011720:Pyrazoles; D016875:tau Proteins; D009536:Niacinamide; D038362:Glycogen Synthase Kinase 3