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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.
Brain Res. 2009 Nov 03; 1296:148-63.BR

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.

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Authors+Show Affiliations

Uno Y
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
Iwashita H
No affiliation info available
Tsukamoto T
No affiliation info available
Uchiyama N
No affiliation info available
Kawamoto T
No affiliation info available
Kori M
No affiliation info available
Nakanishi A
No affiliation info available

MeSH

Administration, OralAgingAnimalsBrainCold TemperatureDose-Response Relationship, DrugEnzyme InhibitorsGlycogen Synthase Kinase 3HumansMaleMiceMice, Inbred C57BLMice, TransgenicMutationNiacinamidePhosphorylationProtein MultimerizationPyrazolesStress, PhysiologicalTime Factorstau Proteins

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19698704

Citation

Uno, Yumiko, et al. "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." Brain Research, vol. 1296, 2009, pp. 148-63.
Uno Y, Iwashita H, Tsukamoto T, et al. 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. Brain Res. 2009;1296:148-63.
Uno, Y., Iwashita, H., Tsukamoto, T., Uchiyama, N., Kawamoto, T., Kori, M., & Nakanishi, A. (2009). 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. Brain Research, 1296, 148-63. https://doi.org/10.1016/j.brainres.2009.08.034
Uno Y, et al. 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. Brain Res. 2009 Nov 3;1296:148-63. PubMed PMID: 19698704.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Uno,Yumiko, AU - Iwashita,Hiroki, AU - Tsukamoto,Tetsuya, AU - Uchiyama,Noriko, AU - Kawamoto,Tomohiro, AU - Kori,Masakuni, AU - Nakanishi,Atsushi, Y1 - 2009/08/19/ PY - 2009/04/10/received PY - 2009/08/07/revised PY - 2009/08/08/accepted PY - 2009/8/25/entrez PY - 2009/8/25/pubmed PY - 2009/12/30/medline SP - 148 EP - 63 JF - Brain research JO - Brain Res VL - 1296 N2 - 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. SN - 1872-6240 UR - https://www.unboundmedicine.com/medline/citation/19698704/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-8993(09)01720-X DB - PRIME DP - Unbound Medicine ER -