Takashi Horikawa's research while affiliated with Mitsubishi Tanabe Pharma Corporation and other places

... RNA interference silencing of the GSK3β isoform has been effective in lowering phosphotau and improving function in mice tauopathy models [54,55]. New inhibitors including AZD1080, BTA-EG 4 and compounds based on 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones are under evaluation [56][57][58] and if successful, they could enter clinical trials of tauopathies, including PSP. ...

... To illustrate the application of this chemistry in synthesis, we prepared the glycogen synthase kinase (GSK)-3β inhibitor 9 (Scheme 5). 23 The chloride 8 was prepared according to the literature 24 and was coupled with the piperazine 6. This was followed directly by acid-promoted deprotection of the Boc group to give the desired bioactive compound 9. ...

... [15] Number of structurally diverse chemical scaffolds were screened for the selective GSK-3β inhibitory activities and pyrimidinone nucleus was identified as promising scaffold displaying significant tau phosphorylation inhibitory activities. [16,17] The quantitative structure-activity relationship (QSAR) is widely used technique in rational drug design [18] as it efficiently correlates the biological activity with variation in the structural features. [19] With the knowledge of 3D-QSAR models, potent lead candidates can be identified without actually synthesizing and screening big library of compounds thus, saving precious time and material and significantly reducing the cost of drug discovery and development. ...

... 2-Chloroisonicotinic acid is a vital pharmaceutical ingredient due to its unique anti-inflammatory property [1], and acts as a primary derivative in the synthesis of active drug intermediates, such as Homocamptothecin derivative and anticancer agent Diflomotecan [2], (phenylmorpholinyl) pyrimidinones [3], trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro-[6-azaisobenzofuran-1(3H),10-cyclohexane]-40-carboxamide [4], and 11-oxo-11 H-pyrido [2,1-b]quinazoline-7-carboxylic acid [5], as well as some monocomposite films. The 2-chloroisonicotinic acid is synthesized using isonicotinic-N-oxide, phosphorous pentachloride and phosphorous oxychloride [6]. ...

... These aim to prevent immune cells from infiltrating the CNS. Regulators of immune homeostasis, such as vitamin D and resveratrol, which regulate PPARγ function(Matsuura et al., 2011), as well as modulators of the intestinal microbiota(Dou et al., 2019), like sodium butyrate and valproic acid, have been shown to reduce infarct size and a decrease in cognitive impairment.The regulation of T-cell-mediated responses in Alzheimer's disease is not well explored compared with other pathologies. While some preliminary studies have investigated the use of monoclonal antibodies against β-amyloid peptides and phosphorylated Tau protein(Wisniewski & Goni, 2015), and early-stage clinical trials aimed at restoring the suppressive activity of Treg cells by expanding them ex vivo(Faridar et al., 2020), a deeper understanding is needed to effectively implement these therapies. ...