2-{3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl}-5-methyl-1,3,4-oxadiazole Derivatives as Novel Inhibitors of Glycogen Synthase Kinase-3β with Good Brain Permeability
| العنوان: | 2-{3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl}-5-methyl-1,3,4-oxadiazole Derivatives as Novel Inhibitors of Glycogen Synthase Kinase-3β with Good Brain Permeability |
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| المؤلفون: | Tomohiro Onishi, Clifford D. Mol, Masakuni Kori, Eiji Kimura, Morihisa Saitoh, Noriko Uchiyama, Toshimasa Tanaka, Hiroki Iwashita, Garret P. Textor, Yumiko Uno, Jun Kunitomo, Gyorgy Snell, Tomohiro Kawamoto, Masayuki Takizawa, Fumio Itoh, Douglas R. Dougan |
| المصدر: | Journal of Medicinal Chemistry. 52:6270-6286 |
| بيانات النشر: | American Chemical Society (ACS), 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Male, Models, Molecular, Molecular Conformation, Oxadiazole, Crystallography, X-Ray, Chemical synthesis, Permeability, Substrate Specificity, Glycogen Synthase Kinase 3, Inhibitory Concentration 50, Mice, chemistry.chemical_compound, In vivo, GSK-3, Drug Discovery, Animals, Humans, Transferase, Protein Kinase Inhibitors, chemistry.chemical_classification, Oxadiazoles, Glycogen Synthase Kinase 3 beta, Brain, Stereoisomerism, Rats, Enzyme, Solubility, Biochemistry, chemistry, Drug Design, Lipophilicity, Molecular Medicine, Tau-protein kinase |
| الوصف: | Glycogen synthase kinase 3beta (GSK-3beta) inhibition is expected to be a promising therapeutic approach for treating Alzheimer's disease. Previously we reported a series of 1,3,4-oxadiazole derivatives as potent and highly selective GSK-3beta inhibitors, however, the representative compounds 1a,b showed poor pharmacokinetic profiles. Efforts were made to address this issue by reducing molecular weight and lipophilicity, leading to the identification of oxadiazole derivatives containing a sulfinyl group, (S)-9b and (S)-9c. These compounds exhibited not only highly selective and potent inhibitory activity against GSK-3beta but also showed good pharmacokinetic profiles including favorable BBB penetration. In addition, (S)-9b and (S)-9c given orally to mice significantly inhibited cold water stress-induced tau hyperphosphorylation in mouse brain. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm900647e |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b8b3317f7f2c64048ad5d5fbf705945c https://doi.org/10.1021/jm900647e |
| رقم الانضمام: | edsair.doi.dedup.....b8b3317f7f2c64048ad5d5fbf705945c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/jm900647e |