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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• 作者：Morihisa Saitoh ; Jun Kunitomo ; Eiji Kimura ; Hiroki Iwashita ; Yumiko Uno ; Tomohiro Onishi ; Noriko Uchiyama ; Tomohiro Kawamoto ; Toshimasa Tanaka ; Clifford D. Mol ; Douglas R. Dougan ; Garret P. Textor ; Gy
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：October 22, 2009
• 年：2009
• 卷：52
• 期：20
• 页码：6270-6286
• 全文大小：1211K
• 年卷期：v.52,no.20(October 22, 2009)
• ISSN：1520-4804

文摘

Glycogen synthase kinase 3β (GSK-3β) 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-3β 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-3β 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.