Synthesis and biological evaluation of glycogen synthase kinase 3 (GSK-3) inhibitors: An fast and atom efficient access to 1-aryl-3-benzylureas

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• 作者：Fabio Lo Monte^a ; ^† ; ; Thomas Kramer^a ; ^† ; ; Alexander Bolä ; nder^a ; Batya Plotkin^b ; Hagit Eldar-Finkelman^b ; Ana Fuertes^c ; Juan Dominguez^c ; Boris Schmidt^a ; ^{schmidt_boris@t-online.de"" rel=""nofollow}
• 关键词：Glycogen synthase kinase 3 (GSK-3) ; Alzheimer disease ; Structure– ; activity relationship (SAR) ; Suzuki coupling ; Microwave irradiation
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 September 2011
• 年：2011
• 卷：21
• 期：18
• 页码：5610-5615
• 全文大小：681 K

文摘

The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of Alzheimer’s disease (AD). In the course of our research topic we synthesized a library of potent GSK-3 inhibitors. We utilized the urea scaffold present in the potent and highly selective GSK-3 inhibitor AR-A014418 (AstraZeneca). This moiety suits both (a) a convergent approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure–activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC₅₀ = 140 nM) and the pyridylurea 62 (IC₅₀ = 98 nM), which displayed two to threefold enhanced activity versus the reference compound 18 (AR-A014418: IC₅₀ = 330 nM) in our assays.