Potent and cellularly active 4-aminoimidazole inhibitors of cyclin-dependent kinase 5/p25 for the treatment of Alzheimer’s disease
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- 作者：Christopher J. Helal ; Zhijun Kang ; John C. Lucas ; Thomas Gant ; Michael K. Ahlijanian ; Joel B. Schachter ; Karl E.G. Richter ; James M. Cook ; Frank S. Menniti ; Kristin Kelly ; Scot Mente ; Jay P ; it ; Natali
- 关键词：Cyclin-dependent kinase 5 ; p25 ; Cyclin-dependent kinase 2 ; Alzheimer’ ; s disease
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2009
- 出版时间：1 October 2009
- 年：2009
- 卷：19
- 期：19
- 页码：5703-5707
- 全文大小：1204 K
文摘
Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.