Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer's disease

…, JC Lucas, Z Kang, S Kupchinsky, MK Ahlijanian…

文献索引：Helal, Christopher J.; Sanner, Mark A.; Cooper, Christopher B.; Gant, Thomas; Adam, Mavis; Lucas, John C.; Kang, Zhijun; Kupchinsky, Stanley; Ahlijanian, Michael K.; Tate, Bonnie; Menniti, Frank S.; Kelly, Kristin; Peterson, Marcia Bioorganic and Medicinal Chemistry Letters, 2004 , vol. 14, # 22 p. 5521 - 5525

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被引用次数: 89

摘要

High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of N-(5-isopropyl-thiazol-2-yl) isobutyramide (1). This compound is an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC50= ca. 320nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved.