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Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer's disease |
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| Authors: | 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 |
| Affiliation: | Neuroscience Medicinal Chemistry and Pharmacology, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. chris_j_helal@groton.pfizer.com |
| Abstract: | 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 (IC(50)=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. |
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