Structure–activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors


Cdk5/p25 has emerged as a principle therapeutic target for numerous acute and chronic neurodegenerative diseases, including Alzheimer’s disease. A structure–activity relationship study of 2,4-diaminothiazole inhibitors revealed that increased Cdk5/p25 inhibitory activity could be accomplished by incorporating pyridines on the 2-amino group and addition of substituents to the 2- or 3-position of the phenyl ketone moiety. Interpretation of the SAR results for many of the analogs was aided through in silico docking with Cdk5/p25 and calculating protein hydrations sites using WaterMap. Finally, improved in vitro mouse microsomal stability was also achieved.



Cdk5, Kinase, Inhibitor, Alzheimer's disease, 2,4-diaminothiazoles


Copyright 2011 Bioorganic and Medicinal Chemistry Letters. This is a post-print version of a published paper that is available at: Recommended citation: Laha, Joydev K., Xuemei Zhang, Lixin Qiao, Min Liu, Snigdha Chatterjee, Shaughnessy Robinson, Kenneth S. Kosik, and Gregory D. Cuny. "Structure–activity relationship study of 2, 4-diaminothiazoles as Cdk5/p25 kinase inhibitors." Bioorganic & medicinal chemistry letters 21, no. 7 (2011): 2098-2101. doi: 10.1016/j.bmcl.2011.01.140. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.