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Structure-activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors |
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| Authors: | Laha Joydev K Zhang Xuemei Qiao Lixin Liu Min Chatterjee Snigdha Robinson Shaughnessy Kosik Kenneth S Cuny Gregory D |
| Affiliation: | a Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women’s Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA b Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106, USA c Schrödinger, Inc., 120 West Forty-Fifth Street, New York, NY 10036, USA |
| Abstract: | 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. |
| Keywords: | Cdk5 Kinase Inhibitor Alzheimer&rsquo s disease 2,4-Diaminothiazoles |
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