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

Bioorg Med Chem Lett. 2011 Apr 1;21(7):2098-101. doi: 10.1016/j.bmcl.2011.01.140. Epub 2011 Feb 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors*
  • Mice
  • Models, Molecular
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • Thiazoles
  • Cyclin-Dependent Kinase 5