Aryl-indolyl maleimides as inhibitors of CaMKIIdelta. Part 1: SAR of the aryl region

Daniel E Levy; Dan-Xiong Wang; Qing Lu; Zheng Chen; John Perumattam; Yong-Jin Xu; Albert Liclican; Jeffrey Higaki; Hanmin Dong; Maureen Laney; Babu Mavunkel; Sundeep Dugar

doi:10.1016/j.bmcl.2008.02.059

Aryl-indolyl maleimides as inhibitors of CaMKIIdelta. Part 1: SAR of the aryl region

Bioorg Med Chem Lett. 2008 Apr 1;18(7):2390-4. doi: 10.1016/j.bmcl.2008.02.059. Epub 2008 Mar 4.

Authors

Daniel E Levy¹, Dan-Xiong Wang, Qing Lu, Zheng Chen, John Perumattam, Yong-Jin Xu, Albert Liclican, Jeffrey Higaki, Hanmin Dong, Maureen Laney, Babu Mavunkel, Sundeep Dugar

Affiliation

¹ Scios, Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA. [email protected]

PMID: 18334294
DOI: 10.1016/j.bmcl.2008.02.059

Abstract

A family of aryl-substituted maleimides was prepared and studied for their activity against calmodulin dependant kinase. Inhibitory activities against the enzyme ranged from 34nM to >20microM and were dependant upon both the nature of the aryl group and the hydrogen bond donating potential of the maleimide ring. Key interactions with the kinase ATP site and hinge region were found to be consistent with homology modeling predictions.

MeSH terms

Adenosine Triphosphate / metabolism
Benzene Derivatives / chemical synthesis
Benzene Derivatives / pharmacology*
Binding Sites
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors*
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
Indoles / chemical synthesis
Indoles / pharmacology*
Maleimides / chemical synthesis
Maleimides / pharmacology*
Models, Chemical
Structure-Activity Relationship
Substrate Specificity

Substances

Benzene Derivatives
Enzyme Inhibitors
Indoles
Maleimides
Adenosine Triphosphate
CAMK2D protein, human
Calcium-Calmodulin-Dependent Protein Kinase Type 2