Aryl-indolyl maleimides as inhibitors of CaMKIIdelta. Part 1: SAR of the aryl region.
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.
Levy
Daniel E
DE
Scios, Inc., 6500 Paseo Padre Parkway, Fremont, CA 94555, USA. del345@gmail.com
Wang
Dan-Xiong
DX
Lu
Qing
Q
Chen
Zheng
Z
Perumattam
John
J
Xu
Yong-Jin
YJ
Liclican
Albert
A
Higaki
Jeffrey
J
Dong
Hanmin
H
Laney
Maureen
M
Mavunkel
Babu
B
Dugar
Sundeep
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008301:Maleimides / Q000138:chemical synthesis / Q000494:pharmacology*; D008956:Models, Chemical; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D000255:Adenosine Triphosphate; C517660:CAMK2D protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2