Aryl-indolyl maleimides as inhibitors of CaMKIIdelta. Part 2: SAR of the amine tether.
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 tether joining the basic amine to the indolyl maleimide core. Key interactions with the kinase ATP site and hinge region, predicted by homology modeling, were confirmed.
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
Higaki
Jeffrey
J
Dong
Hanmin
H
Liclican
Albert
A
Laney
Maureen
M
Mavunkel
Babu
B
Dugar
Sundeep
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; 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
D000588:Amines; 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