Design and synthesis of quinolin-2(1H)-one derivatives as potent CDK5 inhibitors.
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine protein kinase and its deregulation is implicated in a number of neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Using active site homology modeling between CDK5 and CDK2, we explored several different chemical series of potent CDK5 inhibitors. In this report, we describe the design, synthesis, and CDK5 inhibitory activities of quinolin-2(1H)-one derivatives.
Zhong
Wenge
W
Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Liu
Hu
H
Kaller
Matthew R
MR
Henley
Charles
C
Magal
Ella
E
Nguyen
Thomas
T
Osslund
Timothy D
TD
Powers
David
D
Rzasa
Robert M
RM
Wang
Hui-Ling
HL
Wang
Weiya
W
Xiong
Xiaoling
X
Zhang
Jiandong
J
Norman
Mark H
MH
D001665:Binding Sites; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D008958:Models, Molecular; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011804:Quinolines; D051360:Cyclin-Dependent Kinase 5; D051357:Cyclin-Dependent Kinase 2