Structure-activity relationships of 3,4-dihydro-1H-quinazolin-2-one derivatives as potential CDK5 inhibitors.
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that plays a critical role in the early development of the nervous system. Deregulation of CDK5 is believed to contribute to the abnormal phosphorylation of various cellular substrates associated with neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Acyclic urea 3 was identified as a potent CDK5 inhibitor and co-crystallographic data of urea 3/CDK2 enzyme were used to design a novel series of 3,4-dihydroquinazolin-2(1H)-ones as CDK5 inhibitors. In this investigation we present our synthetic studies toward this series of compounds and discuss their biological relevance as CDK5 inhibitors.
Rzasa
Robert M
RM
Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1789, USA. rrzasa@amgen.com
Kaller
Matthew R
MR
Liu
Gang
G
Magal
Ella
E
Nguyen
Thomas T
TT
Osslund
Timothy D
TD
Powers
David
D
Santora
Vincent J
VJ
Viswanadhan
Vellarkad N
VN
Wang
Hui-Ling
HL
Xiong
Xiaoling
X
Zhong
Wenge
W
Norman
Mark H
MH
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006859:Hydrogen / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007536:Isomerism; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry
D001562:Benzimidazoles; D001593:Benzyl Compounds; D001596:Benzylamines; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D052999:Quinazolinones; D013830:Thiadiazoles; D013844:Thiazoles; D006859:Hydrogen; C030796:benzylamine; C031000:benzimidazole; D051360:Cyclin-Dependent Kinase 5; C038682:benzyl bromide