Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer's disease.
High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of N-(5-isopropyl-thiazol-2-yl)isobutyramide (1). This compound is an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC(50)=ca. 320nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved.
Neuroscience Medicinal Chemistry and Pharmacology, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. chris_j_helal@groton.pfizer.com
Christopher J
CJ
Helal
Mark A
MA
Sanner
Christopher B
CB
Cooper
Thomas
T
Gant
Mavis
M
Adam
John C
JC
Lucas
Zhijun
Z
Kang
Stanley
S
Kupchinsky
Michael K
MK
Ahlijanian
Bonnie
B
Tate
Frank S
FS
Menniti
Kristin
K
Kelly
Marcia
M
Peterson
D000544:Alzheimer Disease / Q000188:drug therapy*; D000577:Amides / Q000138:chemical synthesis / Q000627:therapeutic use*; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000627:therapeutic use*
D000577:Amides; C497744:N-(5-isopropyl-thiazol-2-yl)isobutyramide; D009419:Nerve Tissue Proteins; C118136:TPPP protein, human; D013844:Thiazoles; C004483:2-aminothiazole; D051360:Cyclin-Dependent Kinase 5; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases