Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors.
A novel series of pyrazolo[1,5-b]pyridazines have been synthesized and identified as cyclin dependant kinase inhibitors potentially useful for the treatment of solid tumors. Modification of the hinge-binding amine or the C(2)- and C(6)-substitutions on the pyrazolopyridazine core provided potent inhibitors of CDK4 and demonstrated enzyme selectivity against VEGFR-2 and GSK3beta.
Department of Oncology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. Kirk.L.Stevens@gsk.com
Kirk L
KL
Stevens
Michael J
MJ
Reno
Jennifer B
JB
Alberti
Daniel J
DJ
Price
Laurie S
LS
Kane-Carson
Victoria B
VB
Knick
Lisa M
LM
Shewchuk
Anne M
AM
Hassell
James M
JM
Veal
Stephen T
ST
Davis
Robert J
RJ
Griffin
Michael R
MR
Peel
D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D040301:Vascular Endothelial Growth Factor Receptor-2; D000071679:Glycogen Synthase Kinase 3 beta; D051358:Cyclin-Dependent Kinase 4; D038362:Glycogen Synthase Kinase 3