Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors.

Abstract

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.

• Authors: Kirk L Stevens, Michael J Reno, Jennifer B Alberti, Daniel J Price, Laurie S Kane-Carson, Victoria B Knick, Lisa M Shewchuk, Anne M Hassell, James M Veal, Stephen T Davis, Robert J Griffin, Michael R Peel
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 21 Pg. 5758-62 (Nov 01 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18835709 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Pyridazines
• Vascular Endothelial Growth Factor Receptor-2
• Glycogen Synthase Kinase 3 beta
• Cyclin-Dependent Kinase 4
• Glycogen Synthase Kinase 3

Topics

• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Drug Evaluation, Preclinical
• Drug Screening Assays, Antitumor
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta
• Models, Molecular
• Protein Kinase Inhibitors (chemical synthesis, pharmacology)
• Pyridazines (chemical synthesis, pharmacology)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)