Pyridyl aminothiazoles as potent Chk1 inhibitors: Optimization of cellular activity

The optimization of selectivity and physical properties of pyridyl aminothiazole series of Chk1 inhibitors aimed at improving cellular activity levels is described. Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-04, Vol.22 (7), p.2613-2619
Main Authors: Dudkin, Vadim Y., Wang, Cheng, Arrington, Kenneth L., Fraley, Mark E., Hartman, George D., Stirdivant, Steven M., Drakas, Robert A., Rickert, Keith, Walsh, Eileen S., Hamilton, Kelly, Buser, Carolyn A., Hardwick, James, Tao, Weikang, Beck, Stephen C., Mao, Xianzhi, Lobell, Robert B., Sepp-Lorenzino, Laura
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Biological and medical sciences
Carcinoembryonic antigen
Cell Cycle Checkpoints - drug effects
Cell Line, Tumor
Cell Membrane Permeability
Checkpoint Kinase 1
CHK1 protein
Cyclin-Dependent Kinases - antagonists & inhibitors
Cyclin-Dependent Kinases - chemistry
Drug Design
Halogenation
Humans
hydrophobicity
Kinetics
Medical sciences
Molecular Structure
Molecular weight
Pharmacology. Drug treatments
physical properties
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - pharmacology
Protein Kinases - chemistry
Protein Kinases - metabolism
Pyridines - chemical synthesis
Pyridines - pharmacology
Structure-Activity Relationship
Surface area
Thiazoles - chemical synthesis
Thiazoles - pharmacology
Translation
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Summary:The optimization of selectivity and physical properties of pyridyl aminothiazole series of Chk1 inhibitors aimed at improving cellular activity levels is described. Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.01.120