Design and Synthesis of 5-Aryl-pyridone-carboxamides as Inhibitors of Anaplastic Lymphoma Kinase

Anaplastic lymphoma kinase (ALK) is a promising new target for therapy of certain cancers such as anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT). We have identified a series of novel pyridones as kinase inhibitors of ALK by application of a stepwise process involv...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-02, Vol.49 (3), p.1006-1015
Main Authors: Li, Rongshi, Xue, Liquan, Zhu, Tong, Jiang, Qin, Cui, Xiaoli, Yan, Zheng, McGee, Danny, Wang, Jian, Gantla, Vidyasagar Reddy, Pickens, Jason C, McGrath, Doug, Chucholowski, Alexander, Morris, Stephan W, Webb, Thomas R
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Cell Survival - drug effects
Combinatorial Chemistry Techniques
Databases, Factual
Drug Design
Humans
Medical sciences
Mice
Miscellaneous
Models, Molecular
Pharmacology. Drug treatments
Protein-Tyrosine Kinases - antagonists & inhibitors
Pyridones - chemical synthesis
Pyridones - chemistry
Pyridones - pharmacology
Receptor Protein-Tyrosine Kinases
Structure-Activity Relationship
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Summary:Anaplastic lymphoma kinase (ALK) is a promising new target for therapy of certain cancers such as anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT). We have identified a series of novel pyridones as kinase inhibitors of ALK by application of a stepwise process involving in vitro screening of a novel targeted library followed by iterative template modification based on medicinal chemistry insights and computational ranking of virtual libraries. Using this process, we discovered ALK-selective inhibitors with improved potency and selectivity. Herein the details of the design process and synthesis of these novel pyridones, along with their enzymatic and cell-based activity, are discussed.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm050824x