Disubstituted pyrimidines as Lck inhibitors

Compound 4 was found to be a potent inhibitor of Lck activity (IC 50 = 0.1 nM) and cellular IL2 release (IC 50 = 8 nM). We have developed a family of 4-benzimidazolyl- N-piperazinethyl-pyrimidin-2-amines that are subnanomolar inhibitors of Lck. A subset of these Lck inhibitors, with heterocyclic sub...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-09, Vol.19 (18), p.5440-5443
Main Authors: Hunt, Julianne A., Beresis, Richard T., Goulet, Joung L., Holmes, Mark A., Hong, Xinfang J., Kovacs, Ernest, Mills, Sander G., Ruzek, Rowena D., Wong, Frederick, Hermes, Jeffrey D., Park, Young-Whan, Salowe, Scott P., Sonatore, Lisa M., Wu, Lin, Woods, Andrea, Zaller, Dennis M., Sinclair, Peter J.
Format: Article
Language:English
Subjects:
Autoimmune disease
Biological and medical sciences
Immunomodulators
Inhibitory Concentration 50
Interleukin-2 - antagonists & inhibitors
Interleukin-2 - metabolism
Lck
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - antagonists & inhibitors
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism
Medical sciences
Molecular Structure
Pharmacology. Drug treatments
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein tyrosine kinase
Pyrimidine
Pyrimidines - chemistry
Pyrimidines - pharmacology
Rheumatoid arthritis
Src
Structure-Activity Relationship
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Summary:Compound 4 was found to be a potent inhibitor of Lck activity (IC 50 = 0.1 nM) and cellular IL2 release (IC 50 = 8 nM). We have developed a family of 4-benzimidazolyl- N-piperazinethyl-pyrimidin-2-amines that are subnanomolar inhibitors of Lck. A subset of these Lck inhibitors, with heterocyclic substituents at the benzimidazole C5, are also low-nanomolar inhibitors of cellular IL2 release.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.07.102