Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide c-Jun NH2-Terminal Kinase Inhibitors

C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the ther...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-07, Vol.49 (15), p.4455-4458
Main Authors: Zhao, Hongyu, Serby, Michael D, Xin, Zhili, Szczepankiewicz, Bruce G, Liu, Mei, Kosogof, Christi, Liu, Bo, Nelson, Lissa T. J, Johnson, Eric F, Wang, Sanyi, Pederson, Terry, Gum, Rebecca J, Clampit, Jill E, Haasch, Deanna L, Abad-Zapatero, Cele, Fry, Elizabeth H, Rondinone, Cristina, Trevillyan, James M, Sham, Hing L, Liu, Gang
Format: Article
Language:English
Subjects:
Administration, Oral
Amides - chemical synthesis
Amides - pharmacokinetics
Amides - pharmacology
Animals
Biological and medical sciences
Biological Availability
Crystallography, X-Ray
Humans
In Vitro Techniques
JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors
Medical sciences
Mice
Microsomes - metabolism
Miscellaneous
Models, Molecular
Pharmacology. Drug treatments
Pyridines - chemical synthesis
Pyridines - pharmacokinetics
Pyridines - pharmacology
Rats
Structure-Activity Relationship
Thermodynamics
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Summary:C-Jun NH2 terminal kinases (JNKs) are important cell signaling enzymes. JNK1 plays a central role in linking obesity and insulin resistance. JNK2 and JNK3 may be involved in inflammatory and neurological disorders, respectively. Small-molecule JNK inhibitors could be valuable tools to study the therapeutic benefits of inhibiting these enzymes and as leads for potential drugs targeting JNKs. In this report, we disclose a series of potent and highly selective JNK inhibitors with good pharmacokinetic profiles.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060465l