Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): Kinase profiling guided optimization of a 1,2,3-benzotriazole lead

Structure and kinase profiling guided the optimization of a CDK2 1,2,3-benzotriazole hit to give a series of indoles that are selective and potent dual JNK1 and 2 inhibitors. An advanced compound, 24f (IC50 JNK1/2=16/66nM), was developed and suitable for in vivo pharmacological evaluation of JNK inh...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-03, Vol.23 (5), p.1486-1492
Main Authors: Palmer, Wylie S., Alam, Muzaffar, Arzeno, Humberto B., Chang, Kung-Ching, Dunn, James P., Goldstein, David M., Gong, Leyi, Goyal, Bindu, Hermann, Johannes C., Hogg, J. Heather, Hsieh, Gary, Jahangir, Alam, Janson, Cheryl, Jin, Sue, Ursula Kammlott, R., Kuglstatter, Andreas, Lukacs, Christine, Michoud, Christophe, Niu, Linghao, Reuter, Deborah C., Shao, Ada, Silva, Tania, Trejo-Martin, Teresa A., Stein, Karin, Tan, Yun-Chou, Tivitmahaisoon, Parcharee, Tran, Patricia, Wagner, Paul, Weller, Paul, Wu, Shao-Yong
Format: Article
Language:English
Subjects:
Animals
bioavailability
c-Jun N-terminal kinase (JNK)
CDK
chemistry
Crystallography, X-Ray
cyclin-dependent kinase
Drug Design
drugs
Humans
JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases - metabolism
Kinase inhibitor
Kinase selectivity
mitogen-activated protein kinase
Models, Molecular
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Rats
Structure-Activity Relationship
Triazoles - chemical synthesis
Triazoles - chemistry
Triazoles - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Structure and kinase profiling guided the optimization of a CDK2 1,2,3-benzotriazole hit to give a series of indoles that are selective and potent dual JNK1 and 2 inhibitors. An advanced compound, 24f (IC50 JNK1/2=16/66nM), was developed and suitable for in vivo pharmacological evaluation of JNK inhibition. A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC50=16 and 66nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.12.047