Synthesis and SAR of 4-substituted-2-aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors

Paul S Humphries; Jennifer A Lafontaine; Charles S Agree; David Alexander; Ping Chen; Quyen-Quyen T Do; Lilian Y Li; Elizabeth A Lunney; Ranjan J Rajapakse; Karen Siegel; Sergei L Timofeevski; Tianlun Wang; David M Wilhite

doi:10.1016/j.bmcl.2009.03.023

Synthesis and SAR of 4-substituted-2-aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors

Bioorg Med Chem Lett. 2009 Apr 15;19(8):2099-102. doi: 10.1016/j.bmcl.2009.03.023. Epub 2009 Mar 13.

Authors

Paul S Humphries¹, Jennifer A Lafontaine, Charles S Agree, David Alexander, Ping Chen, Quyen-Quyen T Do, Lilian Y Li, Elizabeth A Lunney, Ranjan J Rajapakse, Karen Siegel, Sergei L Timofeevski, Tianlun Wang, David M Wilhite

Affiliation

¹ Pfizer Global R&D, San Diego, CA 92121, USA. phumphri@gmail.com

PMID: 19327989
DOI: 10.1016/j.bmcl.2009.03.023

Abstract

The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported.

Publication types

Comparative Study

MeSH terms

Humans
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
JNK Mitogen-Activated Protein Kinases / metabolism
Microsomes, Liver / drug effects
Microsomes, Liver / enzymology
Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 8 / metabolism
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis*
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrimidines
2-aminopyrimidine
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 8