Amide-based inhibitors of p38alpha MAP kinase. Part 1: discovery of novel N-pyridyl amide lead molecules

Gregory R Luedtke; Kurt Schinzel; Xuefei Tan; Richland W Tester; Imad Nashashibi; Yong-Jin Xu; Sundeep Dugar; Daniel E Levy; Joon Jung

doi:10.1016/j.bmcl.2010.02.088

Amide-based inhibitors of p38alpha MAP kinase. Part 1: discovery of novel N-pyridyl amide lead molecules

Bioorg Med Chem Lett. 2010 Apr 15;20(8):2556-9. doi: 10.1016/j.bmcl.2010.02.088. Epub 2010 Mar 10.

Authors

Gregory R Luedtke¹, Kurt Schinzel, Xuefei Tan, Richland W Tester, Imad Nashashibi, Yong-Jin Xu, Sundeep Dugar, Daniel E Levy, Joon Jung

Affiliation

¹ Department of Medicinal Chemistry, Scios Inc., Fremont, CA 94555, USA.

PMID: 20346653
DOI: 10.1016/j.bmcl.2010.02.088

Abstract

A novel series of N-pyridyl amides as potent p38alpha kinase inhibitors is described. Based on the structural similarities between the initial hit and a well-known imidazole pyrimidine series of p38alpha inhibitors, potencies within the newly discovered series were quickly improved by installation of an (S)-alpha-methylbenzyl moiety at the 2-position of the pyridine ring. The proposed binding modes of the new series to p38alpha were evaluated against SAR findings and provided rationale for further development of this series of molecules.

MeSH terms

Amides / chemistry
Amides / pharmacology*
Drug Discovery
Models, Molecular
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / pharmacology*
Structure-Activity Relationship
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

Amides
Protein Kinase Inhibitors
Pyrimidines
p38 Mitogen-Activated Protein Kinases