Design and synthesis of a pyrido[2,3-d]pyrimidin-5-one class of anti-inflammatory FMS inhibitors

Hui Huang; Daniel A Hutta; Huaping Hu; Renee L DesJarlais; Carsten Schubert; Ioanna P Petrounia; Margery A Chaikin; Carl L Manthey; Mark R Player

doi:10.1016/j.bmcl.2008.02.070

Design and synthesis of a pyrido[2,3-d]pyrimidin-5-one class of anti-inflammatory FMS inhibitors

Bioorg Med Chem Lett. 2008 Apr 1;18(7):2355-61. doi: 10.1016/j.bmcl.2008.02.070. Epub 2008 Mar 4.

Authors

Hui Huang¹, Daniel A Hutta, Huaping Hu, Renee L DesJarlais, Carsten Schubert, Ioanna P Petrounia, Margery A Chaikin, Carl L Manthey, Mark R Player

Affiliation

¹ Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477, USA.

PMID: 18342505
DOI: 10.1016/j.bmcl.2008.02.070

Abstract

A series of pyrimidinopyridones has been designed, synthesized and shown to be potent and selective inhibitors of the FMS tyrosine kinase. Introduction of an amide substituent at the 6-position of the pyridone core resulted in a significant potency increase. Compound 24 effectively inhibited in vivo LPS-induced TNF in mice greater than 80%.

MeSH terms

Amides / chemistry
Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Drug Design*
Lipopolysaccharides / toxicity
Mice
Models, Chemical
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemistry
Pyridones / chemical synthesis
Pyridones / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha / metabolism
Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors*

Substances

Amides
Anti-Inflammatory Agents
Antineoplastic Agents
Lipopolysaccharides
Protein Kinase Inhibitors
Pyridines
Pyridones
Pyrimidines
Tumor Necrosis Factor-alpha
Vascular Endothelial Growth Factor Receptor-1