Design and synthesis of a pyrido[2,3-d]pyrimidin-5-one class of anti-inflammatory FMS inhibitors.
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%.
Huang
Hui
H
Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477, USA.
Hutta
Daniel A
DA
Hu
Huaping
H
DesJarlais
Renee L
RL
Schubert
Carsten
C
Petrounia
Ioanna P
IP
Chaikin
Margery A
MA
Manthey
Carl L
CL
Player
Mark R
MR
D000577:Amides / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008956:Models, Chemical; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry; D011728:Pyridones / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*
D000577:Amides; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011728:Pyridones; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D040281:Vascular Endothelial Growth Factor Receptor-1