Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors.
A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.
Huang
Hui
H
Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477-0776, USA.
Hutta
Daniel A
DA
Rinker
James M
JM
Hu
Huaping
H
Parsons
William H
WH
Schubert
Carsten
C
DesJarlais
Renee L
RL
Crysler
Carl S
CS
Chaikin
Margery A
MA
Donatelli
Robert R
RR
Chen
Yanmin
Y
Cheng
Deping
D
Zhou
Zhao
Z
Yurkow
Edward
E
Manthey
Carl L
CL
Player
Mark R
MR
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001862:Bone Resorption / Q000517:prevention & control; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy; D010010:Osteoclasts / Q000187:drug effects; D010599:Pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D016186:Receptor, Macrophage Colony-Stimulating Factor