Pyrido[2,3-d]pyrimidin-5-ones: A Novel Class of Antiinflammatory Macrophage Colony-Stimulating factor-1 Receptor Inhibitors

J Med Chem. 2009 Feb 26;52(4):1081-99. doi: 10.1021/jm801406h.

Abstract

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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Arthritis, Rheumatoid / drug therapy*
  • Bone Resorption / prevention & control
  • Disease Models, Animal
  • Inflammation / drug therapy
  • Osteoclasts / drug effects
  • Pharmacokinetics
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacology
  • Pyrimidinones / therapeutic use
  • Rats
  • Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Protein Kinase Inhibitors
  • Pyrimidinones
  • Receptor, Macrophage Colony-Stimulating Factor