title: Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors.
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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477-0776, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hutta
authors.forename: James M
authors.initials: JM
authors.lastname: Rinker
authors.forename: Huaping
authors.initials: H
authors.lastname: Hu
authors.forename: William H
authors.initials: WH
authors.lastname: Parsons
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Renee L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: Carl S
authors.initials: CS
authors.lastname: Crysler
authors.forename: Margery A
authors.initials: MA
authors.lastname: Chaikin
authors.forename: Robert R
authors.initials: RR
authors.lastname: Donatelli
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Chen
authors.forename: Deping
authors.initials: D
authors.lastname: Cheng
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhou
authors.forename: Edward
authors.initials: E
authors.lastname: Yurkow
authors.forename: Carl L
authors.initials: CL
authors.lastname: Manthey
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
mesh_terms: 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
chemical_list: D000893:Anti-Inflammatory Agents; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D016186:Receptor, Macrophage Colony-Stimulating Factor