title: Synthesis and evaluation of novel 3,4,6-substituted 2-quinolones as FMS kinase inhibitors.
abstract: A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Wall
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Chen
authors.forename: Sanath
authors.initials: S
authors.lastname: Meegalla
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Ballentine
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Wilson
authors.forename: Renee L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Margery A
authors.initials: MA
authors.lastname: Chaikin
authors.forename: Carl
authors.initials: C
authors.lastname: Crysler
authors.forename: Ioanna P
authors.initials: IP
authors.lastname: Petrounia
authors.forename: Robert R
authors.initials: RR
authors.lastname: Donatelli
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Yurkow
authors.forename: Lisa
authors.initials: L
authors.lastname: Boczon
authors.forename: Marie
authors.initials: M
authors.lastname: Mazzulla
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Patch
authors.forename: Carl L
authors.initials: CL
authors.lastname: Manthey
authors.forename: Christopher
authors.initials: C
authors.lastname: Molloy
authors.forename: Bruce
authors.initials: B
authors.lastname: Tomczuk
authors.forename: Carl R
authors.initials: CR
authors.lastname: Illig
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D049109:Cell Proliferation / Q000187:drug effects; D005454:Fluorescence Polarization; D016762:Genes, fos / Q000235:genetics; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C529338:4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor