Synthesis and evaluation of novel 3,4,6-substituted 2-quinolones as FMS kinase inhibitors.
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.
Wall
Mark J
MJ
Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477, USA.
Chen
Jinsheng
J
Meegalla
Sanath
S
Ballentine
Shelley K
SK
Wilson
Kenneth J
KJ
DesJarlais
Renee L
RL
Schubert
Carsten
C
Chaikin
Margery A
MA
Crysler
Carl
C
Petrounia
Ioanna P
IP
Donatelli
Robert R
RR
Yurkow
Edward J
EJ
Boczon
Lisa
L
Mazzulla
Marie
M
Player
Mark R
MR
Patch
Raymond J
RJ
Manthey
Carl L
CL
Molloy
Christopher
C
Tomczuk
Bruce
B
Illig
Carl R
CR
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
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