Potent 2'-aminoanilide inhibitors of cFMS as potential anti-inflammatory agents.
A series of 2'-aminoanilides have been identified which exhibit potent and selective inhibitory activity against the cFMS tyrosine kinase. Initial SAR studies within this series are described which examine aroyl and amino group substitutions, as well as the introduction of hydrophilic substituents on the benzene core. Compound 47 inhibits the isolated enzyme (IC(50)=0.027 microM) and blocks CSF-1-induced proliferation of bone marrow-derived macrophages (IC(50)=0.11 microM) and as such, serves as a lead candidate for further optimization studies.
Patch
Raymond J
RJ
Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 8 Clarke Drive, Cranbury, NJ 08512, USA.
Brandt
Benjamin M
BM
Asgari
Davoud
D
Baindur
Nand
N
Chadha
Naresh K
NK
Georgiadis
Taxiarchis
T
Cheung
Wing S
WS
Petrounia
Ioanna P
IP
Donatelli
Robert R
RR
Chaikin
Margery A
MA
Player
Mark R
MR
D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000187:drug effects; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000813:Anilides; D000893:Anti-Inflammatory Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor