Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458).
Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition of c-Met over VEGFR2. However, studies revealed the generation of active, nonselective metabolites. Blocking this metabolic hot spot led to the discovery of 17 (AMG 458). When dosed orally, 17 significantly inhibited tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight.
Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. lliu@amgen.com
Longbin
L
Liu
Aaron
A
Siegmund
Ning
N
Xi
Paula
P
Kaplan-Lefko
Karen
K
Rex
April
A
Chen
Jasmine
J
Lin
Jodi
J
Moriguchi
Loren
L
Berry
Liyue
L
Huang
Yohannes
Y
Teffera
Yajing
Y
Yang
Yihong
Y
Zhang
Steven F
SF
Bellon
Matthew
M
Lee
Roman
R
Shimanovich
Annette
A
Bak
Celia
C
Dominguez
Mark H
MH
Norman
Jean-Christophe
JC
Harmange
Isabelle
I
Dussault
Tae-Seong
TS
Kim
D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
C530596:1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; D000631:Aminopyridines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D019859:Proto-Oncogene Proteins c-met