Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series.
As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound 59e (AMG 458) was ultimately advanced into preclinical safety studies.
Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. lliu@amgen.com
Longbin
L
Liu
Mark H
MH
Norman
Matthew
M
Lee
Ning
N
Xi
Aaron
A
Siegmund
Alessandro A
AA
Boezio
Shon
S
Booker
Debbie
D
Choquette
Noel D
ND
D'Angelo
Julie
J
Germain
Kevin
K
Yang
Yajing
Y
Yang
Yihong
Y
Zhang
Steven F
SF
Bellon
Douglas A
DA
Whittington
Jean-Christophe
JC
Harmange
Celia
C
Dominguez
Tae-Seong
TS
Kim
Isabelle
I
Dussault
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D005755:Gastrins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation; D011487:Protein Conformation; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047069:Pyrazolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
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; D000970:Antineoplastic Agents; D005755:Gastrins; D011720:Pyrazoles; D047069:Pyrazolones; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2