Identification of a novel series of potent RON receptor tyrosine kinase inhibitors.
A novel series of N-(3-fluoro-4-(2-substituted-thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamides targeting RON receptor tyrosine kinase was designed and synthesized. SAR study of the series allowed us to identify compounds possessing either inhibitory activity of RON kinase enzyme in the low nanomolar range with low residual activity against the closely related c-Met or potent dual inhibitory activity against RON and c-Met, with no significant activity against VEGFR2 in both cases.
Raeppel
Stéphane
S
Department of Medicinal Chemistry, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1. raeppels@methylgene.com
Gaudette
Frédéric
F
Mannion
Michael
M
Claridge
Stephen
S
Saavedra
Oscar
O
Isakovic
Ljubomir
L
Déziel
Robert
R
Beaulieu
Normand
N
Beaulieu
Carole
C
Dupont
Isabelle
I
Nguyen
Hannah
H
Wang
James
J
Macleod
A Robert
AR
Maroun
Christiane
C
Besterman
Jeffrey M
JM
Vaisburg
Arkadii
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D006574:Heterocyclic Compounds, 2-Ring; C000605132:LCRF-0004; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases