title: Identification of a novel series of potent RON receptor tyrosine kinase inhibitors.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, MethylGene Inc., 7220 rue Frederick-Banting, Montréal, QC, Canada H4S 2A1. raeppels@methylgene.com
authors.forename: Stéphane
authors.initials: S
authors.lastname: Raeppel
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gaudette
authors.forename: Michael
authors.initials: M
authors.lastname: Mannion
authors.forename: Stephen
authors.initials: S
authors.lastname: Claridge
authors.forename: Oscar
authors.initials: O
authors.lastname: Saavedra
authors.forename: Ljubomir
authors.initials: L
authors.lastname: Isakovic
authors.forename: Robert
authors.initials: R
authors.lastname: Déziel
authors.forename: Normand
authors.initials: N
authors.lastname: Beaulieu
authors.forename: Carole
authors.initials: C
authors.lastname: Beaulieu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dupont
authors.forename: Hannah
authors.initials: H
authors.lastname: Nguyen
authors.forename: James
authors.initials: J
authors.lastname: Wang
authors.forename: A Robert
authors.initials: AR
authors.lastname: Macleod
authors.forename: Christiane
authors.initials: C
authors.lastname: Maroun
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
authors.forename: Arkadii
authors.initials: A
authors.lastname: Vaisburg
mesh_terms: 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
chemical_list: 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