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)-1 H-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 act...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-05, Vol.20 (9), p.2745-2749
Hauptverfasser:	Raeppel, Stéphane, Gaudette, Frédéric, Mannion, Michael, Claridge, Stephen, Saavedra, Oscar, Isakovic, Ljubomir, Déziel, Robert, Beaulieu, Normand, Beaulieu, Carole, Dupont, Isabelle, Nguyen, Hannah, Wang, James, Macleod, A. Robert, Maroun, Christiane, Besterman, Jeffrey M., Vaisburg, Arkadii
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Biological and medical sciences c-Met Cell Line, Tumor General aspects Heterocyclic Compounds, 2-Ring - chemical synthesis Heterocyclic Compounds, 2-Ring - chemistry Heterocyclic Compounds, 2-Ring - pharmacokinetics Humans Medical sciences Oncology Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Proto-Oncogene Proteins c-met - antagonists & inhibitors Proto-Oncogene Proteins c-met - metabolism Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacokinetics Rats Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - metabolism RON RTK inhibitors Structure-Activity Relationship Thieno[3,2- b]pyridine
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Zusammenfassung:	A novel series of N-(3-fluoro-4-(2-substituted-thieno[3,2- b]pyridin-7-yloxy)phenyl)-1-phenyl-5-(trifluoromethyl)-1 H-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. A novel series of N-(3-fluoro-4-(2-substituted-thieno[3,2- b]pyridin-7-yloxy)phenyl)-1-phenyl-5-(trifluoromethyl)-1 H-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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.03.073