Design and synthesis of constrained analogs of LCRF-0004 as potent RON tyrosine kinase inhibitors

New bicyclic lactam head groups as rigidified analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent inhibitors of RON tyrosine kinase were obtained. [Display omitted] New fused bicyclic lactam head groups as rigidified analogs of thieno[3,2-b]pyridin...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-09, Vol.25 (17), p.3706-3710
Hauptverfasser:	Raeppel, Stéphane L., Therrien, Eric, Raeppel, Franck
Format:	Artikel
Sprache:	eng
Schlagworte:	Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Bicyclic head group c-Met Cell Line, Tumor - drug effects Chemistry Techniques, Synthetic Drug Design Drug Evaluation, Preclinical - methods Heterocyclic Compounds, 2-Ring - chemistry Homology model Humans Inhibitory Concentration 50 Lactams - chemistry Molecular docking Molecular Docking Simulation Molecular Targeted Therapy Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-met - antagonists & inhibitors Proto-Oncogene Proteins c-met - chemistry Pyrazoles - chemistry Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - chemistry Receptor Protein-Tyrosine Kinases - metabolism RON RTK inhibitors Stomach Neoplasms - drug therapy Stomach Neoplasms - pathology
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Zusammenfassung:	New bicyclic lactam head groups as rigidified analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Potent inhibitors of RON tyrosine kinase were obtained. [Display omitted] New fused bicyclic lactam head groups as rigidified analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Depending on the functionalities and the size of these bicyclic head groups, potent inhibitors of RON tyrosine kinase with various level of selectivity against c-Met tyrosine kinase were obtained.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2015.06.034