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

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 17; pp. 3706 - 3710
• Main Authors: Raeppel, Stéphane L., Therrien, Eric, Raeppel, Franck
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2015; Elsevier
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bicyclic head group; c-Met; Cell Line, Tumor - drug effects; Chemistry; Chemistry Techniques, Synthetic; Chemistry, Medicinal; Chemistry, Organic; Drug Design; Drug Evaluation, Preclinical - methods; Heterocyclic Compounds, 2-Ring - chemistry; Homology model; Humans; Inhibitory Concentration 50; Lactams - chemistry; Life Sciences & Biomedicine; Molecular docking; Molecular Docking Simulation; Molecular Targeted Therapy; Pharmacology & Pharmacy; Physical Sciences; 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; Science & Technology; Stomach Neoplasms - drug therapy; Stomach Neoplasms - pathology; RON; Homology model; c-Met; RTK inhibitors; Bicyclic head group; Molecular docking; RECEPTOR; DOCKING LIGANDS; CANCER PATHOGENESIS; PATHWAY; THERAPEUTIC TARGET; ARYL HALIDES; EXPRESSION
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.06.034

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.