Discovery of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 14; pp. 4223 - 4227
• Main Authors: Cho, Sung Yun, Han, Sun-Young, Ha, Jae Du, Ryu, Jae Wook, Lee, Chong Ock, Jung, Heejung, Kang, Nam Sook, Kim, Hyoung Rae, Koh, Jong Sung, Lee, Jongkook
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.07.2010; Elsevier
• Subjects: Administration, Oral; Aminopyridine; Aminopyridines - administration & dosage; Aminopyridines - chemistry; Aminopyridines - pharmacokinetics; Aminopyridines - pharmacology; Animals; Antineoplastic agents; Benzoxazole; Benzoxazoles - chemistry; Biological and medical sciences; c-Met inhibitor; Drug Discovery; General aspects; hERG; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Rats; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Structure-Activity Relationship; hERG; Aminopyridine; Benzoxazole; c-Met inhibitor; Antineoplastic agent; Five membered ring; Intravenous administration; Rat; Nitrogen heterocycle; Toxicity; Ionic channel; Modeling; Pyridine derivatives; Signal transduction; Structure activity relation; Six membered ring; Piperidine derivatives; Molecular model; Bicyclic compound; Receptor protein-tyrosine kinase; Aromatic compound; Oxygen nitrogen heterocycle; Benzoxazole derivatives; Enzyme; Hepatocyte growth factor; Transferases; Rodentia; Oral administration; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; In vivo; Vertebrata; Growth factor receptor; Mammalia; Animal; Inhibitor; Circulatory system; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.05.031

A series of aminopyridines substituted with benzoxazole were designed and synthesized as very potent c-Met kinase inhibitors. We report the synthesis and biological evaluation of aminopyridines substituted with benzoxazole. The SAR of the aminopyridines was explored to improve the inhibitory activity against c-Met and to decrease hERG affinity. These studies led to the discovery of amide 24 which showed good c-Met inhibitory potency, low affinity to hERG and favorable pharmacokinetic properties in rats.