Synthesis and biological activity of quinolinone and dihydroquinolinone p38 MAP kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2008-03, Vol.18 (6), p.2222-2226
• Main Authors: Chen, Meng-Hsin, Fitzgerald, Patricia, Singh, Suresh B., O’Neill, Edward A., Schwartz, Cheryl D., Thompson, Chris M., O’Keefe, Stephen J., Zaller, Dennis M., Doherty, James B.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Crystallography, X-Ray; Cyclization; Humans; MAP Kinase inhibitors; Medical sciences; Molecular Structure; p38; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Pyridazines - chemistry; Pyrimidines - chemistry; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.10.097

The synthesis and biological activities of some quinolinone and dihydroquinolinone p38 MAP kinase inhibitors are reported. Modifications to the dihydroquinolinone pharmacophore revealed that dihydroquinolinone may be replaced with a quinolinone pharmacophore and this modification led to enhanced p38α inhibitory activity. From a study of C-7 substituents with amino acid side chains, a very potent series of compounds in the p38α enzyme assays was identified. Translation of the in vitro activity into reasonable whole blood activity was improved in this latter series of compounds by judicious modification of the physical properties in appropriate regions of the lead. Synthesis and biological activities of some quinolinone and dihydroquinolinone p38 MAP kinase inhibitors are reported. Modifications to the dihydroquinolinone pharmacophore revealed that dihydroquinolinone may be replaced with a quinolinone pharmacophore and lead to enhanced p38 inhibitory activity. From a study of C-7 substitutions by amino acid side chains, a very potent series of compounds in the p38 enzyme assays was identified. Translation of the in vitro activity into reasonable whole blood activity can be improved in this series of compounds by judicious modification of the physical properties at appropriate regions of the lead.