Design and synthesis of piperazine-indole p38α MAP kinase inhibitors with improved pharmacokinetic profiles

SAR studies of the p38α MAP kinase inhibitor SCIO-469 focused on maintaining activity while improving pharmacokinetic properties. Advantages were noted for compounds bearing substituents on the benzylic methylene carbon. Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38α MAP k...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (3), p.828-831
Hauptverfasser:	Tan, Xuefei, Tester, Richland W., Luedtke, Gregory R., Chakravarty, Sarvajit, Mavunkel, Babu J., Perumattam, John J., Lu, Qing, Nashashibi, Imad, Jung, Joon, Hu, Jie, Liclican, Albert, Almirez, Ramona, Tabora, Jocelyn, Tran, Vinh, Laney, Maureen, Levy, Daniel E., Dugar, Sundeep
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Dogs Drug Design Haplorhini Humans Indoles - chemical synthesis Indoles - pharmacokinetics Inflammatory Inhibitor Kinase Mitogen-Activated Protein Kinase 14 - antagonists & inhibitors Mitogen-Activated Protein Kinase 14 - metabolism p38 Piperazines - chemical synthesis Piperazines - pharmacokinetics Protein Binding - drug effects Protein Binding - physiology Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacokinetics Protein Structure, Secondary Rats
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Zusammenfassung:	SAR studies of the p38α MAP kinase inhibitor SCIO-469 focused on maintaining activity while improving pharmacokinetic properties. Advantages were noted for compounds bearing substituents on the benzylic methylene carbon. Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38α MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.12.091