Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase
| Autor: | Samer Chmait, Lu Min Wong, Faye Hsieh, Liping H. Pettus, Ryan Wurz, Andrew Tasker, Lisa Sherman, Matthew R. Lee, Kent Miner, Helen J. McBride, Matthew H. Plant, Shimin Xu, Christiaan J. M. Saris, Christopher Mohr, Bradley Henkle |
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| Rok vydání: | 2009 |
| Předmět: |
MAPK/ERK pathway
Lipopolysaccharides Male Pyridones p38 mitogen-activated protein kinases Clinical Biochemistry Anti-Inflammatory Agents Pharmaceutical Science Administration Oral Crystallography X-Ray Biochemistry Cell Line Mitogen-Activated Protein Kinase 14 Rats Sprague-Dawley Structure-Activity Relationship Drug Discovery Structure–activity relationship Animals Humans Computer Simulation Protein kinase A Molecular Biology Protein Kinase Inhibitors MAPK14 Binding Sites biology Chemistry Kinase Tumor Necrosis Factor-alpha Organic Chemistry Interleukin-8 Rats Enzyme inhibitor Mitogen-activated protein kinase biology.protein Molecular Medicine Pyrazoles |
| Zdroj: | Bioorganicmedicinal chemistry letters. 19(16) |
| ISSN: | 1464-3405 |
| Popis: | A novel class of pyrazolopyridazine p38α mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38α enzyme, the secretion of TNFα in a LPS-challenged THP1 cell line and TNFα-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38α inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38α/β over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFα production in LPS-stimulated Lewis rats with an ED50 of ca. 0.08 mg/kg. |
| Databáze: | OpenAIRE |
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