Identification of triazolopyridazinones as potent p38α inhibitors
| Autor: | Claire L. M. Jackson, Bradley Henkle, Matthew R. Lee, Brad Herberich, Andrew Tasker, Samer Chmait, Qiurong Liu, Christiaan J. M. Saris, Faye Hsieh, Liping H. Pettus, Christopher Mohr, Lisa Sherman, Ryan Wurz, Lu Min Wong |
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| Rok vydání: | 2012 |
| Předmět: |
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Molecular MAPK/ERK pathway p38 mitogen-activated protein kinases Clinical Biochemistry Pharmaceutical Science Crystallography X-Ray Biochemistry Mitogen-Activated Protein Kinase 14 Structure-Activity Relationship In vivo Drug Discovery Humans Structure–activity relationship Protein Kinase Inhibitors Molecular Biology Dose-Response Relationship Drug Molecular Structure biology Chemistry Kinase Organic Chemistry Stereoisomerism Triazoles In vitro Pyridazines Mitogen-activated protein kinase biology.protein Molecular Medicine Phosphorylation |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 22:1226-1229 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2011.11.067 |
| Popis: | Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles. |
| Databáze: | OpenAIRE |
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