201. The Pyrazolobenzothiazine Core as a New Chemotype of p38 Alpha Mitogen-Activated Protein Kinase Inhibitors
- Author
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Silke M. Bauer, Violetta Cecchetti, Rolando Cannalire, Francesca Fallarino, Andrea Astolfi, Giuseppe Manfroni, Stefano Sabatini, José Brea, Matteo Pirro, Stefan Laufer, Marco Gargaro, Oriana Tabarrini, María Isabel Loza, Serena Massari, Maria Letizia Barreca, Carmine Vacca, Sabatini, Stefano, Manfroni, Giuseppe, Barreca Maria, Letizia, Bauer Silke, M, Gargaro, Marco, Cannalire, Rolando, Astolfi, Andrea, Brea, Jose, Vacca, Carmine, Pirro, Matteo, Massari, Serena, Tabarrini, Oriana, Loza Maria, Isabel, Fallarino, Francesca, Laufer Stefan, A, and Cecchetti, Violetta
- Subjects
pyrazolobenzothiazines ,MAP Kinase Signaling System ,Stereochemistry ,p38 mitogen-activated protein kinases ,Anti-Inflammatory Agents ,Alpha (ethology) ,anti-TNF agent ,Benzothiadiazines ,p38 Mitogen-Activated Protein Kinases ,Biochemistry ,Drug Discovery ,Humans ,Protein Kinase Inhibitors ,IC50 ,Cells, Cultured ,Pharmacology ,Ligand efficiency ,biology ,Chemotype ,ligand efficiency ,Tumor Necrosis Factor-alpha ,Kinase ,Organic Chemistry ,p38α MAPK inhibitors ,Biological activity ,anti-TNF agents ,molecular docking ,Mitogen-activated protein kinase ,biology.protein ,Molecular Medicine ,p38α MAPK inhibitor - Abstract
The identification, synthesis, biological activity, and binding mode prediction of a series of pyrazolobenzothiazines as novel p38α MAPK inhibitors are reported. Some of these compounds showed interesting activity in both p38α MAPK and TNF-α release assays. Derivative 6 emerged as the most interesting compound with IC50 (p38α) = 0.457 μm, IC50 (TNF-α) = 0.5 μm and a promising kinase selectivity profile. The obtained results strongly indicate the pyrazolobenzothiazine core as a new p38α inhibitor chemotype worthy of future chemical optimization efforts directed toward identifying a new generation of anti-inflammatory agents.
- Published
- 2015