The Pyrazolobenzothiazine Core as a New Chemotype of p38 Alpha Mitogen-Activated Protein Kinase Inhibitors

Chem Biol Drug Des. 2015 Oct;86(4):531-45. doi: 10.1111/cbdd.12516. Epub 2015 Feb 19.

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.

Keywords: anti-TNF agents; ligand efficiency; molecular docking; p38α MAPK inhibitors; pyrazolobenzothiazines.

MeSH terms

  • Anti-Inflammatory Agents* / chemical synthesis
  • Anti-Inflammatory Agents* / chemistry
  • Anti-Inflammatory Agents* / pharmacology
  • Benzothiadiazines* / chemical synthesis
  • Benzothiadiazines* / chemistry
  • Benzothiadiazines* / pharmacology
  • Cells, Cultured
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Inflammatory Agents
  • Benzothiadiazines
  • Protein Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases