Design and synthesis of a novel, orally active, brain penetrant, tri-substituted thiophene based JNK inhibitor

Bioorg Med Chem Lett. 2011 Mar 15;21(6):1838-43. doi: 10.1016/j.bmcl.2011.01.046. Epub 2011 Jan 20.

Abstract

The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction.

MeSH terms

  • Administration, Oral
  • Brain / metabolism*
  • Drug Design
  • Hydrogen Bonding
  • MAP Kinase Kinase 4 / antagonists & inhibitors*
  • Models, Molecular
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • MAP Kinase Kinase 4