Conformation constraint of anilides enabling the discovery of tricyclic lactams as potent MK2 non-ATP competitive inhibitors

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3262-6. doi: 10.1016/j.bmcl.2013.03.109. Epub 2013 Apr 4.

Abstract

Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Anilides / chemical synthesis
  • Anilides / chemistry*
  • Anilides / metabolism
  • Binding, Competitive
  • Drug Evaluation, Preclinical
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lactams / chemical synthesis
  • Lactams / chemistry*
  • Lactams / metabolism
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anilides
  • Intracellular Signaling Peptides and Proteins
  • Lactams
  • Protein Kinase Inhibitors
  • Adenosine Triphosphate
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases