A novel series of IKKβ inhibitors part II: description of a potent and pharmacologically active series of analogs

Bioorg Med Chem Lett. 2011 Jan 1;21(1):423-6. doi: 10.1016/j.bmcl.2010.10.125. Epub 2010 Oct 29.

Abstract

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.

MeSH terms

  • Animals
  • Dogs
  • Female
  • Hepatocytes / metabolism
  • High-Throughput Screening Assays
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Macaca mulatta
  • Male
  • Mice
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Quinolines / chemical synthesis
  • Quinolines / chemistry*
  • Quinolines / pharmacokinetics
  • Rats
  • Semicarbazides / chemical synthesis
  • Semicarbazides / chemistry*
  • Semicarbazides / pharmacokinetics
  • Structure-Activity Relationship
  • Thiourea / analogs & derivatives*
  • Thiourea / chemical synthesis
  • Thiourea / chemistry
  • Thiourea / pharmacokinetics

Substances

  • Protein Kinase Inhibitors
  • Quinolines
  • Semicarbazides
  • thiosemicarbazide
  • quinoline
  • I-kappa B Kinase
  • Thiourea