A novel series of IKKβ inhibitors part I: Initial SAR studies of a HTS hit

Bioorg Med Chem Lett. 2011 Jan 1;21(1):417-22. doi: 10.1016/j.bmcl.2010.10.126. 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 early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.

MeSH terms

  • Animals
  • Dogs
  • Female
  • High-Throughput Screening Assays
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Male
  • Microsomes / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Quinolines / chemistry
  • Rats
  • Semicarbazides / chemical synthesis
  • Semicarbazides / chemistry*
  • Semicarbazides / pharmacokinetics
  • Structure-Activity Relationship

Substances

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