Imidazo[4,5-d]thiazolo[5,4-b]pyridine based inhibitors of IKK2: synthesis, SAR, PK/PD and activity in a preclinical model of rheumatoid arthritis

Bioorg Med Chem Lett. 2011 Jan 1;21(1):383-6. doi: 10.1016/j.bmcl.2010.10.133. Epub 2010 Oct 31.

Abstract

The synthesis, structure-activity relationships (SAR) and biological evaluation of thiazole based tricyclic inhibitors of IKK2 are described. Compound 9 was determined to be orally efficacious in a murine model of rheumatoid arthritis.

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / drug therapy*
  • Disease Models, Animal
  • Dogs
  • Drug Evaluation, Preclinical
  • Female
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Imidazoles / chemistry*
  • Mice
  • Mice, Inbred BALB C
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use
  • Rats
  • Structure-Activity Relationship
  • Thiazoles / chemistry*

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridines
  • Thiazoles
  • imidazole
  • I-kappa B Kinase