Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors

Bioorg Med Chem Lett. 2004 Jun 7;14(11):2817-22. doi: 10.1016/j.bmcl.2004.03.058.

Abstract

A hit-to-lead optimisation programme was carried out on the thiophenecarboxamide high throughput screening hits 1 and 2 resulting in the discovery of the potent and orally bioavailable IKK-2 inhibitor 22.

MeSH terms

  • Administration, Oral
  • Amides / chemical synthesis
  • Amides / pharmacology*
  • Animals
  • Binding Sites
  • Cell Line
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Humans
  • I-kappa B Kinase
  • Inhibitory Concentration 50
  • Ligands
  • Models, Molecular
  • Protein Array Analysis
  • Protein Binding
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Rats
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / pharmacology

Substances

  • Amides
  • Enzyme Inhibitors
  • Ligands
  • Thiophenes
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human