Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1

Bioorg Med Chem Lett. 2013 Aug 15;23(16):4517-22. doi: 10.1016/j.bmcl.2013.06.053. Epub 2013 Jun 25.

Abstract

The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ~10nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization.

Keywords: 7-Amino-furo[2,3-c]pyridine; Cancer; Inflammation; Inhibitors; TAK1.

MeSH terms

  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology
  • Animals
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Furans / chemical synthesis
  • Furans / chemistry
  • Furans / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Mice
  • Molecular Structure
  • Neoplasms / drug therapy
  • Pyridines* / chemical synthesis
  • Pyridines* / pharmacokinetics
  • Pyridines* / pharmacology
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Amines
  • Enzyme Inhibitors
  • Furans
  • Pyridines
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7