Design, synthesis and optimization of novel Alk5 (activin-like kinase 5) inhibitors

Bioorg Med Chem Lett. 2016 Sep 1;26(17):4334-9. doi: 10.1016/j.bmcl.2016.07.030. Epub 2016 Jul 16.

Abstract

Using SBDD, a series of 4-amino-7-azaindoles were discovered as a novel class of Alk5 inhibitors that are potent in both Alk5 enzymatic and cellular assays. Subsequently a ring cyclization strategy was utilized to improve ADME properties leading to the discovery of a series of 1H-imidazo[4,5-c]pyridin-2(3H)-one drug like Alk5 inhibitors.

Keywords: Activin; Alk5; Factor; Growth; Inhibitors; Kinase; SBDD; Transforming.

MeSH terms

  • Animals
  • Cyclization
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Molecular Structure
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrimidines / chemistry
  • Pyrroles / chemistry
  • Rats
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Indoles
  • Pyrimidines
  • Pyrroles
  • Receptors, Transforming Growth Factor beta
  • pyrrolopyrimidine
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, rat