Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11

Bioorg Med Chem Lett. 2018 Jul 1;28(12):2143-2147. doi: 10.1016/j.bmcl.2018.05.021. Epub 2018 May 9.

Abstract

N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.

Keywords: HDAC11; HDACs; Hydroxamic acid; Inflammation; Isoindoline; Oncology.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • Isoindoles / chemical synthesis
  • Isoindoles / chemistry
  • Isoindoles / pharmacology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Structure
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Isoindoles
  • Recombinant Proteins
  • HDAC11 protein, human
  • Histone Deacetylases