Identification of the first potent, selective and bioavailable PPARα antagonist

Bioorg Med Chem Lett. 2014 May 15;24(10):2267-72. doi: 10.1016/j.bmcl.2014.03.090. Epub 2014 Apr 4.

Abstract

The discovery and SAR of a novel series of potent and selective PPARα antagonists are herein described. Exploration of replacements for the labile acyl sulfonamide linker led to a biaryl sulfonamide series of which compound 33 proved to be suitable for further profiling in vivo. Compound 33 demonstrated excellent potency, selectivity against other nuclear hormone receptors, and good pharmacokinetics in mouse.

Keywords: Antagonist; Cancer; Fatty acid oxidation; Nuclear hormone receptor; PPAR alpha.

MeSH terms

  • Animals
  • Butyrates / chemistry
  • Butyrates / pharmacology
  • Humans
  • Mice
  • Molecular Structure
  • Oxazoles / chemistry
  • Oxazoles / pharmacology
  • PPAR alpha / antagonists & inhibitors*
  • Phenylurea Compounds / chemistry
  • Phenylurea Compounds / pharmacology
  • Propionates / chemistry
  • Propionates / pharmacology
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*
  • Triazoles / chemistry
  • Triazoles / pharmacology
  • Tyrosine / analogs & derivatives
  • Tyrosine / chemistry
  • Tyrosine / pharmacology

Substances

  • Butyrates
  • GW 409544
  • GW 7647
  • LY 518674
  • Oxazoles
  • PPAR alpha
  • Phenylurea Compounds
  • Propionates
  • Sulfonamides
  • Triazoles
  • Tyrosine