Synthesis and biological evaluation of N-alkylated 8-oxybenz[c]azepine derivatives as selective PPARδ agonists

Bioorg Med Chem Lett. 2011 Jan 1;21(1):531-6. doi: 10.1016/j.bmcl.2010.10.083. Epub 2010 Oct 23.

Abstract

We describe the discovery of small molecule benzazepine derivatives as agonists of human peroxisome proliferator-activated receptor δ (PPARδ) that displayed excellent selectivity over the PPARα and PPARγ subtypes. Compound 8 displayed good PK in the rat and efficacy in upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) mRNA in human primary myotubes, a biomarker for increased fatty acid oxidation.

MeSH terms

  • Anilides / chemical synthesis*
  • Anilides / chemistry
  • Anilides / pharmacokinetics
  • Animals
  • Benzazepines / chemical synthesis
  • Benzazepines / chemistry*
  • Benzazepines / pharmacokinetics
  • Binding Sites
  • Computer Simulation
  • Hepatocytes / metabolism
  • Humans
  • Microsomes, Liver / metabolism
  • PPAR alpha / agonists
  • PPAR alpha / metabolism
  • PPAR delta / agonists*
  • PPAR delta / metabolism
  • PPAR gamma / agonists
  • PPAR gamma / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Rats
  • Up-Regulation

Substances

  • (2-(2-(1-(2,4-dichlorophenylamino)-1-oxobutan-2-yl)-2,3,4,5-tetrahydro-1H-benzo(c)azepin-8-yloxy)acetic acid)
  • Anilides
  • Benzazepines
  • PDK4 protein, human
  • PPAR alpha
  • PPAR delta
  • PPAR gamma
  • Pdk4 protein, rat
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Protein Serine-Threonine Kinases