Modulation of PPAR receptor subtype selectivity of the ligands: aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety

Bioorg Med Chem Lett. 2008 Dec 15;18(24):6471-5. doi: 10.1016/j.bmcl.2008.10.062. Epub 2008 Oct 17.

Abstract

Oxazole containing glycine and oximinobutyric acid derivatives were synthesized as PPARalpha agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. Compound 13a was found to be a selective and potent PPARalpha agonist. Further 1,3-dioxane-2-carboxylic acid derivative 20 was synthesized by replacing the tetramethylene spacer of NS-220, a selective PPARalpha agonist with phenylene group and found to exhibit PPARalpha/gamma dual agonism. These results suggest that compounds possessing polymethylene spacer between pharmacophore and lipophilic tail exhibit predominantly PPARalpha agonism whereas those with an aromatic phenylene spacer shows PPARalpha/gamma dual agonism.

MeSH terms

  • Butyrates / chemistry
  • Chemistry, Pharmaceutical / methods*
  • Dioxanes / chemistry
  • Drug Design
  • Glycine / analogs & derivatives
  • Glycine / chemistry
  • Humans
  • Hydrogen / chemistry
  • Hydrogen Bonding
  • Ligands
  • Models, Chemical
  • Oxazoles / chemistry
  • PPAR alpha / chemistry*
  • PPAR alpha / metabolism
  • Peroxisome Proliferator-Activated Receptors / chemistry*
  • Transcriptional Activation

Substances

  • 2-methyl-c-5-(4-(5-methyl-2-(4-methylphenyl)-4-oxazolyl)butyl)-1,3-dioxane-r-2-carboxylic acid
  • Butyrates
  • Dioxanes
  • Ligands
  • Oxazoles
  • PPAR alpha
  • Peroxisome Proliferator-Activated Receptors
  • Hydrogen
  • Glycine
  • muraglitazar