Structure-activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists

Bioorg Med Chem. 2016 Nov 1;24(21):5455-5461. doi: 10.1016/j.bmc.2016.08.067. Epub 2016 Sep 1.


The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that contribute to the regulation of lipid, glucose and cholesterol homeostases. They are considered as therapeutic targets for metabolic diseases such as dyslipidemia and type 2 diabetes mellitus. Various PPAR agonists have been developed, but most of them contain a carboxylic acid (CA) or thiazolidinedione (TZD) moiety, which is essential for the activity. However, we recently discovered non-CA/non-TZD class PPARα/δ dual agonists having an acetamide structure. Here, we describe structure-activity relationship (SAR) studies of these novel acetamide-based PPARα/δ dual agonists. The SAR studies revealed that the acetamide functionality and adjacent methyl group contribute greatly to the agonistic activity. Compound (S)-10 was the most potent PPARα/δ dual agonist among the compounds synthesized (PPARα EC50=17nM, PPARδ EC50=23nM).

Keywords: Non-carboxylic acid; PPAR; PPAR agonist; Peroxisome proliferator-activated receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • PPAR alpha / agonists*
  • PPAR delta / agonists*
  • Structure-Activity Relationship


  • Acetamides
  • PPAR alpha
  • PPAR delta
  • acetamide