Molecular determinants for improved activity at PPARα: structure-activity relationship of pirinixic acid derivatives, docking study and site-directed mutagenesis of PPARα

Bioorg Med Chem Lett. 2014 Aug 15;24(16):4048-52. doi: 10.1016/j.bmcl.2014.05.058. Epub 2014 Jun 11.

Abstract

Peroxisome proliferator-activated receptors (PPARs) are attractive targets for the treatment of the metabolic syndrome. Especially a combination of PPARα and PPARγ agonistic activity seems worthwhile to be pursued. Herein we present the design and synthesis of a series of pirinixic acid derivatives as potent PPARα particularly dual PPARα/γ agonists with 2-((4-chloro-6-((4-(phenylamino)phenyl)amino)pyrimidin-2-yl)thio)octanoicacid having the highest potential. Our investigations based on molecular docking and structure-activity relationship (SAR) studies elucidated structural determinants affecting the potency at PPARα. A diphenylamine-scaffold seems to play a key role. Careful in silico analysis revealed an essential role for a hydrogen bond between the diphenylamine and a water cluster. We confirmed this hypothesis using a mutated PPARα LBD in our transactivation assay to disrupt the water cluster and to validate the proposed interaction.

Keywords: Dual PPARα/γ agonist; Metabolic syndrome; Peroxisome proliferator-activated receptor; Site-directed mutagenesis; Structure–activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Hydrogen Bonding
  • Molecular Docking Simulation*
  • Molecular Structure
  • Mutagenesis, Site-Directed*
  • PPAR alpha / agonists*
  • PPAR alpha / genetics
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • PPAR alpha
  • Pyrimidines
  • pirinixic acid