Sulindac derivatives that activate the peroxisome proliferator-activated receptor γ but lack cyclooxygenase inhibition Academic Article uri icon

Overview

MeSH Major

  • Cyclooxygenase Inhibitors
  • PPAR gamma
  • Sulindac

abstract

  • A series of novel derivatives of the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide were synthesized as potential agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Nonpolar and aromatic substitutions on the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity. Compound 24 was as potent a compound as any other in the series with an EC50 of 0.1 microM for the induction of peroxisome proliferator response element (PPRE)-luciferase activity. Direct binding of compound 24 to PPARgamma was demonstrated by the displacement of [(3)H]troglitazone, a PPARgamma agonist, in a scintillation proximity assay. Compound 24 also stimulated the binding of PPARgamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPARgamma target genes. Taken together, these compounds represent potential leads in the development of novel PPARgamma agonists.

publication date

  • August 28, 2008

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2651753

Digital Object Identifier (DOI)

  • 10.1021/jm700969c

PubMed ID

  • 18665581

Additional Document Info

start page

  • 4911

end page

  • 9

volume

  • 51

number

  • 16