Effect of Oxime Ether Incorporation in Acyl Indole Derivatives on PPAR Subtype Selectivity

Morgan LeNaour, Veronique Leclerc, Amaury Farce, Daniel Henri Caignard, Nathalie Hennuyer, Bart Staels, Valérie Audinot-Bouchez, Jean Albert Boutin, Michel Lonchampt, Catherine Dacquet, Alain Ktorza, Pascal Berthelot, Nicolas Lebegue

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α-ethoxyphenylpropionic acid bearing 5- or 6-substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20c and 21a. Compound 20c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21a, less potent as a dual PPARα/γ activator than 20c, showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.

Original languageEnglish (US)
Pages (from-to)2179-2193
Number of pages15
Issue number12
StatePublished - Dec 2012
Externally publishedYes


  • 2-ethoxypropionic acid
  • Diabetes
  • Docking
  • Drug design
  • PPAR


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