Structural development studies of PPARs ligands based on tyrosine scaffold

  • Eur J Med Chem. 2015 Jan 7:89:817-25. doi: 10.1016/j.ejmech.2014.10.083.
Barbara De Filippis  1 ,  Pasquale Linciano  1 ,  Alessandra Ammazzalorso  1 ,  Carmen Di Giovanni  2 ,  Marialuigia Fantacuzzi  1 ,  Letizia Giampietro  1 ,  Antonio Laghezza  3 ,  Cristina Maccallini  1 ,  Paolo Tortorella  3 ,  Antonio Lavecchia  4 ,  Fulvio Loiodice  5 ,  Rosa Amoroso  6
Affiliations
  • 1. Dipartimento di Farmacia, Università "G. d'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
  • 2. Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
  • 3. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70126 Bari, Italy.
  • 4. Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. Electronic address: [email protected].
  • 5. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via Orabona 4, 70126 Bari, Italy. Electronic address: [email protected].
  • 6. Dipartimento di Farmacia, Università "G. d'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy. Electronic address: [email protected].
PMID: 25462281 DOI: 10.1016/j.ejmech.2014.10.083
Abstract

PPARs are nuclear receptors with a critical physiological role in lipid and glucose metabolism. As part of our effort to develop new and selective PPAR agonists containing stilbene and its bioisoster phenyldiazene, novel analogs were synthesized starting from tyrosine and evaluated as PPAR agonists. We tested the effects of phenyloxazole replacement of GW409544, a well-known PPARα/γ dual agonist, with stilbene or phenyldiazene moiety, spaced by an ether bridge to tyrosine portion. These structural modifications provided potent and selective PPARγ agonists. Molecular docking studies performed on these new compounds complemented the experimental results and allowed to gain some insights into the nature of binding of the ligands.

Keywords
PPARs; PPARγ agonist; Phenyldiazene; Stilbene; Tyrosine.