2. Academic Validation
  3. Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175

Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175

  • Eur J Med Chem. 2015 Jan 27:90:583-94. doi: 10.1016/j.ejmech.2014.11.044.
Luca Piemontese 1,  Giuseppe Fracchiolla 1,  Antonio Carrieri 1,  Mariagiovanna Parente 1,  Antonio Laghezza 1,  Giuseppe Carbonara 1,  Sabina Sblano 1,  Marilena Tauro 1,  Federica Gilardi 2,  Paolo Tortorella 1,  Antonio Lavecchia 3,  Maurizio Crestani 4,  Béatrice Desvergne 2,  Fulvio Loiodice 5
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy.
  • 2 Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.
  • 3 Dipartimento di Chimica Farmaceutica e Tossicologica, 'Drug Discovery' Laboratory, Università degli Studi di Napoli 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy.
  • 4 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
  • 5 Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy. Electronic address: fulvio.loiodice@uniba.it.
PMID: 25497132 DOI: 10.1016/j.ejmech.2014.11.044
Abstract

The effects resulting from the introduction of an oxime group in place of the distal aromatic ring of the diphenyl moiety of LT175, previously reported as a PPARα/γ dual agonist, have been investigated. This modification allowed the identification of new bioisosteric ligands with fairly good activity on PPARα and fine-tuned moderate activity on PPARγ. For the most interesting compound (S)-3, docking studies in PPARα and PPARγ provided a molecular explanation for its different behavior as full and partial agonist of the two receptor isotypes, respectively. A further investigation of this compound was carried out performing gene expression studies on HepaRG cells. The results obtained allowed to hypothesize a possible mechanism through which this ligand could be useful in the treatment of metabolic disorders. The higher induction of the expression of some genes, compared to selective agonists, seems to confirm the importance of a dual PPARα/γ activity which probably involves a synergistic effect on both receptor subtypes.

Keywords

Bioisosterism; Docking; Gene expression study; PPAR.

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