title: Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175.
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.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Piemontese
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fracchiolla
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Mariagiovanna
authors.initials: M
authors.lastname: Parente
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Carbonara
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Sblano
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Tauro
authors.affiliation: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Gilardi
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortorella
authors.affiliation: Dipartimento di Chimica Farmaceutica e Tossicologica, 'Drug Discovery' Laboratory, Università degli Studi di Napoli 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Crestani
authors.affiliation: Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
authors.affiliation: 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.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Loiodice
mesh_terms: D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D010091:Oximes; D047493:PPAR alpha; D047495:PPAR gamma
keywords: Bioisosterism; Docking; Gene expression study; PPAR