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Eur J Med Chem. 2016 May 23;114:191-200. doi: 10.1016/j.ejmech.2016.02.064. Epub 2016 Feb 27.

Synthesis, in vitro evaluation, and molecular modeling investigation of benzenesulfonimide peroxisome proliferator-activated receptors α antagonists.

Author information

1
Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy. Electronic address: aammazzalorso@unich.it.
2
Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari, Italy.
3
Unità di Patologia Generale, Dipartimento di Farmacia, Università "G. d'Annunzio", Chieti, Italy; Aging Research Center (Ce.S.I.), Università "G. d'Annunzio", Chieti, Italy.
4
Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy.
5
Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy. Electronic address: ramoroso@unich.it.

Abstract

Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARα, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose-dependent antagonistic behavior on PPARα, submicromolar potency, different profiles of selectivity versus PPARγ, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARα antagonism.

KEYWORDS:

Benzenesulfonimides; CPT1A; Docking; Fibrates; Molecular dynamic; PPAR antagonist; PPARs; Transactivation assay

PMID:
26974385
DOI:
10.1016/j.ejmech.2016.02.064
[Indexed for MEDLINE]

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