Unità di Chimica Farmaceutica, Dipartimento di Farmacia, Università"G. d'Annunzio", Chieti, Italy.
Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari, Italy.
Eur J Med Chem. 2016 May 23;114:191-200. doi: 10.1016/j.ejmech.2016.02.064. Epub 2016 Feb 27.
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.
最近的证据表明，过氧化物酶体增殖物激活受体 (PPARs) 的适度激活可能对代谢疾病有利，减少了完全激动剂带来的副作用。PPAR 部分激动剂和拮抗剂是迄今为止阐明这些受体调节的生物学过程的有趣工具。本工作报道了新的苯磺酰胺化合物，能够阻断 PPARα，通过转激活测定和基因表达分析进行合成和测试。其中一些化合物对 PPARα 表现出剂量依赖性拮抗作用，具有亚微摩尔效力，对 PPARγ 的选择性不同，对 CPT1A 表达有抑制作用。对适当选择的苯磺酰胺衍生物进行对接和分子动力学研究，为 PPARα 拮抗作用的最可能分子决定因素提供了新的见解。
