Discovery of novel dual PPARα/δ agonists based on benzimidazole scaffold for the treatment of non-alcoholic fatty liver disease.,Bioorganic Chemistry

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Discovery of novel dual PPARα/δ agonists based on benzimidazole scaffold for the treatment of non-alcoholic fatty liver disease.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-03-31 , DOI: 10.1016/j.bioorg.2020.103803
Zheng Li ₁ , Yawen Xu ₂ , Zongyu Cai ₂ , Xuekun Wang ₃ , Qiang Ren ₂ , Zongtao Zhou ₂ , Rongrong Xie ₂

Affiliation

Many peroxisome proliferator-activated receptors (PPARs) agonists have been developed for the treatment of metabolic disorders, while several PPARs agonists were discontinued in clinical trials because of PPARγ related side effects. In order to increase the selectivity against PPARγ, we performed a structure-activity relationship study based on PPARα/γ/δ agonist MHY2013. These efforts eventually led to the identification of compound 4, a dual PPARα/δ agonist with considerable potencies on PPARα/δ and high selectivity against PPARγ. In the Western Diet and CCl4-induced non-alcoholic steatohepatitis model, compound 4 alleviates the hepatic steatosis, inflammation, and fibrosis. These results indicated that dual PPARα/δ agonist 4 might be a promising lead compound for further investigations.

中文翻译：

基于苯并咪唑支架的新型双PPARα/δ激动剂的发现，用于治疗非酒精性脂肪肝。

已经开发出许多过氧化物酶体增殖物激活受体（PPARs）激动剂来治疗代谢紊乱，而一些PPARs激动剂由于PPARγ相关的副作用而在临床试验中被中止。为了增加对PPARγ的选择性，我们进行了基于PPARα/γ/δ激动剂MHY2013的构效关系研究。这些努力最终导致了化合物4的鉴定，该化合物是对PPARα/δ具有相当大的效力并且对PPARγ具有高选择性的双重PPARα/δ激动剂。在Western Diet和CCl4诱导的非酒精性脂肪性肝炎模型中，化合物4减轻了肝脂肪变性，炎症和纤维化。这些结果表明，双PPARα/δ激动剂4可能是有希望的进一步研究的先导化合物。

更新日期：2020-04-20

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