具有强效法尼醇X受体激动活性的新型异恶唑衍生物可预防对乙酰氨基酚诱导的肝损伤。
Novel Isoxazole Derivatives with Potent FXR Agonistic Activity Prevent Acetaminophen-Induced Liver Injury.
作者信息
Sepe Valentina, Marchianò Silvia, Finamore Claudia, Baronissi Giuliana, Di Leva Francesco Saverio, Carino Adriana, Biagioli Michele, Fiorucci Chiara, Cassiano Chiara, Monti Maria Chiara, Del Gaudio Federica, Novellino Ettore, Limongelli Vittorio, Fiorucci Stefano, Zampella Angela
机构信息
Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy.
Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Perugia, Italy.
出版信息
ACS Med Chem Lett. 2018 Dec 6;10(4):407-412. doi: 10.1021/acsmedchemlett.8b00423. eCollection 2019 Apr 11.
Abstract
Acetaminophen misuse is a leading cause of acute liver failure and liver transplantation for which therapy is poorly effective. FXR ligands have shown effective in reducing liver injury in several experimental and clinical settings. In this Letter, we have elaborated on the structure of GW4064, the first nonsteroidal agonist for FXR, to identify novel isoxazoles endowed with FXR agonistic activity and improved ADME properties. The pharmacological characterization and molecular docking studies for the structure-activity rationalization allowed the identification of several FXR agonists with nanomolar potency in transactivation and SRC-1 recruitment assays. This characterization resulted in the identification of a potent FXR agonist, compound that was orally active, and rescued mice from acute liver failure caused by acetaminophen overdose in a FXR-dependent manner.
摘要
对乙酰氨基酚的不当使用是急性肝衰竭和肝移植的主要原因，而针对此的治疗效果不佳。法尼醇X受体（FXR）配体在多种实验和临床环境中已显示出对减轻肝损伤有效。在本信函中，我们详细阐述了GW4064（首个FXR非甾体激动剂）的结构，以鉴定具有FXR激动活性并改善了吸收、分布、代谢和排泄（ADME）特性的新型异恶唑。通过药理学表征和分子对接研究进行构效关系合理化分析，得以鉴定出几种在反式激活和SRC-1募集试验中具有纳摩尔效力的FXR激动剂。这一表征鉴定出了一种强效FXR激动剂——化合物，它具有口服活性，并以FXR依赖的方式使小鼠免于对乙酰氨基酚过量引起的急性肝衰竭。
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