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本文引用的文献

1
Farnesoid X receptor modulators 2014-present: a patent review.法尼醇 X 受体调节剂 2014 年至今：专利研究综述。
Expert Opin Ther Pat. 2018 May;28(5):351-364. doi: 10.1080/13543776.2018.1459569. Epub 2018 Apr 13.
2
Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH).发现 Tropifexor（LJN452），一种高效的非胆汁酸 FXR 激动剂，用于治疗胆汁淤积性肝病和非酒精性脂肪性肝炎（NASH）。
J Med Chem. 2017 Dec 28;60(24):9960-9973. doi: 10.1021/acs.jmedchem.7b00907. Epub 2017 Dec 8.
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Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers: Understanding and improving key determinants of pharmacological properties.具有环丙基、羟基环丁基和羟基氮杂环丁烷基连接基的新型取代异恶唑法尼醇X受体激动剂：理解和改善药理性质的关键决定因素
Bioorg Med Chem Lett. 2016 Aug 1;26(15):3746-53. doi: 10.1016/j.bmcl.2016.05.070. Epub 2016 May 24.
4
Recent Progress on Bile Acid Receptor Modulators for Treatment of Metabolic Diseases.用于治疗代谢性疾病的胆汁酸受体调节剂的最新进展
J Med Chem. 2016 Jul 28;59(14):6553-79. doi: 10.1021/acs.jmedchem.5b00342. Epub 2016 Feb 29.
5
Knocking on FXR's door: the "hammerhead"-structure series of FXR agonists - amphiphilic isoxazoles with potent in vitro and in vivo activities.叩响法尼醇X受体（FXR）之门：FXR激动剂的“锤头状”结构系列——具有强大体外和体内活性的两亲性异恶唑类化合物
Curr Top Med Chem. 2014;14(19):2143-58. doi: 10.2174/1568026614666141112094430.
6
Design, synthesis, and biological evaluation of potent dual agonists of nuclear and membrane bile acid receptors.设计、合成及强效核受体和膜型胆汁酸受体双重激动剂的生物学评价。
J Med Chem. 2014 Feb 13;57(3):937-54. doi: 10.1021/jm401873d. Epub 2014 Jan 17.
7
Dissociation of intestinal and hepatic activities of FXR and LXRα supports metabolic effects of terminal ileum interposition in rodents.FXR 和 LXRα 的肠肝活性分离支持末端回肠旁路在啮齿动物中的代谢作用。
Diabetes. 2013 Oct;62(10):3384-93. doi: 10.2337/db13-0299. Epub 2013 Jul 8.
8
Binding mechanism of the farnesoid X receptor marine antagonist suvanine reveals a strategy to forestall drug modulation on nuclear receptors. Design, synthesis, and biological evaluation of novel ligands.法尼醇 X 受体海洋拮抗剂苏拉宁的结合机制揭示了一种阻止核受体药物调节的策略。新型配体的设计、合成与生物学评价。
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9
Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis.对乙酰氨基酚的代谢与处置：与肝毒性和诊断相关的最新进展。
Pharm Res. 2013 Sep;30(9):2174-87. doi: 10.1007/s11095-013-1007-6. Epub 2013 Mar 6.
10
Counter-regulatory role of bile acid activated receptors in immunity and inflammation.胆汁酸激活受体在免疫和炎症中的反向调节作用。
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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.

DOI:10.1021/acsmedchemlett.8b00423
PMID:30996771
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6466548/
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。