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GPBAR1 Activation by C6-Substituted Hyodeoxycholane Analogues Protect against Colitis.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-02 , DOI: 10.1021/acsmedchemlett.9b00636 Simona De Marino 1 , Claudia Finamore 1 , Michele Biagioli 2 , Adriana Carino 2 , Silvia Marchianò 2 , Rosalinda Roselli 1 , Cristina Di Giorgio 2 , Martina Bordoni 2 , Francesco Saverio Di Leva 1 , Ettore Novellino 1 , Chiara Cassiano 1 , Vittorio Limongelli 1, 3 , Angela Zampella 1 , Carmen Festa 1 , Stefano Fiorucci 2
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-02 , DOI: 10.1021/acsmedchemlett.9b00636 Simona De Marino 1 , Claudia Finamore 1 , Michele Biagioli 2 , Adriana Carino 2 , Silvia Marchianò 2 , Rosalinda Roselli 1 , Cristina Di Giorgio 2 , Martina Bordoni 2 , Francesco Saverio Di Leva 1 , Ettore Novellino 1 , Chiara Cassiano 1 , Vittorio Limongelli 1, 3 , Angela Zampella 1 , Carmen Festa 1 , Stefano Fiorucci 2
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GPBAR1 agonists have been identified as potential leads for the treatment of diseases related to colon inflammation such as Crohn's and ulcerative colitis. In this paper, we report the discovery of a small library of hyodeoxycholane analogues, decorated at C-6 with different substituents, as potent and selective GPBAR1 agonists. In vitro pharmacological assays showed that compound 6 selectively activates GPBAR1 (EC50 = 0.3 μM) and reduces the production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in THP1 cells. The binding mode of compound 6 in GPBAR1 was elucidated by docking calculations. Moreover, compound 6 protects against TNBS-induced colitis in Gpbar1+/+ rodent model, representing an intriguing lead for the treatment of these inflammatory disorders.
中文翻译：
由C6取代的猪去氧胆碱类似物激活GPBAR1可以预防结肠炎。
GPBAR1激动剂已被确定为治疗与结肠炎症相关的疾病（如克罗恩氏病和溃疡性结肠炎）的潜在先导。在本文中，我们报告了一个小片段的猪去氧胆碱类似物的发现，该类似物在C-6处修饰有不同的取代基，作为强效和选择性GPBAR1激动剂。体外药理分析表明，化合物6在THP1细胞中选择性激活GPBAR1（EC50 = 0.3μM）并减少促炎性细胞因子（IL-1β，IL-6和TNF-α）的产生。通过对接计算阐明了化合物6在GPBAR1中的结合模式。此外，化合物6在Gpbar1 + / +啮齿动物模型中预防TNBS诱导的结肠炎，代表了治疗这些炎症性疾病的诱人先机。
更新日期：2020-03-02
中文翻译：
由C6取代的猪去氧胆碱类似物激活GPBAR1可以预防结肠炎。
GPBAR1激动剂已被确定为治疗与结肠炎症相关的疾病（如克罗恩氏病和溃疡性结肠炎）的潜在先导。在本文中，我们报告了一个小片段的猪去氧胆碱类似物的发现，该类似物在C-6处修饰有不同的取代基，作为强效和选择性GPBAR1激动剂。体外药理分析表明，化合物6在THP1细胞中选择性激活GPBAR1（EC50 = 0.3μM）并减少促炎性细胞因子（IL-1β，IL-6和TNF-α）的产生。通过对接计算阐明了化合物6在GPBAR1中的结合模式。此外，化合物6在Gpbar1 + / +啮齿动物模型中预防TNBS诱导的结肠炎，代表了治疗这些炎症性疾病的诱人先机。
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