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Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-11-28 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00318 Hualing Xiao 1 , Peng Li 1 , Xiaolin Li 1 , Haiying He 1 , Jianhua Wang 1 , Fengxun Guo 1 , Jiliang Zhang 1 , Luxia Wei 1 , Hongmei Zhang 1 , Yueyuan Shi 1 , Lijuan Hou 1 , Liang Shen 1 , Zhengxia Chen 1 , Chunyan Du 1 , Shouliang Fu 1 , Pengtao Zhang 1 , Fei Hao 1 , Ping Wang 1 , Deming Xu 1 , Wei Liang 1 , Xin Tian 2 , Aiming Zhang 2 , Xingdong Cheng 2 , Ling Yang 2 , Xiangjian Wang 2 , Xiquan Zhang 2 , Jian Li 1 , Shuhui Chen 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-11-28 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00318 Hualing Xiao 1 , Peng Li 1 , Xiaolin Li 1 , Haiying He 1 , Jianhua Wang 1 , Fengxun Guo 1 , Jiliang Zhang 1 , Luxia Wei 1 , Hongmei Zhang 1 , Yueyuan Shi 1 , Lijuan Hou 1 , Liang Shen 1 , Zhengxia Chen 1 , Chunyan Du 1 , Shouliang Fu 1 , Pengtao Zhang 1 , Fei Hao 1 , Ping Wang 1 , Deming Xu 1 , Wei Liang 1 , Xin Tian 2 , Aiming Zhang 2 , Xingdong Cheng 2 , Ling Yang 2 , Xiangjian Wang 2 , Xiquan Zhang 2 , Jian Li 1 , Shuhui Chen 1
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Farnesoid X receptor (FXR) has become a particularly attractive target for the discovery of drugs for the treatment of liver and metabolic diseases. Obeticholic acid (INT-747), a FXR agonist, has advanced into clinical phase III trials in patients with nonalcoholic steatohepatitis (NASH), but adverse effects (e.g., pruritus, LDL increase) were observed. Pruritus might be induced by Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1), and there are chances to develop FXR agonists with higher selectivity over TGR5. In this letter, novel bile acids bearing different modifications on ring A and side chain of INT-747 are reported and discussed. Our results indicated that the side chain of INT-747 is amenable to a variety of chemical modifications with good FXR potency in vitro. Especially, compound 18 not only showed promising FXR potency and excellent pharmacokinetic properties, but also proved superior pharmacological efficacy in the HFD + CCl4 model.
中文翻译：
一系列胆汁酸衍生物作为FXR激动剂治疗NASH的合成及生物学评价
Farnesoid X受体（FXR）已成为发现用于治疗肝脏和代谢性疾病的药物的特别有吸引力的靶标。FXR激动剂奥贝胆酸（INT-747）已进入非酒精性脂肪性肝炎（NASH）患者的III期临床试验，但观察到不良反应（例如瘙痒，LDL升高）。武田G蛋白偶联受体5（TGR5，GPBAR1）可能引起瘙痒，并且有机会开发出比TGR5具有更高选择性的FXR激动剂。在这封信中，报道并讨论了在INT-747的A环和侧链上进行不同修饰的新型胆汁酸。我们的结果表明INT-747的侧链在体外具有良好的FXR效力，可进行多种化学修饰。特别地，化合物18不仅显示出有希望的FXR效力和优异的药代动力学性质，而且在HFD + CCl 4模型中证明了优异的药理学功效。
更新日期：2017-11-28
中文翻译：
一系列胆汁酸衍生物作为FXR激动剂治疗NASH的合成及生物学评价
Farnesoid X受体（FXR）已成为发现用于治疗肝脏和代谢性疾病的药物的特别有吸引力的靶标。FXR激动剂奥贝胆酸（INT-747）已进入非酒精性脂肪性肝炎（NASH）患者的III期临床试验，但观察到不良反应（例如瘙痒，LDL升高）。武田G蛋白偶联受体5（TGR5，GPBAR1）可能引起瘙痒，并且有机会开发出比TGR5具有更高选择性的FXR激动剂。在这封信中，报道并讨论了在INT-747的A环和侧链上进行不同修饰的新型胆汁酸。我们的结果表明INT-747的侧链在体外具有良好的FXR效力，可进行多种化学修饰。特别地，化合物18不仅显示出有希望的FXR效力和优异的药代动力学性质，而且在HFD + CCl 4模型中证明了优异的药理学功效。
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