| Literature DB >> 29259742 |
Hualing Xiao1, Peng Li1, Xiaolin Li1, Haiying He1, Jianhua Wang1, Fengxun Guo1, Jiliang Zhang1, Luxia Wei1, Hongmei Zhang1, Yueyuan Shi1, Lijuan Hou1, Liang Shen1, Zhengxia Chen1, Chunyan Du1, Shouliang Fu1, Pengtao Zhang1, Fei Hao1, Ping Wang1, Deming Xu1, Wei Liang1, Xin Tian2, Aiming Zhang2, Xingdong Cheng2, Ling Yang2, Xiangjian Wang2, Xiquan Zhang2, Jian Li1, Shuhui Chen1.
Abstract
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.Entities:
Year: 2017 PMID： 29259742 PMCID： PMC5733277 DOI： 10.1021/acsmedchemlett.7b00318
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345