2. Academic Validation
  3. Discovery of a tricyclic farnesoid X receptor agonist HEC96719, a clinical candidate for treatment of non-alcoholic steatohepatitis

Discovery of a tricyclic farnesoid X receptor agonist HEC96719, a clinical candidate for treatment of non-alcoholic steatohepatitis

  • Eur J Med Chem. 2022 Feb 15;230:114089. doi: 10.1016/j.ejmech.2021.114089.
Shengtian Cao 1,  Xinye Yang 2,  Zheng Zhang 2,  Junwen Wu 2,  Bo Chi 2,  Hong Chen 2,  Jianghong Yu 2,  Shanshan Feng 2,  Yulin Xu 2,  Jing Li 2,  Yingjun Zhang 2,  Xiaojun Wang 3,  Yan Wang 4
Affiliations

Affiliations

  • 1 Southern Medical University Biomedical Research Center, Guangdong Provincial Research Center for Liver Fibrosis, Southern Medical University, Guangzhou, Guangdong, China; Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China.
  • 2 Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China.
  • 3 Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China. Electronic address: wangxiaojun@hec.cn.
  • 4 Southern Medical University Biomedical Research Center, Guangdong Provincial Research Center for Liver Fibrosis, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: yanwang@smu.edu.cn.
PMID: 34998040 DOI: 10.1016/j.ejmech.2021.114089
Abstract

Non-alcoholic fatty liver disease (NAFLD) is becoming the most predominant burden of chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, can develop into cirrhosis and hepatocellular Cancer. Unfortunately, current options for therapeutic treatment of NASH are very limited. Among multiple pathways in NASH, farnesoid X receptor (FXR), a nuclear bile acid receptor, is well-recognized as an important effective target. Here we report the synthesis and characterization of compound HEC96719 a novel tricyclic FXR Agonist based on a prior high-affinity nonsteroidal molecule GW4064. HEC96719 exhibits excellent potency superior to GW4064 and obeticholic acid in in vitro and in vivo assays of FXR activation. It also shows higher FXR selectivity and more favorable tissue distribution dominantly in liver and intestine. Preclinical data on pharmacokinetic properties, efficacy, and safety profiles overall indicate that HEC96719 is a promising drug candidate for NASH treatment.

Keywords

Chemical synthesis; Drug development; Farnesoid X receptor agonist; Non-alcoholic steatohepatitis; Pharmacokinetic assay; Pharmacological assay; Safety profiling.

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