Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, Missouri 63110, United States.
Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, Missouri 63110, United States.
J Med Chem. 2021 Dec 23;64(24):17545-17571. doi: 10.1021/acs.jmedchem.1c01017. Epub 2021 Dec 10.
Farnesoid X receptor (FXR) is an important regulator of bile acid, lipid, amino acid, and glucose homeostasis, hepatic inflammation, regeneration, and fibrosis. FXR has been recognized as a promising drug target for various metabolic diseases such as lipid disorders, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and chronic kidney disease. A large number of FXR ligands have been developed by pharmaceutical companies and academic institutions, and several candidates have progressed into clinical trials in the past decade. However, it is continually a challenge to discover drugs targeting FXR due to side effects associated with long-term administration. In this perspective, we summarize the research progress on medicinal chemistry of FXR modulators from 2018 to the present by discussing the diverse structures of synthetic FXR modulators including steroidal and non-steroidal ligands, their structure-activity relationships (SARs), and their therapeutic applications.
法尼醇 X 受体（FXR）是胆汁酸、脂质、氨基酸和葡萄糖稳态、肝炎症、再生和纤维化的重要调节剂。FXR 已被认为是各种代谢疾病（如脂质紊乱、非酒精性脂肪性肝病（NAFLD）、非酒精性脂肪性肝炎（NASH）和慢性肾脏病）的有前途的药物靶点。制药公司和学术机构已经开发了大量的 FXR 配体，在过去十年中，有几个候选药物已经进入临床试验。然而，由于长期给药相关的副作用，发现针对 FXR 的药物仍然是一个挑战。在这篇观点文章中，我们通过讨论合成 FXR 调节剂的不同结构，包括甾体和非甾体配体、它们的结构-活性关系（SAR）及其治疗应用，总结了 2018 年至今 FXR 调节剂的药物化学研究进展。
