Discovery of betulinic acid derivatives as gut-restricted TGR5 agonists: Balancing the potency and physicochemical properties

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-01-17 DOI:10.1016/j.bioorg.2024.107132

Ning Zhuo , Ying Yun , Chenlu Zhang , Shimeng Guo , Jianpeng Yin , Tingting Zhao , Xiu Ge , Min Gu , Xin Xie , Fajun Nan

{"title":"Discovery of betulinic acid derivatives as gut-restricted TGR5 agonists: Balancing the potency and physicochemical properties","authors":"Ning Zhuo , Ying Yun , Chenlu Zhang , Shimeng Guo , Jianpeng Yin , Tingting Zhao , Xiu Ge , Min Gu , Xin Xie , Fajun Nan","doi":"10.1016/j.bioorg.2024.107132","DOIUrl":null,"url":null,"abstract":"<div><p>The pleiotropic effects of TGR5 make it an appealing target for intervention of metabolic and inflammatory disorders, but systemic activation of TGR5 faces challenges of on-target side effects, especially gallbladder filling. Gut-restricted agonists were proved to be sufficient to circumvent these side effects, but extremely low systemic exposure may not be effective in activating TGR5 since it is located on the basolateral membrane. Herein, to balance potency and physicochemical properties, a series of gut-restricted TGR5 agonists with diversified kinetophores had been designed and synthesized. Compound <strong>22-Na</strong> exhibited significant antidiabetic effect, and showed favorable gallbladder safety after 7 days of oral administration in humanized TGR5<sup>H88Y</sup> mice, confirming that gut-restricted agonism of TGR5 is a viable strategy to alleviate systemic target-related effects.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"144 ","pages":"Article 107132"},"PeriodicalIF":4.5000,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0045206824000373","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

The pleiotropic effects of TGR5 make it an appealing target for intervention of metabolic and inflammatory disorders, but systemic activation of TGR5 faces challenges of on-target side effects, especially gallbladder filling. Gut-restricted agonists were proved to be sufficient to circumvent these side effects, but extremely low systemic exposure may not be effective in activating TGR5 since it is located on the basolateral membrane. Herein, to balance potency and physicochemical properties, a series of gut-restricted TGR5 agonists with diversified kinetophores had been designed and synthesized. Compound 22-Na exhibited significant antidiabetic effect, and showed favorable gallbladder safety after 7 days of oral administration in humanized TGR5^H88Y mice, confirming that gut-restricted agonism of TGR5 is a viable strategy to alleviate systemic target-related effects.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

发现作为肠道限制性 TGR5 激动剂的白桦脂酸衍生物：平衡药效和理化性质

TGR5 的多效应使其成为干预代谢和炎症性疾病的一个有吸引力的靶点，但全身激活 TGR5 面临着靶点副作用的挑战，尤其是胆囊充盈。事实证明，限制肠道的激动剂足以规避这些副作用，但极低的全身暴露量可能无法有效激活 TGR5，因为它位于基底膜上。在此，为了平衡药效和理化性质，我们设计并合成了一系列具有不同酮基的肠道限制性 TGR5 激动剂。化合物 22-Na 在人源化 TGR5H88Y 小鼠口服 7 天后表现出显著的抗糖尿病作用，并显示出良好的胆囊安全性，证实了肠道限制性 TGR5 激动剂是减轻全身靶相关效应的可行策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.