{"title":"作为非系统性肠靶向 TGR5 激动剂的共价黏附性衍生物的设计、合成和生物学评价","authors":"Shizhen Zhao, Le Wang, Xiaotong Huang, Yali Xiao, Mengqi Li, Xueyuan Huang, Xueyu Chen, Shengjie Li, Jing Xie, Peng Liu, Yan-Dong Wang, Wei-Dong Chen","doi":"10.1021/acs.jmedchem.4c01637","DOIUrl":null,"url":null,"abstract":"Takeda G-protein-coupled receptor 5 (TGR5) is considered a promising therapeutic target for treating type 2 diabetes mellitus (T2DM), obesity, and other metabolism-related diseases. Although many TGR5 agonists have been identified, they might cause some side effects in the gallbladder and the heart. To reduce these side effects and improve glucose-lowering capability, we first designed and synthesized a series of 4-phenoxynicotinamide intestine-targeted TGR5 agonist derivatives containing maleimides in the side chains with different linker lengths. All of the target compounds demonstrated significant TGR5 agonistic activity, among which compound <b>22b</b> displayed the best TGR5 agonistic activity. Additionally, compound <b>22b</b> displayed low Caco-2 cell permeability and strong mucoadhesion to mucin and the rat intestine. In C57BL/6J, diet-induced obese, and <i>db</i>/<i>db</i> mice, compound <b>22b</b> demonstrated a robust and prolonged hypoglycemic effect along with an acceptable safety profile.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design, Synthesis, and Biological Evaluation of Covalently Mucoadhesive Derivatives as Nonsystemic Intestine-Targeted TGR5 Agonists\",\"authors\":\"Shizhen Zhao, Le Wang, Xiaotong Huang, Yali Xiao, Mengqi Li, Xueyuan Huang, Xueyu Chen, Shengjie Li, Jing Xie, Peng Liu, Yan-Dong Wang, Wei-Dong Chen\",\"doi\":\"10.1021/acs.jmedchem.4c01637\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Takeda G-protein-coupled receptor 5 (TGR5) is considered a promising therapeutic target for treating type 2 diabetes mellitus (T2DM), obesity, and other metabolism-related diseases. Although many TGR5 agonists have been identified, they might cause some side effects in the gallbladder and the heart. To reduce these side effects and improve glucose-lowering capability, we first designed and synthesized a series of 4-phenoxynicotinamide intestine-targeted TGR5 agonist derivatives containing maleimides in the side chains with different linker lengths. All of the target compounds demonstrated significant TGR5 agonistic activity, among which compound <b>22b</b> displayed the best TGR5 agonistic activity. Additionally, compound <b>22b</b> displayed low Caco-2 cell permeability and strong mucoadhesion to mucin and the rat intestine. In C57BL/6J, diet-induced obese, and <i>db</i>/<i>db</i> mice, compound <b>22b</b> demonstrated a robust and prolonged hypoglycemic effect along with an acceptable safety profile.\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-09-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jmedchem.4c01637\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01637","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Design, Synthesis, and Biological Evaluation of Covalently Mucoadhesive Derivatives as Nonsystemic Intestine-Targeted TGR5 Agonists
Takeda G-protein-coupled receptor 5 (TGR5) is considered a promising therapeutic target for treating type 2 diabetes mellitus (T2DM), obesity, and other metabolism-related diseases. Although many TGR5 agonists have been identified, they might cause some side effects in the gallbladder and the heart. To reduce these side effects and improve glucose-lowering capability, we first designed and synthesized a series of 4-phenoxynicotinamide intestine-targeted TGR5 agonist derivatives containing maleimides in the side chains with different linker lengths. All of the target compounds demonstrated significant TGR5 agonistic activity, among which compound 22b displayed the best TGR5 agonistic activity. Additionally, compound 22b displayed low Caco-2 cell permeability and strong mucoadhesion to mucin and the rat intestine. In C57BL/6J, diet-induced obese, and db/db mice, compound 22b demonstrated a robust and prolonged hypoglycemic effect along with an acceptable safety profile.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.