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

文献类型：期刊论文

作者Zhuo, Ning1; Yun, Ying2; Zhang, Chenlu1; Guo, Shimeng1; Yin, Jianpeng3; Zhao, Tingting4; Ge, Xiu1; Gu, Min1; Xie, Xin1,2,3,4; Nan, Fajun1,2,3
刊名BIOORGANIC CHEMISTRY
出版日期2024-03-01
卷号144页码:18
关键词Type 2 Diabetes TGR5 agonist Betulinic acid Gut-restricted Gallbladder-filling effects Kinetophores
ISSN号0045-2068
DOI10.1016/j.bioorg.2024.107132
通讯作者Xie, Xin(xxie@simm.ac.cn) ; Nan, Fajun(fjnan@simm.ac.cn)
英文摘要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 TGR5H88Y mice, confirming that gut-restricted agonism of TGR5 is a viable strategy to alleviate systemic target-related effects.
WOS关键词BILE-ACIDS ; URSODEOXYCHOLIC ACID ; RECEPTOR ANTAGONIST ; PHYSIOLOGY
资助项目National Natural Science Foundation of China[82030109] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82330113] ; National Natural Science Foundation of China[82003572] ; Shanghai Commission of Science and Technology[19140903900]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:001166467100001
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/309605]  
专题新药研究国家重点实验室
通讯作者Xie, Xin; Nan, Fajun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
推荐引用方式
GB/T 7714		 Zhuo, Ning,Yun, Ying,Zhang, Chenlu,et al. Discovery of betulinic acid derivatives as gut-restricted TGR5 agonists: Balancing the potency and physicochemical properties[J]. BIOORGANIC CHEMISTRY,2024,144:18.
APA Zhuo, Ning.,Yun, Ying.,Zhang, Chenlu.,Guo, Shimeng.,Yin, Jianpeng.,...&Nan, Fajun.(2024).Discovery of betulinic acid derivatives as gut-restricted TGR5 agonists: Balancing the potency and physicochemical properties.BIOORGANIC CHEMISTRY,144,18.
MLA Zhuo, Ning,et al."Discovery of betulinic acid derivatives as gut-restricted TGR5 agonists: Balancing the potency and physicochemical properties".BIOORGANIC CHEMISTRY 144(2024):18.

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来源：上海药物研究所

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