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Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones

文献类型：期刊论文

作者Han, Fanghui1,6; Zhao, Tingting5; Zhang, Yanglong1,6; Yun, Ying4; Xu, Yuanyuan5; Guo, Shimeng6; Zhong, Yongqing3,6; Xie, Xin2,4,5,6; Shen, Jianhua5,6
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-01-15
卷号264页码:16
关键词SSTR5 antagonist Gallbladder emptying Cholesterol gallstones
ISSN号0223-5234
DOI10.1016/j.ejmech.2023.116017
通讯作者Xie, Xin(xxie@simm.ac.cn) ; Shen, Jianhua(jhshen@simm.ac.cn)
英文摘要The shortage of cholesterol gallstones treatment intensifies the need to discover of effective small molecule drugs. Clinical follow-up and studies have found that activation of somatostatin receptor subtype 5 (SSTR5) reduce gallbladder contraction and thus increase the risk of cholesterol gallstones, implying that antagonizing SSTR5 may promote gallbladder emptying and reduce the formation of gallstones. Herein, we discovered novel SSTR5 antagonists and firstly investigated its effects on cholesterol gallstone. From loperamide, a reported seed structure with micromole activity, we identified optimal compound 23 as an SSTR5 antagonist exhibiting singledigit nanomolar potency, low hERG inhibition and oral availability. Further in vivo evaluation revealed that 23 significantly promoted gallbladder emptying. Moreover, in a mouse cholesterol gallstone model, 23 (3 mg/kg) effectively reduced the cholesterol gallstones formation, showing better efficacy than the clinical first-line drug UDCA (60 mg/kg), providing a new insight into the development of anti-gallstone drugs.
WOS关键词GALLBLADDER MOTOR FUNCTION ; SMOOTH-MUSCLE FUNCTION ; INTESTINAL-ABSORPTION ; INSULIN-SECRETION ; DISEASE ; POTENT ; LIVER
资助项目National Natural Science Foundation of China, NSFC[82273764] ; National Natural Science Foundation of China, NSFC[82121005] ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001134387100001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/308541]  
专题新药研究国家重点实验室
通讯作者Xie, Xin; Shen, Jianhua
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Nanchang Univ, Sch Pharm, Nanchang 330000, Jiangxi, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Han, Fanghui,Zhao, Tingting,Zhang, Yanglong,et al. Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,264:16.
APA Han, Fanghui.,Zhao, Tingting.,Zhang, Yanglong.,Yun, Ying.,Xu, Yuanyuan.,...&Shen, Jianhua.(2024).Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,264,16.
MLA Han, Fanghui,et al."Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 264(2024):16.

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来源：上海药物研究所

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