Design and exploration of gut-restricted bifunctional molecule with TGR5 agonistic and DPP4 inhibitory effects for treating ulcerative colitis
文献类型：期刊论文
| 作者 | Han, Fanghui1,2; Ning, Mengmeng1 ; Wang, Kai1; Gu, Yipei1; Qu, Hui1; Leng, Ying1; Shen, Jianhua1
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2022-11-15 |
| 卷号 | 242页码:114697 |
| ISSN号 | 0223-5234 |
| 关键词 | Bifunctional molecule Gut-restricted Ulcerative colitis TGR5 DPP4 |
| DOI | 10.1016/j.ejmech.2022.114697 |
| 文献子类 | Article |
| 英文摘要 | Ulcerative colitis (UC) is a gastrointestinal disease with complex etiology, and the shortage of the treatment further intensifies the need to discover new therapies based on novel mechanisms and strategies. TGR5 and DPP4 are beneficial to treat UC through multiple mechanisms, notably increasing GLP-2 levels by promoting secretion and inhibiting degradation respectively. However, some unwanted systemic effects caused by systemic exposure hinder development, especially the gallbladder-filling effects. Herein, we firstly reported a series of high-potency gut-restricted TGR5-DPP4 bifunctional molecules by gut-restriction and multitarget strategies to utilize the positive impacts of TGR5 and DPP4 on UC and avoid unwanted systemic effects. In particularly, racemic com-pound 15, a high-potency TGR5-DPP4 bifunctional molecule, showed favorable intestinal distribution, preferable efficacy in mice colitis model and good gallbladder safety. Therefore, the feasibility of gut-restricted TGR5-DPP4 bifunctional molecule was confirmed for the treatment UC, providing a new insight into the development of anti-UC drugs. |
| WOS关键词 | DIPEPTIDYL-PEPTIDASE-IV ; BILE-ACID RECEPTOR ; ACTIVATION ; DISCOVERY ; PROGRESS ; LIGANDS ; PATHWAY ; GPBAR1 ; MICE |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| WOS记录号 | WOS:000850132300004 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309308]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Leng, Ying; Shen, Jianhua |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Han, Fanghui,Ning, Mengmeng,Wang, Kai,et al. Design and exploration of gut-restricted bifunctional molecule with TGR5 agonistic and DPP4 inhibitory effects for treating ulcerative colitis[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,242:114697. |
| APA | Han, Fanghui.,Ning, Mengmeng.,Wang, Kai.,Gu, Yipei.,Qu, Hui.,...&Shen, Jianhua.(2022).Design and exploration of gut-restricted bifunctional molecule with TGR5 agonistic and DPP4 inhibitory effects for treating ulcerative colitis.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,242,114697. |
| MLA | Han, Fanghui,et al."Design and exploration of gut-restricted bifunctional molecule with TGR5 agonistic and DPP4 inhibitory effects for treating ulcerative colitis".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 242(2022):114697. |
入库方式： OAI收割
来源：上海药物研究所
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