Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease
文献类型：期刊论文
| 作者 | Li, Yuan6; Xu, Tingting5; Zhao, Yue5; Zhang, Hui5; Liu, Zesheng5; Wang, Hao6; Huang, Chaoying4; Shu, Zhihao6; Gao, Lixin6; Xie, Rongrong6 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2024-03-28 |
| 卷号 | 67期号:7页码:5642-5661 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.3c02304 |
| 通讯作者 | Sun, Yili(yilisun@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhou, Yu(zhouyu@simm.ac.cn) |
| 英文摘要 | Inflammatory bowel disease (IBD) is a multifactorial chronic inflammation of the intestine and has become a global public health concern. A farnesoid X receptor (FXR) was recently reported to play a key role in hepatic-intestinal circulation, intestinal metabolism, immunity, and microbial regulation, and thus, it becomes a promising therapeutic target for IBD. In this study, we identified a series of nonbile acid FXR agonists, in which 33 novel compounds were designed and synthesized by the structure-based drug design strategy from our previously identified hit compound. Compound 33 exhibited a potent FXR agonistic activity, high intestinal distribution, good anti-inflammatory activity, and the ability to repair the colon epithelium in a DSS-induced acute enteritis model. Based on the results of RNA-seq analysis, we further investigated the therapeutic potential of the combination of compound 33 with 5-ASA. Overall, the results indicated that compound 33 is a promising drug candidate for IBD treatment. |
| WOS关键词 | MECHANISMS ; INHIBITORS ; THERAPY ; COLITIS ; CELLS |
| 资助项目 | Shanghai Science and Technology Development Foundation[19431901000] ; Shanghai Science and Technology Development Foundation[LX211010] ; Shanghai Science and Technology Development Funds[81903434] ; Shanghai Science and Technology Development Funds[81903682] ; Shanghai Science and Technology Development Funds[82103969] ; National Natural Science Foundation of China[tstp0648] ; Taishan Scholars Program |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001193728400001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/310508]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Sun, Yili; Liu, Hong; Li, Jia; Zhou, Yu |
| 作者单位 | 1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 3.Lingang Lab, Shanghai 201203, Peoples R China 4.Shanghai Univ, Sch Med, Shanghai 200444, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Yuan,Xu, Tingting,Zhao, Yue,et al. Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(7):5642-5661. |
| APA | Li, Yuan.,Xu, Tingting.,Zhao, Yue.,Zhang, Hui.,Liu, Zesheng.,...&Zhou, Yu.(2024).Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease.JOURNAL OF MEDICINAL CHEMISTRY,67(7),5642-5661. |
| MLA | Li, Yuan,et al."Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease".JOURNAL OF MEDICINAL CHEMISTRY 67.7(2024):5642-5661. |
入库方式： OAI收割
来源：上海药物研究所
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