Discovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio
文献类型：期刊论文
| 作者 | Tang, Xuehang2,3; Ning, Mengmeng3 ; Ye, Yangliang3; Gu, Yipei3; Yan, Hongyi1,3; Leng, Ying3,4; Shen, Jianhua3,4
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2021-08-01 |
| 卷号 | 43页码:13 |
| 关键词 | FXR agonist Ketoxime ether Target genes Liver blood ratio Systemic activation |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2021.116280 |
| 通讯作者 | Leng, Ying(yleng@simm.ac.cn) ; Shen, Jianhua(jhshen@simm.ac.cn) |
| 英文摘要 | The farnesoid X receptor (FXR) is a promising therapeutic target for nonalcoholic steatohepatitis (NASH) and other bile acid related diseases because it plays a critical role in fibrosis, inflammation and bile acid homeostasis. Obeticholic acid (OCA), a FXR agonist which was synthesized from chenodeoxycholic acid, showed desirable curative effects in clinical trials. However, the pruritus which was the main side effect of OCA limited its further applications in NASH. Although pruritus was also observed in the clinical trials of non-steroidal FXR agonists, the proportion of patients with pruritus was much smaller than that of OCA. Thus, we decided to develop non steroidal FXR agonists and discovered a series of novel FXR agonists which were synthesized from GW4064 by replacing the stilbene group with ketoxime ether. Encouragingly, in the following biological tests, our target compounds 13j and 13z not only showed potent FXR agonistic activities in vitro, but also effectively promoted the expression of target genes in vivo. More importantly, in the pharmacokinetic experiments, compounds 13j and 13z displayed high liver/blood ratio characteristics which were helpful to reduce the potential side effects which were caused by prolonged systemic activation of FXR. In summary, our compounds were good choices for the development of non-steroidal FXR agonists and were deserved further investigation. |
| WOS关键词 | TRANS-STILBENE OXIDE ; BILE-ACIDS ; NUCLEAR RECEPTOR ; IDENTIFICATION ; CILOFEXOR ; SERIES ; LIVER ; ITCH |
| 资助项目 | Science and Technology Commission of Shanghai Municipality (STCSM)[19431900900] ; National Natural Science Foun-dation of China[82073683] ; State Key laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM2103ZZ04] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000678339600010 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/298265]  |
| 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.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Peoples R China 2.Nanchang Univ, Sch Pharm, Nanchang 330000, Jiangxi, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Sch Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tang, Xuehang,Ning, Mengmeng,Ye, Yangliang,et al. Discovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2021,43:13. |
| APA | Tang, Xuehang.,Ning, Mengmeng.,Ye, Yangliang.,Gu, Yipei.,Yan, Hongyi.,...&Shen, Jianhua.(2021).Discovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio.BIOORGANIC & MEDICINAL CHEMISTRY,43,13. |
| MLA | Tang, Xuehang,et al."Discovery of novel ketoxime ether derivatives with potent FXR agonistic activity, oral effectiveness and high liver/blood ratio".BIOORGANIC & MEDICINAL CHEMISTRY 43(2021):13. |
入库方式： OAI收割
来源：上海药物研究所
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