中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Discovery of pyridazinone derivatives bearing tetrahydroimidazo[1,2- a ] pyrazine scaffold as potent inhibitors of transient receptor potential canonical 5 to ameliorate hypertension-induced renal injury in rats

文献类型：期刊论文

作者Xu, Yuanyuan3,4; Ren, Younan1,2; Zhang, Jie1,2; Niu, Bo1,2; Liu, Mengru1,2; Xu, Tifei3; Zhang, Xian1,2; Shen, Jianhua3,4; Wang, Kai3; Cao, Zhengyu1,2
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-09-05
卷号275页码:18
关键词Pyridazinone Tetrahydroimidazo[1,2-a]pyrazine Transient receptor potential canonical 5 Chronic kidney disease Focal segmental glomerulosclerosis
ISSN号0223-5234
DOI10.1016/j.ejmech.2024.116565
通讯作者Wang, Kai(kwang@simm.ac.cn) ; Cao, Zhengyu(zcao@cpu.edu.cn)
英文摘要Transient receptor potential canonical 5 (TRPC5) is a calcium -permeable non -selective cation channel involved in various pathophysiological processes, including renal injury. Recently, GFB-887, an investigational pyridazinone TRPC5 inhibitor, demonstrated significant therapeutic potential in a Phase II clinical trial for focal segmental glomerulosclerosis (FSGS), a rare and severe form of chronic kidney disease (CKD). In the current study, based on the structure of GFB-887, we conducted extensive structural modification to explore novel TRPC5 inhibitors with desirable drug -like properties and robust nephroprotective efficacy. A series of pyridazinone derivatives featuring a novel tetrahydroimidazo[1,2- a ]pyrazine scaffold were synthesized and their activities were evaluated in HEK-293 cells stably expressing TRPC5 using a fluorescence -based Ca 2 + mobilization assay. Among these compounds, compound 12 is turned out to be a potent TRPC5 inhibitor with apparent affinity comparable to the parent compound GBF-887. Compound 12 is highly selective on TRPC4/5 over TRPC3/ 6/7 and hERG channels, along with acceptable pharmacokinetic properties and a favorable safety profile. More importantly, in a rat model of hypertension -induced renal injury, oral administration of compound 12 (10 mg/ kg, BID) efficaciously reduced mean blood pressure, inhibited proteinuria, and protected podocyte damage. These findings further confirmed the potential of TRPC5 inhibitors on the CKD treatment and provided compound 12 to be a valuable tool for exploring TRPC4/5 pathophysiology.
WOS关键词FOCAL SEGMENTAL GLOMERULOSCLEROSIS ; RAC1 ACTIVATION ; KIDNEY-DISEASE ; CHANNEL ; REACTIVITY
资助项目National Natural Science Foundation of China[82373929] ; National Natural Science Foundation of China[81972960] ; National Natural Science Foundation of China[82273764] ; Tibet Autonomous Region Science and Technology Plan Project Key Project[XZ202301ZY0014G] ; The Double First-Class University Project[CPU2022QZ30] ; Youth Innovation Promotion Associa- tion, Chinese Academy of Sciences[2019282]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001256953600001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/312029]  
专题新药研究国家重点实验室
通讯作者Wang, Kai; Cao, Zhengyu
作者单位1.China Pharmaceut Univ, Sch Tradit Chinese Pharm, Jiangsu Prov Key Lab TCM Evaluat & Translat Dev, Nanjing 211198, Jiangsu, Peoples R China
2.China Pharmaceut Univ, Sch Tradit Chinese Pharm, State Key Lab Nat Med, Nanjing 211198, Jiangsu, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, 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		 Xu, Yuanyuan,Ren, Younan,Zhang, Jie,et al. Discovery of pyridazinone derivatives bearing tetrahydroimidazo[1,2- a ] pyrazine scaffold as potent inhibitors of transient receptor potential canonical 5 to ameliorate hypertension-induced renal injury in rats[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,275:18.
APA Xu, Yuanyuan.,Ren, Younan.,Zhang, Jie.,Niu, Bo.,Liu, Mengru.,...&Cao, Zhengyu.(2024).Discovery of pyridazinone derivatives bearing tetrahydroimidazo[1,2- a ] pyrazine scaffold as potent inhibitors of transient receptor potential canonical 5 to ameliorate hypertension-induced renal injury in rats.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,275,18.
MLA Xu, Yuanyuan,et al."Discovery of pyridazinone derivatives bearing tetrahydroimidazo[1,2- a ] pyrazine scaffold as potent inhibitors of transient receptor potential canonical 5 to ameliorate hypertension-induced renal injury in rats".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 275(2024):18.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。