靶向THRβ的新化合物YWS01125对NASH小鼠的治疗作用  

Therapeutic effect of a new compound YWS01125 targeting THRβon NASH mice

作　　者：程昊 刘波 李妍[1,2,3,4] 刘娜 牟艳玲[1,2,3,4] CHENG Hao;LIU Bo;LI Yan;LIU Na;MU Yanling(School of Pharmacy and Pharmaceutical Sciences,Shandong First Medical University,Jinan 250117,China;Institute of Materia Medica,Shandong Academy of Medical Sciences,Jinan 250062,China;Key Laboratory for Biotech-Drugs Ministry of Health,Jinan 250062,China;Key Laboratory for Rare&Uncommon Diseases of Shandong Province,Jinan 250062,China)

机构地区：[1]山东第一医科大学药学与制药科学学院,山东济南250117 [2]山东省医学科学院药物研究所,山东济南250062 [3]国家卫生部生物技术药物重点实验室,山东济南250062 [4]山东省罕少见病重点实验室,山东济南250062

出　　处：《药学研究》2022年第4期211-216,共6页Journal of Pharmaceutical Research

基　　金：山东省重大科技创新工程项目(No.2019JZZY020902)。

摘　　要：目的研究特异性靶向甲状腺激素β受体(THRβ)的哒嗪酮类化合物YWS01125对非酒精性脂肪肝(NASH)小鼠的治疗作用。方法采用多肽募集实验验证YWS01125甲状腺激素β受体选择性及细胞存活率,高脂饮食结合四氯化碳法建立慢性肝损伤小鼠模型,造模成功后随机将小鼠分为模型组、阳性药(MGL-3196)对照组以及YWS01125不同剂量组(10、20、40 mg·kg^(-1))。MGL-3196及YWS01125连续给药30 d,于末次给药后24 h进行B超检查、血生化相关指标检测及肝组织病理切片观察。结果YWS01125和T3的存活率分别为110.3%±11.5%和110.3%±11.5%,说明YWS01125对L929细胞系无毒性作用。与模型组比较,YWS01125不同剂量组均能显著降低血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)水平(P≤0.01),不同程度降低非酒精性脂肪肝小鼠肝脏指数,以中高剂量组效果更为显著(P≤0.01)。结论YWS01125(20和40 mg·kg^(-1))特异性靶向激活甲状腺激素β受体,对造模成功小鼠肝损伤具有较好的治疗作用,有望研发成治疗非酒精性脂肪肝的创新药物。Objective To study the therapeutic effect of pyrazinone YWS01125,which specifically targets THRβ,on nonalcoholic fatty liver(NASH)mice.Methods The selectivity and cell viability of YWS01125 THRβwere verified by peptide recruitment experiment.The mouse model of chronic liver injury was established by high fat diet combined with carbon tetrachloride method.Then,mice were randomly divided into modeling group,positive drug(MGL-3196)control group and YWS01125 groups with different doses(10,20,40 mg·kg^(-1)).MGL-3196 and YWS01125 were administered continuously for 30 d.B-ultrasonography,blood biochemical indicators and liver biopsy were performed 24 h after the last administration.Results The survival rates of YWS01125 and T3 were 110.3%±11.5%and 110.3%±11.5%,respectively,indicating that YWS01125 had no toxic effect on L929 cell line.Compared with the modeling group,YWS01125 groups could significantly reduce the serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels(P≤0.01),reduce liver index of NASH mice to varying degrees and the effect of YWS01125 group was more significant(P≤0.01).Conclusion YWS01125(20,40 mg·kg^(-1))specific targeted activation of THRβhas a good therapeutic effect on liver injury in mice successfully modeled,which is expected to be developed into an innovative drug for NASH.

关 键 词：非酒精性脂肪性肝病 动物模型 哒嗪酮类化合物 甲状腺激素β受体 治疗作用 

分 类 号：R965[医药卫生—药理学]