Synthesis and biological evaluation of novel urea- and guanidine-based derivatives for the treatment of obesity-related hepatic steatosis.
Leptin, the product of the obese gene, is an adipocyte-secreted protein hormone playing a key role in the progression of obesity and hepatic steatosis. In this study, 28 novel (thio)urea and guanidine-based analogues have been synthesized and N-(1-(4-(3-(2-chloroethyl)ureido)benzyl)piperidin-4-yl)-3-(trifluoromethyl) benzamide (7i) was found to be a potent regulator of leptin expression in 3T3-L1 adipocytes. Treatment with 7i at a dose of 50 mg/kg/day for 35 days reduced the body weight and liver weight of diet-induced obesity mice by 13.5% and 18.4%, respectively, while also improving the serum levels of triglyceride, total cholesterol, leptin, adiponectin, LDL-c, HDL-c. Hematoxylin-eosin (H&amp;E) and Oil Red O staining also confirmed that 7i ameliorated fat deposition in liver tissue and restricted the size of adipocytes in obesity-related fatty liver disease.
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China. liang_11@hsit.edu.cn.
Xiaolin
X
Liang
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China. pei_2014@hsit.edu.cn.
Heying
H
Pei
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China. liang_m@scu.edu.cn.
Liang
L
Ma
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China. ran_2014@hsit.edu.cn.
Yan
Y
Ran
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China. chen_2011@hsit.edu.cn.
Jinying
J
Chen
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China. wang_gc12@hsit.edu.cn.
Guangcheng
G
Wang
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China. chen_2011@hsit.edu.cn.
Lijuan
L
Chen
D041721:3T3-L1 Cells; D000818:Animals; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects; D019791:Guanidine / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D020738:Leptin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D009765:Obesity / Q000150:complications / Q000188:drug therapy*; D014508:Urea / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry
D020738:Leptin; D014508:Urea; D019791:Guanidine