Synthesis and Biological Evaluation of Novel Urea- and Guanidine-Based Derivatives for the Treatment of Obesity-Related Hepatic Steatosis
Xiaolin Liang,
Heying Pei,
Liang Ma,
Yan Ran,
Jinying Chen,
Guangcheng Wang,
Lijuan Chen
Affiliations
Xiaolin Liang
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China
Heying Pei
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China
Liang Ma
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China
Yan Ran
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China
Jinying Chen
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China
Guangcheng Wang
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China
Lijuan Chen
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Gaopeng Street, Chengdu 610041, China
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&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.
