Synthesis and Biological Evaluation of 5-Benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione Derivatives for the Treatment of Obesity-Related Nonalcoholic Fatty Liver Disease
| Autor: | Li Huang, Aihua Peng, Yuquan Wei, Mingli Xiang, Juan Liu, Xiaolin Liang, Huijun Lai, Caifeng Xie, Yan Ran, Liang Ma, Heying Pei, Jinying Chen, Yun Sang, Lijuan Chen |
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| Rok vydání: | 2012 |
| Předmět: |
Leptin
Male medicine.medical_specialty medicine.medical_treatment Adipose tissue Diet High-Fat Rats Sprague-Dawley Mice chemistry.chemical_compound Piperidines Non-alcoholic Fatty Liver Disease Oral administration 3T3-L1 Cells Adipocyte Internal medicine Drug Discovery Nonalcoholic fatty liver disease Adipocytes medicine Animals Humans Insulin Tissue Distribution Obesity Rats Wistar Triglycerides Adiponectin Body Weight Alanine Transaminase Hep G2 Cells Glucose Tolerance Test medicine.disease Rats Fatty Liver Mice Inbred C57BL Disease Models Animal Cholesterol Glucose Pyrimidines Endocrinology chemistry Barbiturates Molecular Medicine Female Insulin Resistance |
| Zdroj: | Journal of Medicinal Chemistry. 55:9958-9972 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm301164y |
| Popis: | Nonalcoholic fatty liver disease (NAFLD), one of chronic liver diseases, seems to be rising as the obesity epidemic continues. In this study, 54 novel (thio)barbituric acid derivatives have been synthesized and evaluated for pharmacological activity. 7h exhibited potent glucose-lowering effects on insulin-resistant HepG2 cells and regulated adiponectin and leptin expression in 3T3-L1 adipocytes. Oral administration of 7h at 25 mg kg(-1) day(-1) for 4 weeks improved the progression of high fat diet-induced NAFLD by reducing the weight of body, liver, and fat, as well as modulating serum levels of fasting glucose, insulin, triglycerides, LDL-c, ALT, adiponectin and hepatic contents of triglycerides, total cholesterol. HE stainings revealed that 7h blocked fat deposition in liver and the increase of adipocyte number and size in adipose tissues from NAFLD. Furthermore, treatment with 7h alleviated the obese clinical symptoms, recovered serum biomarkers to appropriate ranges, and improved glucose tolerance by OGTT and IGTT in DIO mice. |
| Databáze: | OpenAIRE |
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