title: 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.
abstract: 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. H&E 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.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School,  Sichuan University , Keyuan Road 4, Gaopeng Street, Chengdu 610041, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Caifeng
authors.initials: C
authors.lastname: Xie
authors.forename: Yan
authors.initials: Y
authors.lastname: Ran
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Liang
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: Heying
authors.initials: H
authors.lastname: Pei
authors.forename: Jinying
authors.initials: J
authors.lastname: Chen
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Sang
authors.forename: Huijun
authors.initials: H
authors.lastname: Lai
authors.forename: Aihua
authors.initials: A
authors.lastname: Peng
authors.forename: Mingli
authors.initials: M
authors.lastname: Xiang
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects*; D052242:Adiponectin / Q000378:metabolism; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001463:Barbiturates / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000209:etiology*; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014018:Tissue Distribution; D014280:Triglycerides / Q000378:metabolism
chemical_list: C577950:5-(4-(1-(4-(difluoromethoxy)benzoyl)piperidin-4-yloxy)benzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione; D052242:Adiponectin; D001463:Barbiturates; D007328:Insulin; D020738:Leptin; D010880:Piperidines; D011743:Pyrimidines; D014280:Triglycerides; D002784:Cholesterol; D000410:Alanine Transaminase; D005947:Glucose