title: Synthesis and lipid-lowering evaluation of 3-methyl-1H-purine-2,6-dione derivatives as potent and orally available anti-obesity agents.
abstract: Obesity accompanied with metabolic disorder is often complicated with a strong link of dyslipidemia and insulin resistance, whose indicator is the excess accumulation of triglycerides (TG) in cells. Consideration the idea of lipid-lowering and improving insulin resistance, 34 novel compounds by combination the xanthine scaffold with the chain of Rosiglitazone have been synthesized. Among them, several compounds showed efficiency on reducing TG in 3T3-L1 adipoctyes, and 11c exhibited the most optimal capacity in lipid-lowering and improving obese clinical symptoms in DIO mice. Furthermore, the hydrochloride of 11c (11c·HCl) showed excellent bioavailability, 58.94%, over 2 folds than that (28.03%) of 11c, and the anti-obesity effect of 11c·HCl at 50 mg/kg dose was better than that of Metformin at 150 mg/kg dose in DIO mice, almost reversed HFD to a normal level. Thus, 11c·HCl might be a potent and orally available anti-obesity agent via alleviating the obese clinical symptoms, body fat, improving serum parameters and insulin resistance and TG clearance in liver.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Linhong
authors.initials: L
authors.lastname: He
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Heying
authors.initials: H
authors.lastname: Pei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Pu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Jinying
authors.initials: J
authors.lastname: Chen
authors.affiliation: Guangdong ZhongSheng Pharmaceutical Co. Ltd., Dongguan 440100, Guangdong, PR China.
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ran
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Suhong
authors.initials: S
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Minghai
authors.initials: M
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Peng
authors.affiliation: Guangdong ZhongSheng Pharmaceutical Co. Ltd., Dongguan 440100, Guangdong, PR China.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Long
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: chenlijuan125@163.com.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D041721:3T3-L1 Cells; D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D059305:Diet, High-Fat; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D011687:Purines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D019440:Anti-Obesity Agents; D000960:Hypolipidemic Agents; D011687:Purines
keywords: Diet induced obesity; Insulin resistance; Lipid-lowering; Triglycerides