title: Design, synthesis, and evaluation of a new class of noncyclic 1,3-dicarbonyl compounds as PPARalpha selective activators.
abstract: Lipid accumulation in nonadipose tissues is increasingly linked to the development of type 2 diabetes in obese individuals. We report here the design, synthesis, and evaluation of a series of novel PPARalpha selective activators containing 1,3-dicarbonyl moieties. Structure-activity relationship studies led to the identification of PPARalpha selective activators (compounds 10, 14, 17, 18, and 21) with stronger potency and efficacy to activate PPARalpha over PPARgamma and PPARdelta. Experiments in vivo showed that compounds 10, 14, and 17 had blood glucose lowering effect in diabetic db/db mouse model after two weeks oral dosing. The data strongly support further testing of these lead compounds in other relevant disease animal models to evaluate their potential therapeutic benefits.
authors.affiliation: Chipscreen Biosciences, Ltd, Research Institute of Tsinghua University, Suite C301, PO Box 28, Shenzhen 518057, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Li
authors.forename: Chenzhong
authors.initials: C
authors.lastname: Liao
authors.forename: Ben C B
authors.initials: BC
authors.lastname: Ko
authors.forename: Song
authors.initials: S
authors.lastname: Shan
authors.forename: Edith H Y
authors.initials: EH
authors.lastname: Tong
authors.forename: Zihui
authors.initials: Z
authors.lastname: Yin
authors.forename: Desi
authors.initials: D
authors.lastname: Pan
authors.forename: Vincent K W
authors.initials: VK
authors.lastname: Wong
authors.forename: Leming
authors.initials: L
authors.lastname: Shi
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Ning
authors.forename: Weiming
authors.initials: W
authors.lastname: Hu
authors.forename: Jiaju
authors.initials: J
authors.lastname: Zhou
authors.forename: Stephen S M
authors.initials: SS
authors.lastname: Chung
authors.forename: Xian-Ping
authors.initials: XP
authors.lastname: Lu
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000284:Administration, Oral; D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004195:Disease Models, Animal; D015195:Drug Design; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D050356:Lipid Metabolism; D051379:Mice; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000447:Aldehydes; D001786:Blood Glucose; D000960:Hypolipidemic Agents; D007659:Ketones; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma