title: Scaffold-based design of xanthine as highly potent inhibitors of DPP-IV for improving glucose homeostasis in DIO mice.
abstract: Diabetes mellitus, commonly characterized by hyperglycemia, is a group of metabolic diseases. Some oral anti-diabetic drugs show poor tolerability during chronic treatment, and associate with undesired side effects. Recent advances in the understanding of physiological functions of incretins and their degrading enzyme dipeptidyl peptidase DPP-IV have led to the discovery of DPP-IV inhibitors as a new class of oral anti-diabetic drugs. Several DPP-IV inhibitors have different chemical structures of which the xanthine scaffold has specific advantages. Combining previous work with the research strategy of pharmacophore hybridization, we retained this scaffold and synthesized a new series of amino-alcohol or diamino-modified xanthine compounds. Some xanthines exhibited submicromolar inhibitory activities against DPP-IV. The most potent compound 40 [Formula: see text] exhibits a good in vivo efficacy in reducing glucose excursion at a single dose and a better chronic effect in reducing body weight than metformin in DIO mice. In other words, the combined effect improved the pathological state of DIO mice.
authors: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors: Yan
authors: Y
authors: Ran
authors: Heying
authors: H
authors: Pei
authors: Caifeng
authors: C
authors: Xie
authors: Liang
authors: L
authors: Ma
authors: Yuzhe
authors: Y
authors: Wu
authors: Kai
authors: K
authors: Lei
authors: Mingfeng
authors: M
authors: Shao
authors: Minghai
authors: M
authors: Tang
authors: Mingli
authors: M
authors: Xiang
authors: Aihua
authors: A
authors: Peng
authors: Yuquan
authors: Y
authors: Wei
authors: Lijuan
authors: L
authors: Chen
mesh_terms: D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D051379:Mice; D013997:Time Factors; D019820:Xanthine / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D019820:Xanthine; D018819:Dipeptidyl Peptidase 4; D005947:Glucose