title: Discovery of novel xanthine compounds targeting DPP-IV and GPR119 as anti-diabetic agents.
abstract: A series of xanthine derivatives as potent dual ligands targeting DPP-IV and GPR119 was discovered through an approach of the merged pharmacophores of GPR119 agonists and DPP-IV inhibitor linagliptin. Systematic optimization of general structure 5 led to the identification of compound 20i with selective DPP-IV inhibition, good GPR119 agonism activity and favorable metabolic stability. Docking study was performed to elucidate the potent DPP-IV inhibition of 20i. Compound 20i may serve as a tool compound for further design of anti-diabetic drugs targeting both DPP-IV and GPR119.
authors: State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Gang
authors: G
authors: Li
authors: State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Yi
authors: Y
authors: Huan
authors: State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Baokun
authors: B
authors: Yuan
authors: State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Jin
authors: J
authors: Wang
authors: State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Qian
authors: Q
authors: Jiang
authors: State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China.
authors: Ziyun
authors: Z
authors: Lin
authors: State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: shenzhf@imm.ac.cn.
authors: Zhufang
authors: Z
authors: Shen
authors: State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address: joyce@imm.ac.cn.
authors: Haihong
authors: H
authors: Huang
mesh_terms: D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055808:Drug Discovery; D004355:Drug Stability; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship; D019820:Xanthine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D019820:Xanthine; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
keywords: DPP-IV; Dual ligands; GPR119; Merged pharmacophores; Xanthine derivatives