title: Design, Synthesis and Biological Evaluation of Imidazo[1,2-a]pyridine Derivatives as Novel DPP-4 Inhibitors.
abstract: A new series of DPP-4 inhibitors with imidazo[1,2-a]pyridine scaffold were designed by exploiting scaffold hopping strategy and docking study. Based on docking binding model, structural modifications of 2-benzene ring and pyridine moieties of compound 5a led to the identification of compound 5d with 2, 4-dichlorophenyl group at the 2-position as a potent (IC50  = 0.13 μm), selective (DPP-8/DPP-4 = 215 and DPP-9/DPP-4 = 192) and in vivo efficacious DPP-4 inhibitor. Further, molecular docking revealed that compound 5d could retain key binding features of DPP-4 with the pyridine moiety of imidazo[1,2-a]pyridine ring providing an additional π-π interaction with Phe357 of DPP-4. Compound 5d might be a promising lead for further development of novel DPP-4 inhibitor treating T2DM.
authors: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors: Qing
authors: Q
authors: Li
authors: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors: Muxing
authors: M
authors: Zhou
authors: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors: Li
authors: L
authors: Han
authors: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors: Qing
authors: Q
authors: Cao
authors: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors: Xinning
authors: X
authors: Wang
authors: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors: LeiLei
authors: L
authors: Zhao
authors: Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing, 210009, China.
authors: Jinpei
authors: J
authors: Zhou
authors: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing, 210009, China.
authors: Huibin
authors: H
authors: Zhang
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D062105:Molecular Docking Simulation; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007093:Imidazoles; D011725:Pyridines; D018819:Dipeptidyl Peptidase 4
keywords: dipeptidyl peptidase-4 inhibitor; docking study; imidazo[1,2-a]pyridine derivatives; type 2 diabetes mellitus