title: Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin.
abstract: Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. The most promising compound 2h (IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that of alogliptin (IC50 = 2.63 nM) and linagliptin (IC50 = 0.77 nM), respectively. Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus was selected for further biological evaluation, including oral glucose tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute toxicity and hERG inhibition. The assay results showed that 2h displayed significant in vivo glucose-lowering effect and low risk of toxicity. Further studies are expected to confirm 2h as a potential drug candidate for the treatment of type 2 diabetes.
authors.affiliation: State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
authors.forename: Zeng-Wei
authors.initials: ZW
authors.lastname: Lai
authors.affiliation: State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
authors.forename: Lingyi
authors.initials: L
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China. Electronic address: wxagj@126.com.
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Wen
authors.affiliation: State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China. Electronic address: hbsun2000@yahoo.com.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Sun
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D000069476:Linagliptin; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D011687:Purines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D014498:Uracil; D018819:Dipeptidyl Peptidase 4; C520853:alogliptin
keywords: Alogliptin; DPP-4 inhibitors; Diabetes; Hybrid compound design; Linagliptin