title: Design, synthesis, and pharmacological evaluation of highly potent and selective dipeptidyl peptidase-4 inhibitors.
abstract: The optimization of a series of fused β-homophenylalanine inhibitors of dipeptidyl peptidase-4 (DPP-4) is described. Modification on the P2-binding moiety of 6 (IC50 = 10 nM) led to the discovery of β-homophenylalanine derivatives containing pyrrolidin-2-ylmethyl amides. The introduction of a sulfamine in the meta position of the phenyl ring improved the potency against DPP-4 (6-12-fold increase). Compound 14k showed DPP-4 inhibitory activity with an IC50 value of 0.87 nM. Meanwhile, in vivo experiments exhibited that 14h had an efficiency comparable to sitagliptin at the dose of 10 mg/kg.
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Tao
authors: T
authors: Jiang
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Yuren
authors: Y
authors: Zhou
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Jianming
authors: J
authors: Zhu
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Zhuxi
authors: Z
authors: Chen
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Peng
authors: P
authors: Sun
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Qiang
authors: Q
authors: Zhang
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Zhen
authors: Z
authors: Wang
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Qiang
authors: Q
authors: Shao
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Xiangrui
authors: X
authors: Jiang
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Bo
authors: B
authors: Li
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Heyao
authors: H
authors: Wang
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Weiliang
authors: W
authors: Zhu
authors: Drug Discovery and Design Center, Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Jingshan
authors: J
authors: Shen
mesh_terms: D000613:Aminobutyrates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D018938:Caco-2 Cells; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D000068900:Sitagliptin Phosphate / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000613:Aminobutyrates; D015415:Biomarkers; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; C014328:2-amino-4-phenylbutyric acid; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000068900:Sitagliptin Phosphate
keywords: DPP-4; Drug design; Inhibitors; P2-binding moiety; β-Homophenylalanine