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Discovering Novel α‐aminoacyl‐Containing Proline Derivatives with Potent and Selective Inhibitory Activity Against Dipeptidyl Peptidase IV: Design, Synthesis, Biological Evaluation, and Molecular Modeling
Author(s) -
Zhang Xiaodong,
Wang Jiang,
Su Mingbo,
Li Zeng,
Li Jingya,
Li Jia,
Liu Hong
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2012.01438.x
Subject(s) - dipeptidyl peptidase , chemistry , dipeptidyl peptidase 4 , enzyme , nuclear magnetic resonance spectroscopy , proline , molecular model , biochemistry , stereochemistry , combinatorial chemistry , amino acid , biology , type 2 diabetes , diabetes mellitus , endocrinology
On the basis of the enzyme‐binding features of known potent inhibitors of dipeptidyl peptidase IV, novel α‐aminoacyl‐containing proline analogs ( 8Aa–8Ak , 8Ba–8Bj , 8Ca–8Ck , and 8Da–8Di ) with the S configuration were designed, synthesized, and their activity profiled. Their structural features were determined by nuclear magnetic resonance (NMR) spectroscopy, low‐ and high‐resolution mass spectroscopy. Five compounds ( 8Aa , 8Aj , 8Ch , 8Ck , and 8Dc ) were shown to have promising inhibitory activities against dipeptidyl peptidase IV. Two of them, compounds 8Aa and 8Aj inhibited dipeptidyl peptidase IV with IC 50 values of 4.56 and 8.4 μ m , respectively, and displayed no inhibition at other dipeptidyl peptidase IV. The possible binding modes of compounds 6 , 7 , 8Aa , and 8Aj with dipeptidyl peptidase IV were also explored by molecular docking simulation. This study provides promising new templates for the further development of antidiabetic agents.