Design of potent dipeptidyl peptidase IV (DPP-4) inhibitors by employing a strategy to form a salt bridge with Lys554

[Display omitted] We report a design strategy to obtain potent DPP-4 inhibitors by incorporating salt bridge formation with Lys554 in the S1′ pocket. By applying the strategy to the previously identified templates, quinoline 4 and pyridines 16a, 16b, and 17 have been identified as subnanomolar or na...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-08, Vol.27 (15), p.3565-3571
Main Authors: Maezaki, Hironobu, Tawada, Michiko, Yamashita, Tohru, Banno, Yoshihiro, Miyamoto, Yasufumi, Yamamoto, Yoshio, Ikedo, Koji, Kosaka, Takuo, Tsubotani, Shigetoshi, Tani, Akiyoshi, Asakawa, Tomoko, Suzuki, Nobuhiro, Oi, Satoru
Format: Article
Language:English
Subjects:
Animals
Diabetes Mellitus, Type 2 - drug therapy
Dipeptidyl Peptidase 4 - chemistry
Dipeptidyl Peptidase 4 - metabolism
Dipeptidyl peptidase IV (DPP-4)
Dipeptidyl-Peptidase IV Inhibitors - chemistry
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
Drug Design
Female
Glucose Tolerance Test
Humans
Molecular Docking Simulation
Pyridine-based inhibitors
Pyridines - chemistry
Pyridines - pharmacology
Quinoline-based inhibitors
Quinolines - chemistry
Quinolines - pharmacology
Rats, Sprague-Dawley
Rats, Wistar
S1′ pocket
Salt bridge formation
Structure-Activity Relationship
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Summary:[Display omitted] We report a design strategy to obtain potent DPP-4 inhibitors by incorporating salt bridge formation with Lys554 in the S1′ pocket. By applying the strategy to the previously identified templates, quinoline 4 and pyridines 16a, 16b, and 17 have been identified as subnanomolar or nanomolar inhibitors of human DPP-4. Docking studies suggested that a hydrophobic interaction with Tyr547 as well as the salt bridge interaction is important for the extremely high potency. The design strategy would be useful to explore a novel design for DPP-4 inhibitors having a distinct structure with a unique binding mode.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.05.048