1. Design of potent dipeptidyl peptidase IV (DPP-4) inhibitors by employing a strategy to form a salt bridge with Lys554
- Author
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Akiyoshi Tani, Yoshio Yamamoto, Takuo Kosaka, Tomoko Asakawa, Yasufumi Miyamoto, Tohru Yamashita, Yoshihiro Banno, Shigetoshi Tsubotani, Satoru Oi, Michiko Tawada, Hironobu Maezaki, Nobuhiro Suzuki, and Koji Ikedo
- Subjects
0301 basic medicine ,Pyridines ,Stereochemistry ,Dipeptidyl Peptidase 4 ,Clinical Biochemistry ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,Dipeptidyl peptidase ,Rats, Sprague-Dawley ,Hydrophobic effect ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Humans ,Rats, Wistar ,Molecular Biology ,Dipeptidyl-Peptidase IV Inhibitors ,DPP-4 Inhibitors ,Organic Chemistry ,Quinoline ,Glucose Tolerance Test ,Combinatorial chemistry ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,chemistry ,Docking (molecular) ,Drug Design ,Quinolines ,Molecular Medicine ,Female - Abstract
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.
- Published
- 2017