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Design of potent dipeptidyl peptidase IV (DPP-4) inhibitors by employing a strategy to form a salt bridge with Lys554.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Aug 01; Vol. 27 (15), pp. 3565-3571. Date of Electronic Publication: 2017 May 17. - Publication Year :
- 2017
-
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.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Diabetes Mellitus, Type 2 drug therapy
Dipeptidyl Peptidase 4 chemistry
Dipeptidyl Peptidase 4 metabolism
Drug Design
Female
Glucose Tolerance Test
Humans
Molecular Docking Simulation
Rats, Sprague-Dawley
Rats, Wistar
Structure-Activity Relationship
Dipeptidyl-Peptidase IV Inhibitors chemistry
Dipeptidyl-Peptidase IV Inhibitors pharmacology
Pyridines chemistry
Pyridines pharmacology
Quinolines chemistry
Quinolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 27
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 28579121
- Full Text :
- https://doi.org/10.1016/j.bmcl.2017.05.048