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

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3565-3571. doi: 10.1016/j.bmcl.2017.05.048. Epub 2017 May 17.


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.

Keywords: Dipeptidyl peptidase IV (DPP-4); Pyridine-based inhibitors; Quinoline-based inhibitors; S1′ pocket; Salt bridge formation.

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dipeptidyl Peptidase 4 / chemistry
  • Dipeptidyl Peptidase 4 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Drug Design
  • Female
  • Glucose Tolerance Test
  • Humans
  • Molecular Docking Simulation
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Quinolines / chemistry*
  • Quinolines / pharmacology*
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Structure-Activity Relationship


  • Dipeptidyl-Peptidase IV Inhibitors
  • Pyridines
  • Quinolines
  • quinoline
  • Dipeptidyl Peptidase 4