Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8

Bioorg Med Chem Lett. 2005 Feb 1;15(3):687-91. doi: 10.1016/j.bmcl.2004.11.023.


DPP8 is a prolyl dipeptidase homologous to DPP-IV, which is a drug target for Type II diabetes. The biological function of DPP8 is not known. To identify potent and selective chemical compounds against DPP8, we have synthesized a series of isoquinoline and isoindoline derivatives and have tested their inhibitory activity against DPP8, DPP-IV and DPP-II. Isoindoline derivatives were found to be more potent DPP8 inhibitors than isoquinoline derivatives. Isoindoline with a 1-(4,4'-difluor-benzhydryl)-piperazine group at the P2 site was observed to be a very potent DPP8 inhibitor, having an IC(50) value of 14nM with at least a 2500-fold selectivity over either DPP-IV or DPP-II. From SAR results, we speculate that the S1 site of DPP8 may be larger than that of DPP-IV, which would allow the accommodation of larger C-terminal residues, such as isoquinoline or isoindoline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Dipeptidases / antagonists & inhibitors*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / pharmacology*
  • Inhibitory Concentration 50
  • Isoquinolines / chemical synthesis
  • Isoquinolines / pharmacology
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Indoles
  • Isoquinolines
  • indoline
  • Dipeptidases
  • DPP8 protein, human