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

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Abstract

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 IC50 value of 14 nM 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.

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Acknowledgements

We would like to thank Dr. Yu-Sheng Chao for his support and encouragement, and Dr. Peter Nell for critically reading the manuscript and making suggestions. The study was financially supported by National Health Research Institutes, Taiwan.

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