Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8
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- 作者：Jiaang ; Weir-Torn ; Chen ; Yuan-Shou ; Hsu ; Tsu ; Wu ; Ssu-Hui ; Chien ; Chia-Hui ; Chang ; Chung-Nien ; et. al.
- 关键词：DPP8 ; Isoindoline ; Isoquinoline ; Prolyl dipeptidase ; Type II diabetes
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2005
- 出版时间：February 1, 2005
- 年：2005
- 卷：15
- 期：3
- 页码：687-691
- 全文大小：291 K
文摘
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-(4,4aaa-difluor-benzhydryl)-piperazine group at the P2 site was observed to be a very potent DPP8 inhibitor, having an IC50 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.