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

被引：98

作者：

Jiaang, WT

Chen, YS

Hsu, T

Wu, SH

Chien, CH

Chang, CN

Chang, SP

Lee, SJ

Chen, X

机构：

[1] Natl Hlth Res Inst, Div Biotechnol & Pharmaceut Res, Taipei 114, Taiwan

[2] Taipei Vet Gen Hosp, Dept Obstet & Gynecol, Taipei 112, Taiwan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 03期

关键词：

DPP8; isoindoline; isoquinoline; prolyl dipeptidase; type II diabetes;

D O I：

10.1016/j.bmcl.2004.11.023

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

DPP8 is a prolyl dipeptidase homologous to DPP-IV, which is a drug target for Type 11 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 14nM with at least a 2500-fold selectivity over either DPP-IV or DPP-II. From SAR results, we speculate that the S I site of DPP8 may be larger than that of DPPIV, which would allow the accommodation of larger C-terminal residues, such as isoquinoline or isoindoline. (C) 2004 Elsevier Ltd. All rights reserved.

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页码：687 / 691

页数：5

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