Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8 |
| |
Authors: | Jiaang Weir-Torn Chen Yuan-Shou Hsu Tsu Wu Ssu-Hui Chien Chia-Hui Chang Chung-Nien Chang Sheng-Ping Lee Shiow-Ju Chen Xin |
| |
Institution: | Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 161, Sec. 6, Minchiuan E. Rd., Neihu, Taipei 114, Taiwan, ROC. wtjiaang@nhri.org.tw |
| |
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 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. |
| |
Keywords: | |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|