Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: Determinants of potency and in vivo efficacy and safety

被引：61

作者：

Connolly, Beth A. ^{[1
]}

Sanford, David G. ^{[1
]}

Chiluwal, Amrita K. ^{[1
]}

Healey, Sarah E. ^{[1
]}

Peters, Diane E. ^{[1
]}

Dimare, Matthew T. ^{[1
]}

Wu, Wengen ^{[1
]}

Liu, Yuxin ^{[1
]}

Maw, Hlaing ^{[1
]}

Zhou, Yuhong ^{[1
]}

Li, Youhua ^{[1
]}

Jin, Zhiping ^{[1
]}

Sudmeier, James L. ^{[1
]}

Lai, Jack H. ^{[1
]}

Bachovchin, William W. ^{[1
]}

机构：

[1] Tufts Univ, Dept Biochem, Boston, MA 02111 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 19期

关键词：

D O I：

10.1021/jm800390n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (> 500) in rodents.

引用

页码：6005 / 6013

页数：9

共 37 条

[1] Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8 [J].