Dipeptide Boronic Acid Inhibitors of Dipeptidyl Peptidase IV: Determinants of Potency and in Vivo Efficacy and Safety.
作者
Connolly, Beth A.;Sanford, David G.;Chiluwal, Amrita K.;Healey, Sarah E.;Peters, Diane E.;Dimare, Matthew T.;Wu, Wengen;Liu, Yuxin;Maw, Hlaing;Zhou, Yuhong;Li, Youhua;Jin, Zhiping;Sudmeier, James L.;Lai, Jack H.;Bachovchin, William W.;
[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 obsd. 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 rodents.
