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

BA Connolly, DG Sanford, AK Chiluwal… - Journal of medicinal …, 2008 - ACS Publications
BA Connolly, DG Sanford, AK Chiluwal, SE Healey, DE Peters, MT Dimare, W Wu, Y Liu…
Journal of medicinal chemistry, 2008ACS Publications
Dipeptidyl peptidase IV (DPP-IV; EC 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 …
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.
ACS Publications