alanylpyrrolidine-boronic-acid and Drug-Related-Side-Effects-and-Adverse-Reactions

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.

Topics: Administration, Oral; Animals; Blood Glucose; Boronic Acids; Cell Line; Cloning, Molecular; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Female; Glucose; Glucose Tolerance Test; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Conformation; Peptide Library; Rats; Rats, Sprague-Dawley; Serine Proteinase Inhibitors; Structure-Activity Relationship; Substrate Specificity; Time Factors