Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9.

Abstract

Dipeptidyl peptidase (DPP)-IV inhibitors are a new approach to the treatment of type 2 diabetes. DPP-IV is a member of a family of serine peptidases that includes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9; DPP-IV is a key regulator of incretin hormones, but the functions of other family members are unknown. To determine the importance of selective DPP-IV inhibition for the treatment of diabetes, we tested selective inhibitors of DPP-IV, DPP8/DPP9, or QPP in 2-week rat toxicity studies and in acute dog tolerability studies. In rats, the DPP8/9 inhibitor produced alopecia, thrombocytopenia, reticulocytopenia, enlarged spleen, multiorgan histopathological changes, and mortality. In dogs, the DPP8/9 inhibitor produced gastrointestinal toxicity. The QPP inhibitor produced reticulocytopenia in rats only, and no toxicities were noted in either species for the selective DPP-IV inhibitor. The DPP8/9 inhibitor was also shown to attenuate T-cell activation in human in vitro models; a selective DPP-IV inhibitor was inactive in these assays. Moreover, we found DPP-IV inhibitors that were previously reported to be active in models of immune function to be more potent inhibitors of DPP8/9. These results suggest that assessment of selectivity of potential clinical candidates may be important to an optimal safety profile for this new class of antihyperglycemic agents.

• Authors: George R Lankas, Barbara Leiting, Ranabir Sinha Roy, George J Eiermann, Maria G Beconi, Tesfaye Biftu, Chi-Chung Chan, Scott Edmondson, William P Feeney, Huaibing He, Dawn E Ippolito, Dooseop Kim, Kathryn A Lyons, Hyun O Ok, Reshma A Patel, Aleksandr N Petrov, Kelly Ann Pryor, Xiaoxia Qian, Leah Reigle, Andrea Woods, Joseph K Wu, Dennis Zaller, Xiaoping Zhang, Lan Zhu, Ann E Weber, Nancy A Thornberry
• Journal: Diabetes (Diabetes) Vol. 54 Issue 10 Pg. 2988-94 (Oct 2005) ISSN: 0012-1797 [Print] United States
• PMID: 16186403 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Hypoglycemic Agents
• Protease Inhibitors
• Recombinant Proteins
• Thiazoles
• isoleucyl-thiazolidide
• Isoleucine
• Dipeptidases
• DPP9 protein, human
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• dipeptidyl peptidase II
• DPP8 protein, human
• Dipeptidyl Peptidase 4

Topics

• Animals
• Diabetes Mellitus, Type 2 (drug therapy)
• Dipeptidases (antagonists & inhibitors)
• Dipeptidyl Peptidase 4 (genetics, physiology)
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (antagonists & inhibitors)
• Dogs
• Female
• Humans
• Hypoglycemic Agents (therapeutic use, toxicity)
• Isoleucine (analogs & derivatives, chemistry, therapeutic use, toxicity)
• Isomerism
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Protease Inhibitors (therapeutic use, toxicity)
• Rats
• Recombinant Proteins (antagonists & inhibitors)
• Thiazoles (chemistry, therapeutic use, toxicity)