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

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

  • Diabetes. 2005 Oct;54(10):2988-94. doi: 10.2337/diabetes.54.10.2988.
George R Lankas 1,  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
Affiliations

Affiliation

  • 1 Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA.
PMID: 16186403 DOI: 10.2337/diabetes.54.10.2988
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.

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