Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes

Potential Importance of Selectivity Over Dipeptidyl Peptidases 8 and 9

  1. George R. Lankas1,
  2. Barbara Leiting2,
  3. Ranabir Sinha Roy2,
  4. George J. Eiermann3,
  5. Maria G. Beconi4,
  6. Tesfaye Biftu5,
  7. Chi-Chung Chan6,
  8. Scott Edmondson5,
  9. William P. Feeney7,
  10. Huaibing He5,
  11. Dawn E. Ippolito3,
  12. Dooseop Kim5,
  13. Kathryn A. Lyons5,
  14. Hyun O. Ok5,
  15. Reshma A. Patel2,
  16. Aleksandr N. Petrov3,
  17. Kelly Ann Pryor2,
  18. Xiaoxia Qian5,
  19. Leah Reigle5,
  20. Andrea Woods8,
  21. Joseph K. Wu2,
  22. Dennis Zaller8,
  23. Xiaoping Zhang2,
  24. Lan Zhu2,
  25. Ann E. Weber5 and
  26. Nancy A. Thornberry2
  1. 1Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania
  2. 2Department of Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey
  3. 3Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey
  4. 4Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey
  5. 5Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey
  6. 6Merck Frosst Centre for Therapeutic Research, Pointe Claire, Dorval, Quebec, Canada
  7. 7Department of Laboratory Animal Resources, Merck Research Laboratories, Rahway, New Jersey
  8. 8Department of Immunology, Merck Research Laboratories, Rahway, New Jersey
  1. Address correspondence and reprint requests to Nancy A. Thornberry, Merck Research Laboratories, R50G-2A-201, PO Box 2000, E. Lincoln Avenue, Rahway, New Jersey. E-mail: nancy_thornberry{at}merck.com

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.

Footnotes

  • M.G.B. is currently affiliated with GlaxoSmithKline.

    • Accepted June 20, 2005.
    • Received March 3, 2005.
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