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Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes

Potential Importance of Selectivity Over Dipeptidyl Peptidases 8 and 9

¹ Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania
² Department of Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey
³ Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey
⁴ Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey
⁵ Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey
⁶ Merck Frosst Centre for Therapeutic Research, Pointe Claire, Dorval, Quebec, Canada
⁷ Department of Laboratory Animal Resources, Merck Research Laboratories, Rahway, New Jersey
⁸ Department of Immunology, Merck Research Laboratories, Rahway, New Jersey

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.

Abbreviations: AMC, aminomethylcoumarin; DASH, DPP-IV activity and/or structure homologues; DPP, dipeptidyl peptidase; GLP-1, glucagon-like peptide 1; IL, interleukin; QPP, quiescent cell proline dipeptidase

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