Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes

Dipeptidyl Peptidase IV Inhibition for the Treatment of Type 2 Diabetes Potential Importance of Selectivity Over Dipeptidyl Peptidases 8 and 9 George R. Lankas 1 , Barbara Leiting 2 , Ranabir Sinha Roy 2 , George J. Eiermann 3 , Maria G. Beconi 4 , Tesfaye Biftu 5 , Chi-Chung Chan 6 , Scott Edmondson 5 , William P. Feeney 7 , Huaibing He 5 , Dawn E. Ippolito 3 , Dooseop Kim 5 , Kathryn A. Lyons 5 , Hyun O. Ok 5 , Reshma A. Patel 2 , Aleksandr N. Petrov 3 , Kelly Ann Pryor 2 , Xiaoxia Qian 5 , Leah Reigle 5 , Andrea Woods 8 , Joseph K. Wu 2 , Dennis Zaller 8 , Xiaoping Zhang 2 , Lan Zhu 2 , Ann E. Weber 5 and Nancy A. Thornberry 2 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 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 hu