Journal Article
Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9
Lankas, GR; Leiting, B; Roy, RS; Eiermann, GJ; Beconi, MG; Biftu, T; Chan, CC; Edmondson, S; Feeney, WP; He, H; Ippolito, DE; Kim, D; Lyons, KA; Ok, HO; Patel, RA; Petrov, AN; Pryor, KA; Qian, X; Reigle, L; Woods, A; Wu, JK; Zaller, D; Zhang, X; Zhu, L; Weber, AE; Thornberry, NA; ,
Diabetes
ISSN: 0012-1797
EISSN: 1939-327X
AMER DIABETES ASSOC
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.
(1 valylpyrrolidin 2 yl)boronic acid; 1 [[2 amino 2 [1 (4 iodophenyl)sulfonyl]pyrrolidin 3 yl] 1 oxoethyl]thiazolidine; 2 (2 amino 3 methyl 1 oxopentan 1 yl) 1,3 dihydro 2h isoindole; 2 [4 [[[[1 [3 amino 4 (2,5 difluorophenyl) 1 oxobutyl] 2 pyrrolidinyl]carbonyl]amino]methyl]phenoxy] 3 methylbutanoic acid; 4 nitrobenzyl [5 amino 6 oxo 6 (1 piperidinyl)hexyl]carbamate; 4 nitrobenzyl [5 amino 6 oxo 6 (1 pyrrolidinyl)hexyl]carbamate; 4 nitrobenzyl [5 amino 6 oxo 6 (1,3 thiazolidin 3 yl)hexyl]carbamate; 4 oxo 4 [3 (trifluoromethyl) 5,6 dihydro[1,2,4]triazolo[4,3 a]pyrazin 7(8h) yl] 1 (2,5 difluorophenyl)butan 2 amine fumarate; antidiabetic agent; dipeptidyl peptidase; dipeptidyl peptidase IV; dipeptidyl peptidase IV inhibitor; dipeptidyl peptidase IX; dipeptidyl peptidase VIII; hormone; incretin; isoleucyl thiazolidine fumarate; peptidase; quiescent cell proline dipeptidase; unclassified drug; alopecia; animal experiment; animal tissue; article; controlled study; dog; drug classification; drug safety; drug selectivity; drug tolerability; enzyme inhibition; enzyme regulation; female; gastrointestinal toxicity; histopathology; human; human cell; immune response; in vitro study; male; mortality; mouse; multiple organ failure; non insulin dependent diabetes mellitus; nonhuman; normal human; priority journal; protein family; protein function; rat; reticulocyte; splenomegaly; T lymphocyte activation; thrombocytopenia; toxicity testing; Animals; Antigens, CD26; Diabetes Mellitus, Type 2; Dipeptidases; Dipeptidyl Peptidases; Dogs; Female; Humans; Hypoglycemic Agents; Isoleucine; Isomerism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protease Inhibitors; Rats; Recombinant Proteins; Thiazoles