Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9.
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.
Lankas
George R
GR
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA.
Leiting
Barbara
B
Roy
Ranabir Sinha
RS
Eiermann
George J
GJ
Beconi
Maria G
MG
Biftu
Tesfaye
T
Chan
Chi-Chung
CC
Edmondson
Scott
S
Feeney
William P
WP
He
Huaibing
H
Ippolito
Dawn E
DE
Kim
Dooseop
D
Lyons
Kathryn A
KA
Ok
Hyun O
HO
Patel
Reshma A
RA
Petrov
Aleksandr N
AN
Pryor
Kelly Ann
KA
Qian
Xiaoxia
X
Reigle
Leah
L
Woods
Andrea
A
Wu
Joseph K
JK
Zaller
Dennis
D
Zhang
Xiaoping
X
Zhu
Lan
L
Weber
Ann E
AE
Thornberry
Nancy A
NA
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004150:Dipeptidases / Q000037:antagonists & inhibitors*; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000502:physiology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D004285:Dogs; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use / Q000633:toxicity; D007532:Isoleucine / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D007536:Isomerism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013844:Thiazoles / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity
D007004:Hypoglycemic Agents; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D013844:Thiazoles; C114061:isoleucyl-thiazolidide; D007532:Isoleucine; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100151:dipeptidyl peptidase II; C487997:DPP8 protein, human; D018819:Dipeptidyl Peptidase 4