title: Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9.
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.
authors.affiliation: Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Lankas
authors.forename: Barbara
authors.initials: B
authors.lastname: Leiting
authors.forename: Ranabir Sinha
authors.initials: RS
authors.lastname: Roy
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.forename: Maria G
authors.initials: MG
authors.lastname: Beconi
authors.forename: Tesfaye
authors.initials: T
authors.lastname: Biftu
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Scott
authors.initials: S
authors.lastname: Edmondson
authors.forename: William P
authors.initials: WP
authors.lastname: Feeney
authors.forename: Huaibing
authors.initials: H
authors.lastname: He
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Ippolito
authors.forename: Dooseop
authors.initials: D
authors.lastname: Kim
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Lyons
authors.forename: Hyun O
authors.initials: HO
authors.lastname: Ok
authors.forename: Reshma A
authors.initials: RA
authors.lastname: Patel
authors.forename: Aleksandr N
authors.initials: AN
authors.lastname: Petrov
authors.forename: Kelly Ann
authors.initials: KA
authors.lastname: Pryor
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qian
authors.forename: Leah
authors.initials: L
authors.lastname: Reigle
authors.forename: Andrea
authors.initials: A
authors.lastname: Woods
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wu
authors.forename: Dennis
authors.initials: D
authors.lastname: Zaller
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Zhu
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
mesh_terms: 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
chemical_list: 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