| Autor: |
Rosenblum, Jonathan S., Minimo, Lauro C., Liu, Yongsheng, Wu, Jiangyue, Kozarich, John W. |
| Předmět: |
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| Zdroj: |
Diabetes; Jun2007 Supplement 1, Vol. 56, pA138-A138, 1/4p, 1 Chart |
| Abstrakt: |
DPP IV inhibitors are being developed for treatment of type II diabetes. DPP IV is a member of a class of dipeptidyl peptidases whose members exhibit a variety of subcellular and tissue distributions. Among these family members, DPP8 and DPP9 have garnered much attention recently as it has been suggested that they are the relevant off targets for gastrointestinal toxicity following acute dosing in preclinical animal models. We now show that "G", a highly potent DPP IV inhibitor with only modest selectivity over DPP8 and DPP9 in vitro, is cell permeable and not acutely toxic in dogs at doses up to 600mg/kg. At Cmax, "G" was present in plasma at greater than 1000-fold the IC50 of both DPP8 and DPP9. We have used activity-based protein profiling to determine the level of DPP8/9 inhibition within tissues of treated animals. Importantly, this technique allows the characterization of levels of individual enzyme activity in highly complex environments and can, for example, assay DPP8/9 inhibition in the context of high levels of fully active DPP IV. Surprisingly, we found that this compound extensively inhibits DPP8/9 throughout the dog GI tract and brain, whereas "M", a previously described, GI toxic DPP8/9 inhibitor, exhibits much less extensive DPP8/9 inhibition in treated dogs. Taken together our results suggest that DPP8/9 inhibition in the affected organs alone cannot account for the acute toxicity described in animals treated with inhibitors of these enzymes. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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