RESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidases/antagonistas & inibidores , Dipeptidil Peptidase 4 , Dipeptidil Peptidases e Tripeptidil Peptidases/antagonistas & inibidores , Hipoglicemiantes , Inibidores de Proteases/uso terapêutico , Animais , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/fisiologia , Cães , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/toxicidade , Isoleucina/análogos & derivados , Isoleucina/química , Isoleucina/uso terapêutico , Isoleucina/toxicidade , Isomerismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibidores de Proteases/toxicidade , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Tiazóis/química , Tiazóis/uso terapêutico , Tiazóis/toxicidadeRESUMO
Substituted 4-amino cyclohexylglycine analogues were evaluated for DP-IV inhibitory properties. Bis-sulfonamide 15e was an extremely potent 2.6 nM inhibitor of the enzyme with excellent selectivity over all counterscreens. 2,4-difluorobenzenesulfonamide 15b and 1-naphthyl amide 16b, however, combined an acceptable in vitro profile with good pharmacokinetic properties in the rat, and 15b was orally efficacious at 3 mpk in an OGTT in lean mice.