RESUMEN
A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/síntesis química , Proteínas Activadoras de la 5-Lipooxigenasa/química , Alcanos/síntesis química , Antialérgicos/síntesis química , Derivados del Benceno/síntesis química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Alcanos/farmacocinética , Alcanos/farmacología , Animales , Antialérgicos/farmacocinética , Antialérgicos/farmacología , Derivados del Benceno/farmacocinética , Derivados del Benceno/farmacología , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidasas/antagonistas & inhibidores , Dipeptidil Peptidasa 4 , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/antagonistas & inhibidores , Hipoglucemiantes , Inhibidores de Proteasas/uso terapéutico , Animales , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/fisiología , Perros , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/toxicidad , Isoleucina/análogos & derivados , Isoleucina/química , Isoleucina/uso terapéutico , Isoleucina/toxicidad , Isomerismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Inhibidores de Proteasas/toxicidad , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Tiazoles/química , Tiazoles/uso terapéutico , Tiazoles/toxicidadRESUMEN
Modification of in-house screening lead beta-aminoacyl proline 8 gave an equipotent thiazolidide 9. Extensive SAR studies on the phenyl ring of 9 led to the discovery of a novel series of potent and selective DP-IV inhibitors. Introduction of a fluorine at the 2-position proved to be crucial for the potency of this series. The 2,5-difluoro (22q) and 2,4,5-trifluoro (22t) analogues were potent inhibitors of DP-IV (IC(50)=270, 119nM, respectively).