RESUMO
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.
Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/síntese química , Proteínas Ativadoras de 5-Lipoxigenase/química , Alcanos/síntese química , Antialérgicos/síntese química , Derivados de Benzeno/síntese química , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacocinética , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Alcanos/farmacocinética , Alcanos/farmacologia , Animais , Antialérgicos/farmacocinética , Antialérgicos/farmacologia , Derivados de Benzeno/farmacocinética , Derivados de Benzeno/farmacologia , Humanos , Concentração Inibidora 50 , Injeções Intravenosas , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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
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).
