RESUMO
Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.
Assuntos
Ativadores de Enzimas/química , Glucoquinase/química , Hipoglicemiantes/química , Animais , Sítios de Ligação , Glicemia/análise , Cristalografia por Raios X , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ativadores de Enzimas/metabolismo , Ativadores de Enzimas/uso terapêutico , Glucoquinase/metabolismo , Teste de Tolerância a Glucose , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/metabolismoRESUMO
The inconsistent findings among association studies that have examined the relationship between factor XIIIA Val34Leu and thrombosis may be owing to (1) population differences in the prevalence of other risk factors that modify the association with Val34Leu, or (2) linkage disequilibrium with other functional factor XIIIA polymorphisms. We therefore performed genotyping for factor XIIIA Val34Leu, Tyr204Phe and Pro564Leu in a population-based study of myocardial infarction (MI) and ischaemic stroke among white women <45-years of age and 345 demographically similar controls, and examined potential interactions with other risk factors. The presence of the factor XIIIA Leu34 allele was associated with a slight decreased risk of MI [odds ratio (OR) = 0.80] that was most pronounced among women with traditional cardiovascular risk factors. Paradoxically, women carrying two copies of the Leu34 allele had a nearly fourfold increased risk of ischaemic stroke relative to the Val34/Val34 genotype. Heterozygosity for factor XIIIA Phe204 was associated with a milder increased risk of ischaemic stroke, and analysis of a kindred with congenital dysfibrinogenaemia suggested that co-inheritance of the factor XIIIA Phe204 allele may increase susceptibility to ischaemic stroke. Our results suggest that the factor XIIIA Val34Leu variant may be associated with a decreased risk of MI among young women with other risk factors. The relationship of factor XIIIA polymorphisms to cerebrovascular disease requires further study.
