RESUMO
A novel series of symmetrical ureas of [(7-amino(2-naphthyl))sulfonyl]phenylamines were designed, synthesized, and tested for their ability to increase glucose transport in mouse 3T3-L1 adipocytes, a surrogate readout for activation of the insulin receptor (IR) tyrosine kinase (IRTK). A structure-activity relationship was established that indicated glucose transport activity was dependent on the presence of two acidic functionalities, two sulfonamide linkages, and a central urea or 2-imidazolidinone core. Compound 30 was identified as a potent and selective IRTK activator. At low concentrations, 30 was able to increase the tyrosine phosphorylation of the IR stimulated by submaximal insulin. At higher concentrations, 30 was able to increase tyrosine the phosphorylation levels of the IR in the absence of insulin. When administered intraperitoneally (ip) and orally (po), 30 improved glucose tolerance in hypoinsulinemic, streptozotocin-treated rats. These data provide pharmacological validation that small molecule IRTK activators represent a potential new class of antidiabetic agents.
Assuntos
Compostos de Anilina/farmacologia , Desenho de Fármacos , Receptor de Insulina/efeitos dos fármacos , Sulfonamidas/farmacologia , Ureia/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Administração Oral , Compostos de Anilina/síntese química , Compostos de Anilina/química , Animais , Sítios de Ligação , Glicemia/análise , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/efeitos dos fármacos , Teste de Tolerância a Glucose , Injeções Intraperitoneais , Masculino , Camundongos , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Estreptozocina/administração & dosagem , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Ureia/análogos & derivados , Ureia/químicaRESUMO
Protease inhibitor (PI) therapy for the treatment of patients infected with human immunodeficiency virus is frequently associated with insulin resistance and diabetic complications. These adverse effects of PI treatment result to a large extent from their inhibition of insulin-stimulated glucose transport. Insulin receptor (IR) activators that enhance the insulin signaling pathway could be effective in treating this resistance. However, there are no agents reported that reverse inhibition of insulin action by PIs. Herein, we describe the effects of TLK19781. This compound is a non-peptide, small molecule, activator of the IR. We now report in cultured cells, made insulin resistant HIV by PI treatment, that TLK19781 both increased the content of insulin-stimulated GLUT4 at the plasma membrane, and enhanced insulin-stimulated glucose transport. In addition, oral administration of TLK19781 with the PI, indinavir improved glucose tolerance in rats made insulin resistant. These results suggest, therefore, that IR activators such as TLK19781 may be useful in treating the insulin resistance associated with PIs.
