RESUMO
A novel series of 5-substituted isophthalamides and their structure-activity relationship as insulin receptor sensitizers is discussed.
Assuntos
Adipócitos/efeitos dos fármacos , Amidas/farmacologia , Receptor de Insulina/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/metabolismo , Amidas/síntese química , Amidas/química , Animais , Avaliação Pré-Clínica de Medicamentos , Glucose/farmacocinética , Insulina/farmacologia , Camundongos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor. These compounds are structurally distinct from those used to build the model and were discovered by testing only 62 library compounds. The discovery of these leads demonstrates the efficiency with which affinity fingerprints can identify novel bioactive chemotypes from known drugs.
Assuntos
Técnicas de Química Combinatória/métodos , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Isoenzimas/antagonistas & inibidores , Modelos Teóricos , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1 , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Ibuprofeno/química , Ibuprofeno/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Estudos Prospectivos , Prostaglandina-Endoperóxido Sintases , Relação Quantitativa Estrutura-AtividadeRESUMO
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
To develop a novel route for the scaleable synthesis of the chiral xanthine CVT-124 (1, aka. BG9719), a method for the late stage pyrimidine ring closure of the nitrogen-protected endo 2-norbornenyl imidazole 3 was developed. The three-component coupling of benzylamine, 2-cyanoglycine ethyl ester (4), and methyl 5-norbornene-2-carboximidate hydrochloride (5) was demonstrated to achieve 3 in 23-46% isolated yields. The imidazole 3 was then elaborated to construct the N-benzyl xanthine 2 as a 1:1 mixture of exo and endo isomers, which were separable at this stage by chromatography. The nitrogen-protected endo xanthine 2 is a key intermediate in the synthesis of CVT-124.
Assuntos
Xantinas/síntese química , Ciclização , Antagonistas de Receptores Purinérgicos P1 , Pirimidinas/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.