RESUMO
Through the application of TRAP (target-related affinity profiling), we identified a novel class of heteroaroylphenylureas that inhibit human CCL2-induced chemotaxis of monocytes/macrophages both in vitro and in vivo. This inhibition was concentration-dependent and selective with regard to other chemokines. The compounds, however, did not antagonize the binding of (125)I-labeled CCL2 to the CCR2 receptor nor did they block CCR2-mediated signal transduction responses such as calcium mobilization. Optimization of early leads for potency and pharmacokinetic parameters resulted in the identification of 17, a potent inhibitor of chemotaxis (IC(50) = 80 nM) with excellent oral bioavailability in rats (F = 60%). Compound 17 reduced swelling and joint destruction in two rat models of rheumatoid arthritis and delayed disease onset and produced near complete resolution of symptoms in a mouse model of multiple sclerosis.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Quimiocina CCL2/antagonistas & inibidores , Compostos de Fenilureia/síntese química , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Disponibilidade Biológica , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células CHO , Linhagem Celular Tumoral , Quimiotaxia/efeitos dos fármacos , Cricetinae , Cricetulus , Humanos , Articulações/efeitos dos fármacos , Articulações/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos ICR , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Esclerose Múltipla/tratamento farmacológico , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Ensaio Radioligante , Ratos , Receptores CCR2/metabolismo , Relação 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
A novel series of 5-substituted isophthalamides and their structure-activity relationship as insulin receptor sensitizers is discussed.