RESUMO
The long chain free fatty acid receptor 4 (FFA4/GPR120) has recently been recognized as lipid sensor playing important roles in nutrient sensing and inflammation and thus holds potential as a therapeutic target for type 2 diabetes and metabolic syndrome. To explore the effects of stimulating this receptor in animal models of metabolic disease, we initiated work to identify agonists with appropriate pharmacokinetic properties to support progression into in vivo studies. Extensive SAR studies of a series of phenylpropanoic acids led to the identification of compound 29, a FFA4 agonist which lowers plasma glucose in two preclinical models of type 2 diabetes.
Assuntos
Fenilpropionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Fenilpropionatos/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.
Assuntos
Receptores Acoplados a Proteínas G/agonistas , Sulfonamidas/farmacologia , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Insulina/agonistas , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
This unit describes the use of cannabinoid radioligands in competitive binding assays for determining affinity parameters (IC50, Ki ) of unlabeled compounds at transfected CB1 and CB2 receptors expressed in cell lines.
Assuntos
Encéfalo/metabolismo , Receptores de Canabinoides/metabolismo , Ligação Competitiva/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Indicadores e Reagentes/farmacologia , Ensaio Radioligante/métodosRESUMO
This unit describes the use of cannabinoid radioligands in competitive binding assays for determining affinity parameters (IC(50), K(i)) of unlabeled compounds at cloned CB1 and CB2 receptors expressed in cells.