RESUMO
Much has been learned about the consequences of glucocorticoid receptor antagonism by studying steroidal active antagonists such as RU-38486 (1). In the liver glucocorticoid receptor antagonism suppresses hepatic glucose production decreasing plasma glucose levels; however, extrahepatic antagonism produces several undesirable side effects including activation of the hypothalamic pituitary adrenal axis. A series of nonsteroidal passive N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamide glucocorticoid receptor modulators was discovered. Liver selective and systemically available members of this series were found and characterized in diabetes and side effect rodent models. A highly liver selective member of this series, acid 14, shows efficacy in the ob/ob model of diabetes. It lowers plasma glucose, cholesterol, and free fatty acid concentrations and reduces the rate of body weight gain. The structurally related systemically available passive modulator 12 lowers glucose, HbA(1c), triglyceride, free fatty acid, and cholesterol levels. Interestingly, it did not acutely activate the hypothalamic pituitary adrenal axis in unstressed CD-1 mice or have the abortive effects observed with 1. These results indicate that passive GR antagonists may have utility as antidiabetic agents.
Assuntos
Benzilaminas/síntese química , Hipoglicemiantes/síntese química , Receptores de Glucocorticoides/antagonistas & inibidores , Sulfonamidas/síntese química , Fosfatase Alcalina/biossíntese , Fosfatase Alcalina/genética , Animais , Benzilaminas/efeitos adversos , Benzilaminas/farmacologia , Células Cultivadas , Cricetinae , Cricetulus , Dexametasona/farmacologia , Feminino , Genes Reporter , Glucocorticoides/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Masculino , Camundongos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Gravidez , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacologia , Ativação Transcricional/efeitos dos fármacos , Tirosina Transaminase/biossíntese , Útero/efeitos dos fármacosRESUMO
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.