RESUMEN
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.
Asunto(s)
Bencilaminas/síntesis química , Hipoglucemiantes/síntesis química , Receptores de Glucocorticoides/antagonistas & inhibidores , Sulfonamidas/síntesis química , Fosfatasa Alcalina/biosíntesis , Fosfatasa Alcalina/genética , Animales , Bencilaminas/efectos adversos , Bencilaminas/farmacología , Células Cultivadas , Cricetinae , Cricetulus , Dexametasona/farmacología , Femenino , Genes Reporteros , Glucocorticoides/farmacología , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Ratones , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Embarazo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/genética , Sulfonamidas/efectos adversos , Sulfonamidas/farmacología , Activación Transcripcional/efectos de los fármacos , Tirosina Transaminasa/biosíntesis , Útero/efectos de los fármacosRESUMEN
We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.