ABSTRACT
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.
Subject(s)
Benzylamines/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Receptors, Glucocorticoid/antagonists & inhibitors , Sulfonamides/chemical synthesis , Alkaline Phosphatase/biosynthesis , Alkaline Phosphatase/genetics , Animals , Benzylamines/adverse effects , Benzylamines/pharmacology , Cells, Cultured , Cricetinae , Cricetulus , Dexamethasone/pharmacology , Female , Genes, Reporter , Glucocorticoids/pharmacology , Hepatocytes/drug effects , Hepatocytes/enzymology , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Male , Mice , Pituitary-Adrenal System/drug effects , Pregnancy , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/genetics , Sulfonamides/adverse effects , Sulfonamides/pharmacology , Transcriptional Activation/drug effects , Tyrosine Transaminase/biosynthesis , Uterus/drug effectsABSTRACT
A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.