Antidiabetic Activity of Passive Nonsteroidal Glucocorticoid Receptor Modulators

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.

Development of selective androgen receptor modulators (SARMs)

“…Decades after the discovery of SERMs, Selective Androgen Receptor Modulators (SARMs) (20) were first described and subsequently developed to facilitate tissue-selective activation of the AR. This was followed by the discovery of Selective Glucocorticoid Receptor Modulators (SGRMs) (21), Selective Progesterone Receptor Modulators (SPRMs) (22) and others. Recently, a tissue-selective Farnesoid X receptor modulator was discovered with potential as a treatment for metabolic diseases (23), further increasing the number of tissue-selective nuclear receptor modulators available for therapeutic purposes.…”

Molecular Switch in the Glucocorticoid Receptor: Active and Passive Antagonist Conformations

“…6 A ligand of GR inhibiting this mechanism or preventing coregulator recruitment and keeping GR in an inactive state is defined as a 'passive antagonist' (initially named 'competitive antagonist'). 7,8 In the presence of an agonist or an active antagonist, GR is translocated to the nucleus where it actively recruits nuclear coregulator proteins such as TIF2 and nuclear receptor corepressor (NCoR) and regulates gene expression. The nuclear coregulator binding site overlaps with the HSP90 binding site.…”

Recent and emerging anti‐diabetes targets

“…PRECLINICAL REPORTS. A series of N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamides was discovered as passive non-steroidal GR modulators and evaluated for potential as antidiabetic agents by Link et al 243,244 from Abbott. Among these, (105) (Fig.…”