Identification of novel inverse agonists of estrogen-related receptors ERR gamma and ERR beta

摘要

Estrogen-related receptors (ERRs, alpha, beta, and gamma) are orphan nuclear receptors most closely related in sequence to estrogen receptors (ER alpha and ER beta). Much attention has been paid recently to the functions of ERRs for their potential roles as new therapeutic targets implicated in the etiology of metabolic disorders. While no endogenous ligand has been identified for any of the ERR isoforms to date, the potential for using synthetic small molecules to modulate their activity has been demonstrated. In the present study, a series of novel inverse agonists of ERR gamma and ERR beta were synthesized using regio- and stereo-specific direct substitution of triarylethylenes. These compounds were evaluated for their ability to modulate the activities of ERRs. The rational directed substitution approach and extensive SAR studies resulted in the discovery of compound 4a (DY40) as the most potent ERR gamma inverse agonist described to date with mixed ERR gamma/ERR beta functional activities, which potently suppressed the transcriptional functions of ERR gamma with IC50 = 0.01 mu M in a cell-based reporter gene assay and antagonized ERR gamma with a potency approximately 60 times greater than its analog Z-4-OHT (Z-4-hydroxytamoxifen). In addition, compound 3h (DY181) was identified as the most potent synthetic inverse agonist for the ERR beta that exhibited excellent selectivity over ERR alpha/gamma in functional assays. This selectivity was also supported by computational docking models that suggest DY181 forms more extensive hydrogen bound network with ERR beta which should result in higher binding affinity on ERR beta over ERR gamma. (C) 2017 Published by Elsevier Ltd.