Abstract
Several nuclear receptors (NRs) are still character-ized as orphan receptors because ligands have not yet been identified for these proteins. The retinoic acid receptor-related receptors (RORs) have no well-defined physiological ligands. Here, we describe the identification of a selective RORα synthetic ligand, SR3335 (ML-176). SR3335 directly binds to RORα, but not other RORs, and functions as a selective partial inverse agonist of RORα in cell-based assays. Furthermore, SR3335 suppresses the expression of endogenous RORα target genes in HepG2 involved in hepatic gluconeogenesis including glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Pharmacokinetic studies indicate that SR3335 displays reasonable exposure following an ip injection into mice. We assess the ability of SR3335 to suppress gluconeogenesis in vivo using a diet-induced obesity (DIO) mouse model where the mice where treated with 15 mg/kg b.i.d., ip for 6 days followed by a pyruvate tolerance test. SR3335-treated mice displayed lower plasma glucose levels following the pyruvate challenge consistent with suppression of gluconeogenesis. Thus, we have identified the first selective synthetic RORα inverse agonist, and this compound can be utilized as a chemical tool to probe the function of this receptor both in vitro and in vivo. Additionally, our data suggests that RORα inverse agonists may hold utility for suppression of elevated hepatic glucose production in type 2 diabetics.