Identification of SR3335 (ML-176): A Synthetic RORα Selective Inverse Agonist

Several nuclear receptors (NRs) are still characterized 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 ROR alpha synthetic ligand, SR3335 (ML 176) SR3335 directly binds to RORa, but not other RORs, and functions as a selective partial inverse agonist of RORa in cell base assays. furthermore, SR3335 suppresses the expression of endogenous ROR alpha 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 ROR alpha 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 ROR alpha inverse agonists may hold utility for suppression of elevated hepatic glucose production in type 2 diabetics.