SR3335

SR3335 is a synthetic selective inverse agonist of RORα with Ki value of 220 nM [1][2].
The retinoic acid receptor-related orphan receptor α (RORα) is an orphan receptor that plays an important role in the regulation of metabolism.
SR3335 prevented the expression of endogenous RORα in HepG2. And it may suppress hepatic glucose production in type 2 diabetics. SR3335 was able to repress the expression of G6Pase. In ChIP trial, ML-176 reduced the amount of SRC2 at the G6Pase promoter [3]. In a GAL4-RORR ligand binding domain cotransfection assay, SR3335 inhibited the constitutive activity of RORα and the Ki was calculated as 220 nM [1].
When treat diet-induced obese mice with SR3335 (15 mg/kg), after injected with pyruvate, the plasma glucose levels were significantly lower at each time point compared with vehicle-treated animals. The results indicated SR3335 suppressed hepatic gluconeogenesis [1].
References:
[1]. Naresh Kumar, Douglas J. Kojetin, et al. Identification of SR3335 (ML176): a Synthetic RORα Selective Inverse Agonist. ACS Chem Biol. 2011 March 18; 6(3): 218-222.
[2]. Laura A. Solt, Thomas P. Burris. Action of RORs and their ligands in (patho)physiology. Trends in Endocrinology & Metabolism, 2012, 23(12): 619-627.
[3]. Kumar N, Nuhant P, Solt LA, et al. Identification of a novel selective inverse agonist probe and analogs for the Retinoic acid receptor-related Orphan Receptor Alpha (RORα). Probe Reports from the NIH Molecular Libraries Program [Internet], Bethesda (MD): National Center for Biotechnology Information (US),2010-.2010.

Identification of SR3335 (ML-176): a synthetic RORalpha selective inverse agonist.[Pubmed:21090593]

ACS Chem Biol. 2011 Mar 18;6(3):218-22.

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 RORalpha synthetic ligand, SR3335 (ML-176). SR3335 directly binds to RORalpha, but not other RORs, and functions as a selective partial inverse agonist of RORalpha in cell-based assays. Furthermore, SR3335 suppresses the expression of endogenous RORalpha 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 RORalpha 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 RORalpha inverse agonists may hold utility for suppression of elevated hepatic glucose production in type 2 diabetics.