Discovery and Optimization of a Series of Sulfonamide Inverse Agonists for the Retinoic Acid Receptor-Related Orphan Receptor-α
Background: Despite a massive industry endeavor to develop RORγ-modulators for
autoimmune disorders, there has been no indication of efforts to target the close family member
RORα for similar indications. This may be due to the misconception that RORα is redundant to
RORγ, or the inherent difficulty in cultivating tractable starting points for RORα. RORα-selective
modulators would be useful tools to interrogate the biology of this understudied orphan nuclear receptor.
Objective: The goal of this research effort was to identify and optimize synthetic ligands for RORα
starting from the known LXR agonist T0901317.
Methods: Fourty-five analogs of the sulfonamide lead (1) were synthesized and evaluated for their
ability to suppress the transcriptional activity of RORα, RORγ, and LXRα in cell-based assays.
Analogs were characterized by 1H-NMR, 13C-NMR, and LC-MS analysis. The pharmacokinetic
profile of the most selective RORα inverse agonist was evaluated in rats with intraperitoneal (i.p.)
and per oral (p.o.)dosing.
Results: Structure-activity relationship studies led to potent dual RORα/RORγ inverse agonists as
well as RORα-selective inverse agonists (20, 28). LXR activity could be reduced by removing the
sulfonamide nitrogen substituent. Attempts to improve the potency of these selective leads by
varying substitution patterns throughout the molecule proved challenging.
Conclusion: The synthetic RORα-selective inverse agonists identified (20, 28) can be utilized as
chemical tools to probe the function of RORα in vitro and in vivo.Journal Title: