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 ROR gamma-modulators for autoimmune disorders, there has been no indication of efforts to target the close family member ROR alpha for similar indications. This may be due to the misconception that ROR alpha is redundant to ROR gamma, or the inherent difficulty in cultivating tractable starting points for ROR alpha. ROR alpha-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 ROR alpha 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 ROR alpha, ROR gamma, and LXR alpha in cell-based assays. Analogs were characterized by H-1-NMR, C-13-NMR, and LC-MS analysis. The pharmacokinetic profile of the most selective ROR alpha 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 ROR alpha/ROR gamma inverse agonists as well as ROR alpha-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 ROR alpha-selective inverse agonists identified (20, 28) can be utilized as chemical tools to probe the function of ROR alpha in vitro and in vivo.