Discovery of <i>N</i> -Ethyl Sulfonamide Derivatives as Potent Intestinal-Restricted Farnesoid X Receptor Antagonists for the Treatment of Metabolic Disorders

Farnesoid X receptor (FXR) plays a critical role in regulating bile acid and lipid metabolism, and intestinal FXR antagonism contributes to significant metabolic improvements. Herein, we report the discovery of a series of FXR antagonists featuring an <i>N</i>-ethyl sulfonamide scaffold. Through systematic structural optimization and structure-activity relationship studies, 101 derivatives were synthesized, among which <b>F44-S101</b> was identified as a potent and selective intestine-restricted FXR antagonist with an IC₅₀ value of 0.48 μM. In Triton-induced hyperlipidemic mice, <b>F44-S101</b> significantly reduced total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels. In high-fat diet-fed mice, <b>F44-S101</b> ameliorated lipid metabolic disorders, decreased adipose mass, and lowered serum ceramide levels. Mechanistically, <b>F44-S101</b> selectively antagonizes intestinal FXR and feedback-activates hepatic FXR, thereby promoting cholesterol metabolism and reducing lipid accumulation. Collectively, these findings highlight <b>F44-S101</b> as a promising lead compound for hyperlipidemia and support intestinal FXR antagonism as a potential therapeutic strategy for metabolic disorders.