Discovery and Optimization of Novel Nonbile Acid FXR Agonists as Preclinical Candidates for the Treatment of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a multifactorial
chronic inflammation
of the intestine and has become a global public health concern. A
farnesoid X receptor (FXR) was recently reported to play a key role
in hepatic-intestinal circulation, intestinal metabolism, immunity,
and microbial regulation, and thus, it becomes a promising therapeutic
target for IBD. In this study, we identified a series of nonbile acid
FXR agonists, in which 33 novel compounds were designed and synthesized
by the structure-based drug design strategy from our previously identified
hit compound. Compound 33 exhibited a potent FXR agonistic
activity, high intestinal distribution, good anti-inflammatory activity,
and the ability to repair the colon epithelium in a DSS-induced acute
enteritis model. Based on the results of RNA-seq analysis, we further
investigated the therapeutic potential of the combination of compound 33 with 5-ASA. Overall, the results indicated that compound 33 is a promising drug candidate for IBD treatment.