Redesigning Berberines and Sanguinarines to Target Soluble Epoxide Hydrolase for Enhanced Anti-Inflammatory Efficacy

Amino-berberine has remained underexplored due to limited
biological
evaluation and total synthesis approaches. In inflammation therapy,
soluble Epoxide Hydrolase (sEH) is a promising target, yet natural
scaffolds remain underutilized. Our study advances the field by redesigning
natural compoundsberberine and sanguinarinewith strategic
urea modifications and hydrogenated frameworks, creating novel sEH
inhibitors with enhanced in vivo efficacy. Through
total synthesis and structure–activity relationship studies
of amino-berberine derivatives, chiral tetrahydroberberine (R)-14i (coded LXZ-42) emerged as the
most potent lead, with an IC50 value of 1.20 nM. (R)-14i showed reduced CYP enzyme impact,
potent therapeutic effects on acute pancreatitis, no acute in vivo toxicity, and superior pharmacokinetic properties,
with an oral bioavailability of 89.3%. Structural insights from crystallography
of (R)-14i bound to sEH revealed key
interactions: three with the tetrahydroberberine framework and three
hydrogen bonds with the urea group, highlighting (R)-14i as a novel lead for sEH-targeted therapies in inflammation.