Discovery of Novel Snail Inhibitors Derived from Omeprazole for Antiatherosclerotic Therapy: A Structure-Based Approach

The transcription factor Snail plays an important role in the progression of atherosclerosis (AS), actively contributing to plaque formation and instability. Thus, targeting Snail is a promising therapeutic strategy for developing antiatherosclerotic agents possessing both anti-inflammatory and plaque-stabilizing properties. Taking advantage of omeprazole's Snail-inhibitory activity, as determined through drug repurposing and structure-activity relationships, we identified a novel compound S29, which possesses excellent Snail inhibitory activity, favorable pharmacokinetic properties (F = 82.3% and T_1/2 = 5.05 h), and enhanced safety profiles. In vivo pharmacodynamic evaluation revealed that S29 remarkably reduced atherosclerotic plaque burden by 56%, as quantified using en face aortas. Mechanistic studies indicated that S29 exerted its therapeutic effects by modulating key factors associated with inflammation and plaque stability, specifically, CCL5, CXCL10, MMP2, MMP9, and α-smooth muscle actin. These findings highlight S29's dual anti-inflammatory and plaque-stabilizing properties, making it a promising candidate for the treatment of AS.