Discovery, Optimization, and Evaluation of Novel ANGPTL3 Modulators for the Treatment of Hyperlipidemia

Angiopoietin-like protein 3 (ANGPTL3) has emerged as an attractive therapeutic target for treating hyperlipidemia. Evinacumab, a monoclonal antibody targeting ANGPTL3, was approved by the FDA for homozygous familial hypercholesterolemia in 2021. Here, a series of novel sulfonamide scaffold ANGPTL3 modulators were designed and synthesized based on the structure-activity relationship (SAR) analysis. Among them, compound <b>20</b> exhibited potent inhibition of <i>ANGPTL3</i> gene expression with an IC₅₀ value of 0.22 μM, reduced both <i>ANGPTL3</i> mRNA and protein levels, and significantly enhanced lipoprotein lipase (LPL) activity. More importantly, compound <b>20</b> remarkably lowered serum levels of triglycerides (TG), total cholesterol, and LDL cholesterol (LDL-C) in high-fat-diet-induced hyperlipidemic models, with favorable pharmacokinetic properties and safety profiles. Collectively, a novel ANGPTL3 small-molecule modulator compound <b>20</b> with a distinct core structure was first reported, offering potential for therapeutic development in hyperlipidemia.