Zhang_2025_J.Med.Chem__

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 20 exhibited potent inhibition of ANGPTL3 gene expression with an IC(50) value of 0.22 microM, reduced both ANGPTL3 mRNA and protein levels, and significantly enhanced lipoprotein lipase (LPL) activity. More importantly, compound 20 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 20 with a distinct core structure was first reported, offering potential for therapeutic development in hyperlipidemia.