Substituted oxazolidinones as novel NPC1L1 ligands for the inhibition of cholesterol absorption

This manuscript describes the synthesis and evaluation of a series of oxazolidinone-based NPC1L1 ligands for the inhibition of cholesterol absorption. Cholesterol absorption inhibition (CAI) represents an important treatment option for hypercholesterolemia. Herein, we report the design and evaluation of a series of substituted oxazolidinones as ligands for the Niemann Pick C1 Like 1 (NPC1L1) protein, a key mediator of cholesterol transport. Novel analogs were initially evaluated in a brush border membrane NPC1L1 binding assay; subsequently, promising compounds were evaluated in vivo for acute inhibition of cholesterol absorption. These studies identified analogs with low micromolar NPC1L1 binding affinity and acute in vivo efficacy of >50% absorption inhibition at 3 mg/kg.