Author/Authors :
Jeffrey A. Pfefferkorn، نويسنده , , Scott D. Larsen، نويسنده , , Chad Van Huis، نويسنده , , Roderick Sorenson، نويسنده , , Tom Barton، نويسنده , , Thomas Winters، نويسنده , , Bruce Auerbach، نويسنده , , Chenyan Wu، نويسنده , , Thaddeus J. Wolfram، نويسنده , , Hongliang Cai، نويسنده , , Kathleen Welch، نويسنده , , Nadia Esmaiel، نويسنده , , JoAnn Davis، نويسنده , , Richard Bousley، نويسنده , , Karl Olsen، نويسنده , , Sandra Bak Mueller، نويسنده , , Thomas Mertz، نويسنده ,
Abstract :
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.
Keywords :
Cholesterol absorption inhibitor , dyslipidemia , Hypercholesterolemia , NPC1L1
