Substituted oxazolidinones as novel 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 3mg/kg.
Pfizer Global Research & Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. jeffrey.a.pfefferkorn@pfizer.com
Jeffrey A
JA
Pfefferkorn
Scott D
SD
Larsen
Chad
C
Van Huis
Roderick
R
Sorenson
Tom
T
Barton
Thomas
T
Winters
Bruce
B
Auerbach
Chenyan
C
Wu
Thaddeus J
TJ
Wolfram
Hongliang
H
Cai
Kathleen
K
Welch
Nadia
N
Esmaiel
JoAnn
J
Davis
Richard
R
Bousley
Karl
K
Olsen
Sandra Bak
SB
Mueller
Thomas
T
Mertz
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects*; D008024:Ligands; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008871:Microvilli / Q000378:metabolism; D023303:Oxazolidinones / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D014961:X-Ray Diffraction
D008024:Ligands; D026901:Membrane Transport Proteins; C482444:NPC1L1 protein, rat; D023303:Oxazolidinones; D002784:Cholesterol