Synthesis, in vitro and in vivo biological evaluation of new oxysterols as modulators of the liver X receptors
ForfatterÅstrand, Ove Alexander Høgmoen; Viktorsson, Elvar Örn; Kristensen, Aleksander Lim; Ekeberg, Dag; Røberg-Larsen, Hanne; Wilson, Steven Ray Haakon; Gabrielsen, Mari; Sylte, Ingebrigt; Rustan, Arild; Thoresen, G. Hege; Rongved, Pål; Kase, Eili Tranheim
Liver X Receptor (LXR) modulators have shown potential as drugs since they target genes affecting metabolism and fatty acid synthesis. LXR antagonists are of particular interest since they are able to reduce the synthesis of complex fatty acids and glucose uptake. Based on molecular modeling, five new cholesterol mimics were synthesized, where four contained a hydroxyl group in the 22-S-position. The new compounds were screened in vitro against several genes affecting lipid metabolism. The compound that performed best in vitro was a dimethylamide derivative of 22(S)-hydroxycholesterol and it was chosen for in vivo testing. However, the blood plasma analysis from the in vivo tests revealed a concentration lower than needed to give any response, indicating either rapid metabolism or low bioavailability.