title: Synthesis, in vitro and in vivo biological evaluation of new oxysterols as modulators of the liver X receptors.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
authors.forename: Ove Alexander Høgmoen
authors.initials: OAH
authors.lastname: Åstrand
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
authors.forename: Elvar Örn
authors.initials: EÖ
authors.lastname: Viktorsson
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
authors.forename: Aleksander Lim
authors.initials: AL
authors.lastname: Kristensen
authors.affiliation: Department of Chemistry, Biotechnology and Food Sciences, Norwegian University of Life Sciences, PO Box 5003, N-1432, Aas, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Ekeberg
authors.affiliation: Department of Chemistry, University of Oslo, PO Box 1033 Blindern, NO-0315 Oslo, Norway.
authors.forename: Hanne
authors.initials: H
authors.lastname: Røberg-Larsen
authors.affiliation: Department of Chemistry, University of Oslo, PO Box 1033 Blindern, NO-0315 Oslo, Norway.
authors.forename: Steven Ray
authors.initials: SR
authors.lastname: Wilson
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
authors.forename: Mari
authors.initials: M
authors.lastname: Gabrielsen
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
authors.forename: Arild Christian
authors.initials: AC
authors.lastname: Rustan
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway; Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: G Hege
authors.initials: GH
authors.lastname: Thoresen
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Rongved
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway. Electronic address: e.t.kase@farmasi.uio.no.
authors.forename: Eili Tranheim
authors.initials: ET
authors.lastname: Kase
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000577:Amides / Q000737:chemistry; D000818:Animals; D002784:Cholesterol / Q000737:chemistry; D015195:Drug Design; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D050155:Lipogenesis; D000071518:Liver X Receptors / Q000037:antagonists & inhibitors*; D008297:Male; D062105:Molecular Docking Simulation; D000072376:Oxysterols / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D014280:Triglycerides / Q000737:chemistry; D015430:Weight Gain
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000577:Amides; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D000072376:Oxysterols; D014280:Triglycerides; D002784:Cholesterol; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D005947:Glucose
keywords: Biological evaluation; Molecular modelling; Nuclear receptor modulation; Steroid synthesis