title: Liver X receptor agonists with selectivity for LXRbeta; N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropionamides.
abstract: The synthesis and SAR of a new series of LXR agonist is reported. The N-Aryl-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamide hits were found in a limited screen of the AstraZeneca compound collection. The effort to optimize these hits into LXRbeta selectivity is described. Compound 20 displayed desirable pharmacokinetic profile and up regulation of ABCA1 and ABCG1 mRNA in the brain were achieved when evaluated in vivo in mice.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden. britt-marie.swahn@astrazeneca.com
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Swahn
authors.forename: Istvan
authors.initials: I
authors.lastname: Macsari
authors.forename: Jenny
authors.initials: J
authors.lastname: Viklund
authors.forename: Liselotte
authors.initials: L
authors.lastname: Ohberg
authors.forename: Johanna
authors.initials: J
authors.lastname: Sjödin
authors.forename: Jan
authors.initials: J
authors.lastname: Neelissen
authors.forename: Johanna
authors.initials: J
authors.lastname: Lindquist
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003198:Computer Simulation; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D007773:Lactates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000577:Amides; D004268:DNA-Binding Proteins; D007773:Lactates; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides