title: Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer's Disease.
abstract: Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Stachel
authors.forename: Celina
authors.initials: C
authors.lastname: Zerbinatti
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rudd
authors.forename: Mali
authors.initials: M
authors.lastname: Cosden
authors.forename: Sokreine
authors.initials: S
authors.lastname: Suon
authors.forename: Kausik K
authors.initials: KK
authors.lastname: Nanda
authors.forename: Keith
authors.initials: K
authors.lastname: Wessner
authors.forename: Jillian
authors.initials: J
authors.lastname: DiMuzio
authors.forename: Jill
authors.initials: J
authors.lastname: Maxwell
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wu
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
authors.forename: Maria S
authors.initials: MS
authors.lastname: Michener
authors.forename: Peter
authors.initials: P
authors.lastname: Szczerba
authors.forename: Edward
authors.initials: E
authors.lastname: Brnardic
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rada
authors.forename: Yuntae
authors.initials: Y
authors.lastname: Kim
authors.forename: Robert
authors.initials: R
authors.lastname: Meissner
authors.forename: Peter
authors.initials: P
authors.lastname: Wuelfing
authors.forename: Yang
authors.initials: Y
authors.lastname: Yuan
authors.forename: Jeanine
authors.initials: J
authors.lastname: Ballard
authors.forename: Marie
authors.initials: M
authors.lastname: Holahan
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klein
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Xavier
authors.initials: X
authors.lastname: Fradera
authors.forename: Gopal
authors.initials: G
authors.lastname: Parthasarathy
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.affiliation: WuXi AppTec Company, Ltd. , Shanghai 200131, P. R. China.
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: WuXi AppTec Company, Ltd. , Shanghai 200131, P. R. China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: WuXi AppTec Company, Ltd. , Shanghai 200131, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cooke
authors.forename: D Jonathan
authors.initials: DJ
authors.lastname: Bennett
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
authors.forename: John
authors.initials: J
authors.lastname: Renger
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000818:Animals; D001057:Apolipoproteins E / Q000134:cerebrospinal fluid*; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D056945:Hep G2 Cells; D006801:Humans; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008124:Locomotion / Q000187:drug effects; D008253:Macaca mulatta; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C000611072:2-chloro-4-(1'-(2-hydroxy-3,3-dimethyl-2-(trifluoromethyl)butanoyl)-(4,4'-bipiperidin)-1-yl)-N,N-dimethylbenzamide; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D001549:Benzamides; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010880:Piperidines