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Title: Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease

Journal Article · · Journal of Medicinal Chemistry
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  1. Merck Research Labs, West Point, PA (United States)
  2. WuXi AppTec Company, Ltd., Shanghai (China)
+ Show Author Affiliations

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. Lastly, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
Shanghai Synchrotron Radiation Facility (SSRF)
OSTI ID:
1404984
Journal Information:
Journal of Medicinal Chemistry, Vol. 59, Issue 7; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 35 works
Citation information provided by
Web of Science

References (27)

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Apolipoprotein E4 promotes the early deposition of Aβ42 and then Aβ40 in the elderly journal July 2000
Fibrillar amyloid-  burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease journal April 2009
Effect of Domain Interaction on Apolipoprotein E Levels in Mouse Brain journal November 2005
Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels journal November 2008
Human APOE Isoform-Dependent Effects on Brain  -Amyloid Levels in PDAPP Transgenic Mice journal May 2009
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy journal April 2009
Systemic treatment with liver X receptor agonists raises apolipoprotein E, cholesterol, and amyloid-β peptides in the cerebral spinal fluid of rats journal January 2010
Human apoE Isoforms Differentially Regulate Brain Amyloid-  Peptide Clearance journal June 2011
ABCA1 Is Required for Normal Central Nervous System ApoE Levels and for Lipidation of Astrocyte-secreted apoE journal September 2004
A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes journal February 2004
Decreased Clearance of CNS  -Amyloid in Alzheimer's Disease journal December 2010
Different roles of liver X receptor α and β in lipid metabolism: Effects of an α-selective and a dual agonist in mice deficient in each subtype journal February 2006
Role of LXRs in control of lipogenesis journal November 2000
Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines journal April 2002
Indazole-Based Liver X Receptor (LXR) Modulators with Maintained Atherosclerotic Lesion Reduction Activity but Diminished Stimulation of Hepatic Triglyceride Synthesis journal October 2008
Liver X Receptor (LXR) partial agonists: Biaryl pyrazoles and imidazoles displaying a preference for LXRβ journal January 2015
LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse journal December 2009
Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of LXR-623, a Novel Liver X-Receptor Agonist, in Healthy Participants journal June 2009
TBAF-Catalyzed Direct Nucleophilic Trifluoromethylation of α-Keto Amides with Trimethyl(trifluoromethyl)silane journal April 1999
Absolute configuration determination of chiral molecules in the solution state using vibrational circular dichroism journal January 2003
X-ray Crystal Structure of the Liver X Receptor β Ligand Binding Domain journal July 2003
Liver X receptor in cholesterol metabolism journal October 2009
Increase of locomotor activity underlying the behavioral disinhibition in Tg2576 mice. journal January 2007
Behavioral characterization of the Tg2576 transgenic model of Alzheimer's disease through 19 months journal April 2002
LXRα regulates human CETP expression in vitro and in transgenic mice journal September 2010

Cited By (9)

Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer's disease journal May 2019
Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions journal August 2019
Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer’s disease mouse model journal March 2019
Therapeutic potential of nuclear receptor agonists in Alzheimer’s disease journal March 2017
Synthesis and In Vitro Evaluation of Novel Liver X Receptor Agonists Based on Naphthoquinone Derivatives journal November 2019
New Insights in Prostate Cancer Development and Tumor Therapy: Modulation of Nuclear Receptors and the Specific Role of Liver X Receptors journal August 2018
Liver X receptors in lipid signalling and membrane homeostasis journal June 2018
Structural analysis identifies an escape route from the adverse lipogenic effects of liver X receptor ligands journal November 2019
Ligands of Therapeutic Utility for the Liver X Receptors journal January 2017

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
rodent models
lipids
peptides and proteins
agonists
central nervous system