5HJP

Identification of LXRbeta selective agonists for the treatment of Alzheimer's Disease

Summary for 5HJP

• Entry DOI: 10.2210/pdb5hjp/pdb
• Related: 5HJS
• Descriptor: Retinoic acid receptor RXR-beta, Oxysterols receptor LXR-beta, 2-chloro-4-{1'-[(2R)-2-hydroxy-3-methyl-2-(trifluoromethyl)butanoyl]-4,4'-bipiperidin-1-yl}-N,N-dimethylbenzamide, ... (5 entities in total)
• Functional Keywords: agonist, alzheimer's, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: P28702 P55055
• Total number of polymer chains: 4
• Total formula weight: 117279.40

Authors

Parthasarathy, G.,Klein, D. (deposition date: 2016-01-13, release date: 2016-04-06, Last modification date: 2024-03-06)

Primary citation

Stachel, S.J.,Zerbinatti, C.,Rudd, M.T.,Cosden, M.,Suon, S.,Nanda, K.K.,Wessner, K.,DiMuzio, J.,Maxwell, J.,Wu, Z.,Uslaner, J.M.,Michener, M.S.,Szczerba, P.,Brnardic, E.,Rada, V.,Kim, Y.,Meissner, R.,Wuelfing, P.,Yuan, Y.,Ballard, J.,Holahan, M.,Klein, D.J.,Lu, J.,Fradera, X.,Parthasarathy, G.,Uebele, V.N.,Chen, Z.,Li, Y.,Li, J.,Cooke, A.J.,Bennett, D.J.,Bilodeau, M.T.,Renger, J.
Identification and in Vivo Evaluation of Liver X Receptor beta-Selective Agonists for the Potential Treatment of Alzheimer's Disease.
J.Med.Chem., 59:3489-3498, 2016

PubMed 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.

PubMed: 27011007
DOI: 10.1021/acs.jmedchem.6b00176

Experimental method

X-RAY DIFFRACTION (2.6 Å)