5HJS

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

5HJS の概要

• エントリーDOI: 10.2210/pdb5hjs/pdb
• 関連するPDBエントリー: 5HJP
• 分子名称: Oxysterols receptor LXR-alpha, Nuclear receptor coactivator 1, 2-chloro-4-{1'-[(2R)-2-hydroxy-3-methyl-2-(trifluoromethyl)butanoyl]-4,4'-bipiperidin-1-yl}-N,N-dimethylbenzamide, ... (5 entities in total)
• 機能のキーワード: agonist, alzheimer's, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus : Q13133 Q15788
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 72573.26

構造登録者

Parthasarathy, G.,Klein, D. (登録日: 2016-01-13, 公開日: 2016-04-06, 最終更新日: 2024-03-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.72 Å)