5hjs | pdb_00005hjs
Identification of LXRbeta selective agonists for the treatment of Alzheimer's Disease
Structural highlights
FunctionNR1H3_HUMAN Orphan receptor. Interaction with RXR shifts RXR from its role as a silent DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXRES. LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half-sites spaced by four nucleotides. Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8 (By similarity). Publication Abstract from PubMedHerein, we describe the development of a functionally selective liver X receptor beta (LXRbeta) 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-beta 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. Identification and in Vivo Evaluation of Liver X Receptor beta-Selective Agonists for the Potential Treatment of Alzheimer's Disease.,Stachel SJ, Zerbinatti C, Rudd MT, Cosden M, Suon S, Nanda KK, Wessner K, DiMuzio J, Maxwell J, Wu Z, Uslaner JM, Michener MS, Szczerba P, Brnardic E, Rada V, Kim Y, Meissner R, Wuelfing P, Yuan Y, Ballard J, Holahan M, Klein DJ, Lu J, Fradera X, Parthasarathy G, Uebele VN, Chen Z, Li Y, Li J, Cooke AJ, Bennett DJ, Bilodeau MT, Renger J J Med Chem. 2016 Apr 14;59(7):3489-98. doi: 10.1021/acs.jmedchem.6b00176. Epub, 2016 Apr 1. PMID:27011007[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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