5avl
From Proteopedia
Crystal structure of LXRalpha in complex with tert-butyl benzoate analog, compound 32b
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 PubMedTo obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys. Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoates as liver X receptor agonists.,Matsui Y, Yamaguchi T, Yamazaki T, Yoshida M, Arai M, Terasaka N, Honzumi S, Wakabayashi K, Hayashi S, Nakai D, Hanzawa H, Tamaki K Bioorg Med Chem Lett. 2015 Sep 15;25(18):3914-20. doi:, 10.1016/j.bmcl.2015.07.047. Epub 2015 Jul 23. PMID:26238323[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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