Design, synthesis, and biological evaluation of novel transrepression-selective liver X receptor (LXR) ligands with 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one skeleton.

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Aoyama A, Endo-Umeda K, Kishida K, Ohgane K, Noguchi-Yachide T, Aoyama H, Ishikawa M, Miyachi H, Makishima M, Hashimoto Y

Design, synthesis, and biological evaluation of novel transrepression-selective liver X receptor (LXR) ligands with 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one skeleton.

J Med Chem. 2012 Sep 13;55(17):7360-77. doi: 10.1021/jm3002394. Epub 2012 Aug 27.

PubMed ID

22873709 [ View in PubMed

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Abstract

To obtain novel transrepression-selective liver X receptor (LXR) ligands, we adopted a strategy of reducing the transactivational agonistic activity of the 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one derivative 10, which exhibits LXR-mediated transrepressional and transactivational activity. Structural modification of 10 based on the reported X-ray crystal structure of the LXR ligand-binding domain led to a series of compounds, of which almost all exhibited transrepressional activity at 1 or 10 muM but showed no transactivational activity even at 30 muM. Among the compounds obtained, 18 and 22 were confirmed to have LXR-dependent transrepressional activity by using peritoneal macrophages from wild-type and LXR-null mice. A newly developed fluorescence polarization assay indicated that they bind directly to LXRalpha. Next, further structural modification was performed with the guidance of docking simulations with LXRalpha, focusing on enhancing the binding of the ligands with LXRalpha through the introduction of substituents or heteroatom(s). Among the compounds synthesized, compound 48, bearing a hydroxyl group, showed potent, selective, and dose-dependent transrepressional activity.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
TO-901317	Oxysterols receptor LXR-alpha	EC 50 (nM)	340	N/A	N/A	Details