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

Aoyama, Atsushi; Endo-Umeda, Kaori; Kishida, Kenji; Ohgane, Kenji; Noguchi‐Yachide, Tomomi; Aoyama, Hiroshi; Ishikawa, Minoru; Miyachi, Hiroyuki; Makishima, Makoto; Hashimoto, Yuichi

doi:10.1021/jm3002394

Cited by 56 publications

(28 citation statements)

References 55 publications

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“…Moreover, physical interactions between β-catenin and either TRs or LXRs have been also described improving their effects. [32,[52][53][54] can be used as pharmacological inducers of ABCD2. Further studies are needed to confirm whether such molecules, by their ability to induce ABCD2 and to reduce oxidative stress, may have a therapeutic value in the context of X-ALD.…”

Section: Discussionmentioning

confidence: 99%

LXR antagonists induce ABCD2 expression

Gondcaille

Génin

López

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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X-linked adrenoleukodystrophy (X-ALD) is a rare neurodegenerative disorder characterized by the accumulation of very-long-chain fatty acids resulting from a beta-oxidation defect. Oxidative stress and inflammation are also key components of the pathogenesis. X-ALD is caused by mutations in the ABCDI gene, which encodes for a peroxisomal half ABC transporter predicted to participate in the entry of VLCFA-CoA into the peroxisome, the unique site of their beta-oxidation. Two homologous peroxisomal ABC transporters, ABCD2 and ABCD3 have been proven to compensate for ABCD1 deficiency when overexpressed. Pharmacological induction of these target genes could therefore represent an alternative therapy for X-ALD patients. Since LXR activation was shown to repress ABCD2 expression, we investigated the effects of LXR antagonists in different cell lines. Cells were treated with GSK(17) (a LXR antagonist recently discovered from the GlaxoSmithKline compound collection), 22(S)-hydroxycholesterol (22S-HC, another LXR antagonist) and 22R-HC (an endogenous LXR agonist). We observed up-regulation of ABCD2,ABCD3 and CTNNB1 (the gene encoding for beta-catenin, which was recently demonstrated to induce ABCD2 expression) in human HepG2 hepatoma cells and in X-ALD skin fibroblasts treated with LXR antagonists. Interestingly, induction in X-ALD fibroblasts was concomitant with a decrease in oxidative stress. Rats treated with 22S-HC showed hepatic induction of the 3 genes of interest. In human, we show by multiple tissue expression array that expression of ABCD2 appears to be inversely correlated with NR1H3 (LXRalpha) expression. Altogether, antagonists of LXR that are currently developed in the context of dyslipidemia may find another indication with X-ALD.

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Section: Discussionmentioning

confidence: 99%

LXR antagonists induce ABCD2 expression

Gondcaille

Génin

López

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…At the same time, a methoxy group was introduced at the paraposition of the phenethylphenyl group because many types of LXR ligands possess a methoxy group(s). 11,23,26,27 However, introduction of the methoxy group (20b) did not result in any increase of IL-6-inhibitory activity compared with 7. Replacement of the ethyl linker of methoxy analogue 20b with the …”

Section: Lettermentioning

confidence: 93%

“…Although LXR ligands such as 3 and 4 exhibit both transactivating and transrepressional activities, the first transrepression-selective LXR modulators were reported by GlaxoSmithKline in 2008. 23 Compound 5 has similar transrepressional activity to 3 and does not increase TG accumulation. However, 5 showed transactivating-agonistic activity in a cell-based reporter assay.…”

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confidence: 95%

“…In 2012, we reported that 6 showed more potent transrepressional activity than 3 or 5 and lacked transactivating activity at 30 μM under our assay conditions. 24 Very few transrepression-selective LXR modulators have yet been reported, 23,24 and a recent Perspective noted that "SAR of transrepression is not well understood, and this remains an underexplored area with potential in several disease areas." 8 Therefore, investigation of the SAR of transrepression-selective LXR modulators having various scaffolds should improve our understanding of the molecular basis of LXR-mediated transrepression.…”

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confidence: 99%

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Styrylphenylphthalimides as Novel Transrepression-Selective Liver X Receptor (LXR) Modulators

Nomura

Endo-Umeda

Aoyama

et al. 2015

ACS Med. Chem. Lett.

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Anti-inflammatory effects of liver X receptor (LXR) ligands are thought to be largely due to LXR-mediated transrepression, whereas side effects are caused by activation of LXR-responsive gene expression (transactivation). Therefore, selective LXR modulators that preferentially exhibit transrepression activity should exhibit anti-inflammatory properties with fewer side effects. Here, we synthesized a series of styrylphenylphthalimide analogues and evaluated their structure-activity relationships focusing on LXRs-transactivating-agonistic/antagonistic activities and transrepressional activity. Among the compounds examined, 17l showed potent LXR-transrepressional activity with high selectivity over transactivating activity and did not show characteristic side effects of LXR-transactivating agonists in cells. This representative compound, 17l, was confirmed to have LXR-dependent transrepressional activity and to bind directly to LXRβ. Compound 17l should be useful not only as a chemical tool for studying the biological functions of LXRs transrepression but also as a candidate for a safer agent to treat inflammatory diseases.

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“…Unfortunately, the trial was terminated due to adverse central nervous system effects. [19][20][21] LXR antagonists reported so far include riccardin C (4, antagonist of LXRβ), naringenin (5, antagonist of LXRα), genistein (6, inhibition of LXRα or activation of LXRβ), taurine (7, antagonist of LXRα), rhein (8, antagonist of LXRα/β), SR-9238 (9, antagonist of LXRα/β), and 10 (antagonist of LXRα), among others [22][23][24][25][26][27][28] (Fig. 1).…”

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confidence: 99%

Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists

Nian

Gan

Tan

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/β were tested in vitro. Compound 26 had an IC 50 value of 6.4 µM against LXRα and an IC 50 value of 5.6 µM against LXRβ. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRα/β antagonists.Key words liver X receptor α; liver X receptor β; antagonistic activity Nuclear receptors (NRs) are ligand-activated transcription factors that coordinate gene expression in response to the modulation of metabolism, development, proliferation, and inflammation.1,2) Liver X receptors (LXRs) belonging to the NR superfamily are activated by specific oxidized forms of cholesterol and intermediate products of the cholesterol biosynthetic pathway. 1,3,4) There are two LXR isoforms in mammals, termed LXRα and LXRβ. LXRα is abundantly expressed mainly in the liver, intestine, kidney, spleen, and adipose tissue, whereas LXRβ is more ubiquitously expressed, with particularly high levels in the developing brain. [5][6][7][8] Both isoforms share almost 80% homology of their amino acid sequences in their DNA-binding domain and ligand-binding domain. 5,7)The LXR consists of four domains: N-terminal ligandindependent activation function domain (AF-1); DNA-binding domain (DBD); hydrophobic ligand-binding domain (LBD); and C-terminal ligand-dependent transactivation sequence (AF-2).5,9,10) By forming heterodimers with retinoid X receptors (RXRs), LXRs bind to LXR response elements (LXREs) in the promoter or enhancer elements of LXR target genes. The activation of LXR-RXR heterodimers not only induces the expression of a variety of target genes (CYP7A, ABCA1, SREBP-1) that are involved in lipid and glucose metabolism, but also results in the inhibition of genes encoding inflammatory factors such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ. 1,[11][12][13][14][15] In the last decade, GlaxoSmithKline and other several pharmaceutical companies have been active in developing synthetic LXR agonists (Fig. 1). T0901317 (1, Tularik) and GW3965 (2, GSK) exhibit nonselectivity for LXRα and LXRβ with high affinity.11,16-18) The first compound to enter the clinic was LXR-623 (3, Wyeth), an LXRα/β partial agonist for the potential treatment of atherosclerosis and dyslipidemia. Unfortunately, the trial was terminated due to adverse central nervous system effects.19-21) LXR antagonists reported so far include riccardin C (4, antagonist of LXRβ), naringenin (5, antagonist of LXRα), genistein (6, inhibition of LXRα or activation of LXRβ), taurine (7, antagonist of LXRα), rhein (8, antagonist of LXRα/β), SR-9238 (9, antagonist of LXRα/β), and 10 (antagonist of LXRα), among others 22-28) (Fig. 1).SR-9238 was the first selective synthetic LXR inverse agonist that displays a degree of LXRβ selectivity with an IC 50 value of 214 nM for LXRα and 43 nM for LXRβ, and this compound effectively suppressed hepatic lipogenesis, inflammation, and hepatic lipid...

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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

Cited by 56 publications

References 55 publications

LXR antagonists induce ABCD2 expression

LXR antagonists induce ABCD2 expression

Styrylphenylphthalimides as Novel Transrepression-Selective Liver X Receptor (LXR) Modulators

Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists

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