Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) β Agonist

Zheng, Ya-Jun; Zhuang, Liujing; Fan, Kristi; Tice, Colin M.; Zhao, Wei; Dong, Chen; Lotesta, Stephen D.; Leftheris, Katerina; Lindblom, Peter; Zhijie, Liu; Shimada, Jun; Noto, Paul; Shi, Meng; Hardy, Anne-Chantal; Howard, Lamont; Krosky, Paula M.; Guo, Joan; Lipinski, Kerri; Kandpal, Geeta; Bukhtiyarov, Yuri; Zhao, Yi; Lala, Deepak S.; Orden, Rebecca Van; Zhou, Jing; Chen, Guozhou; Wu, Zhenyong; McKeever, Brian; McGeehan, Gerard M.; Gregg, Richard E.; Claremon, David A.; Singh, Suresh B.

doi:10.1021/acs.jmedchem.5b02029

Cited by 29 publications

(21 citation statements)

References 37 publications

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“…Recently, the application of structure-based drug design technology to a phenylsulfone fragment led to development of a novel, orally bioavailable LXRβ-selective partial agonist (Zheng, et al, 2016). This prototype has reportedly been further optimized for human trials (Zheng, et al, 2016).…”

Section: Advanced Lxr Therapeuticsmentioning

confidence: 99%

The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease

Fessler

2018

Pharmacology & Therapeutics

115

112

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The Liver X Receptors (LXRs) are oxysterol-activated transcription factors that upregulate a suite of genes that together promote coordinated mobilization of excess cholesterol from cells and from the body. The LXRs, like other nuclear receptors, are anti-inflammatory, inhibiting signal-dependent induction of pro-inflammatory genes by nuclear factor-κB, activating protein-1, and other transcription factors. Synthetic LXR agonists have been shown to ameliorate atherosclerosis and a wide range of inflammatory disorders in preclinical animal models. Although this has suggested potential for application to human disease, systemic LXR activation is complicated by hepatic steatosis and hypertriglyceridemia, consequences of lipogenic gene induction in the liver by LXRα. The past several years have seen the development of multiple advanced LXR therapeutics aiming to avoid hepatic lipogenesis, including LXRβ-selective agonists, tissue-selective agonists, and transrepression-selective agonists. Although several synthetic LXR agonists have made it to phase I clinical trials, none have progressed due to unforeseen adverse reactions or undisclosed reasons. Nonetheless, several sophisticated pharmacologic strategies, including structure-guided drug design, cell-specific drug targeting, as well as non-systemic drug routes have been initiated and remain to be comprehensively explored. In addition, recent studies have identified potential utility for targeting the LXRs during therapy with other agents, such as glucocorticoids and rexinoids. Despite the pitfalls encountered to date in translation of LXR agonists to human disease, it appears likely that this accelerating field will ultimately yield effective and safe applications for LXR targeting in humans.

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Section: Advanced Lxr Therapeuticsmentioning

confidence: 99%

The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease

Fessler

2018

Pharmacology & Therapeutics

115

112

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“…With the utilization of the structure-based drug design platform, Contour, Zheng et al synthesized LXRβ agonists mainly containing a 2-(methylsulfonyl)benzyl alcohol and a piperazine core. One such compound (514V, Figure 8 ) exhibited 27 fold selectivity for LXRβ over LXRα, and is currently in clinical trials for the treatment of atopic dermatitis [ 112 ].…”

Section: Ligands Of Liver X Receptorsmentioning

confidence: 99%

Ligands of Therapeutic Utility for the Liver X Receptors

et al. 2017

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Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism. This review provides a summary of known endogenous, naturally occurring, and synthetic ligands. The review also offers considerations from a molecular modeling perspective with which to design more specific LXRβ ligands based on the interaction energies of ligands and the important amino acid residues in the LXRβ ligand binding domain.

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“…Compound 9 showed 27-fold selectivity for LXRb (IC 50 = 3nm)i na nL XR bindinga ssay,a nd induced ABCA1 gene expression in HEK293 cells. [20] Compound 9 also induced SREBP-1c gene expression (91 %r elative to 3)i n HepG2 cells. Therefore, overall, these reported agonists show insufficient LXRb selectivity in reporterg ene assays or have problematic pharmacokinetics.…”

Section: Introductionmentioning

confidence: 89%

“…Compound 8 exhibited five‐fold selectivity for LXRβ in a reporter gene assay with HepG2 (human liver hepatocellular carcinoma) cells: LXRβ EC 50 =0.063 μ m (98 % efficacy) and LXRα EC 50 =0.346 μ m (41 % efficacy). Compound 9 showed 27‐fold selectivity for LXRβ (IC 50 =3 n m ) in an LXR binding assay, and induced ABCA1 gene expression in HEK293 cells . Compound 9 also induced SREBP‐1c gene expression (91 % relative to 3 ) in HepG2 cells.…”

Section: Introductionmentioning

confidence: 98%

Development of Tetrachlorophthalimides as Liver X Receptor β (LXRβ)‐Selective Agonists

et al. 2016

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Liver X receptor (LXR) agonists are candidates for the treatment of atherosclerosis via induction of ABCA1 (ATP-binding cassette A1) gene expression, which contributes to reverse cholesterol transport (RCT) and to cholesterol efflux from the liver and intestine. However, LXR agonists also induce genes involved in lipogenesis, such as SREBP-1c (sterol regulatory binding element protein 1c) and FAS (fatty acid synthase), thereby causing an undesirable increase in plasma and hepatic triglyceride (TG) levels. Recent studies indicate that LXRα contributes to lipogenesis in liver, and selective LXRβ activation improves RCT in mice. Therefore, LXRβ-selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. However, the ligand-binding domains in the two LXR isoforms α/β share high sequence identity, and few LXR ligands show subtype selectivity. In this study we identified a tetrachlorophthalimide analogue as an LXRβ-selective agonist. Structural development led to (E)-4,5,6,7-tetrachloro-2-(2-styrylphenyl)isoindoline-1,3-dione (24 a), which shows potent and selective LXRβ agonistic activity in reporter gene assays. In binding assays, compound 24 a bound to LXRβ preferentially over LXRα. It also induced the expression of ABCA1 mRNA but not SREBP-1c mRNA in cells. Compound 24 a appears to be a promising lead compound for therapeutic agents to treat atherosclerosis without the side effects induced by LXRα/β dual agonists.

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Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) β Agonist

Cited by 29 publications

References 37 publications

The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease

The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease

Ligands of Therapeutic Utility for the Liver X Receptors

Development of Tetrachlorophthalimides as Liver X Receptor β (LXRβ)‐Selective Agonists

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