Discovery and Optimization of a Novel Series of Liver X Receptor‐α Agonists.

Li, Leping; Liu, Jiwen; Zhu, Linchao; Cutler, Serena; Hasegawa, Hirohiko; Shan, Bei; Medina, Julio C.

doi:10.1002/chin.200623225

Cited by 10 publications

(19 citation statements)

References 1 publication

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“…The LXR agonists GW3965 and T0901317 were synthesized as described (Collins et al, 2002; Collins, 2002; Li, 2000). Primary peritoneal macrophages were collected four days after thioglycollate injection (Hong et al, 2011).…”

Section: Methodsmentioning

confidence: 99%

The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice

et al. 2014

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Summary The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR–IDOL axis are both tissue- and species-specific. In mice, LXR agonist induces Idol transcript levels in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues but not in the liver. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a potential strategy for LDL lowering in humans.

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Section: Methodsmentioning

confidence: 99%

The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice

et al. 2014

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“…We thus turned our attention to corresponding alcohols 13 and 14 that are easily accessible from ketones 11 and 12. Although alcohols were not active, we were inspired by work of Li et al 26 describing the hexafluoroisopropyl group as viable moiety in a drug design which uniquely combines lipophilicity with a relatively acidic hydroxyl group. Again, screening revealed no activity of such amphiphilic alcohols.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Specific Inhibitors of HIV Capsid Assembly Binding to the C-Terminal Domain of the Capsid Protein: Evaluation of 2-Arylquinazolines as Potential Antiviral Compounds

et al. 2016

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Assembly of human immunodeficiency virus (HIV-1) represents an attractive target for antiretroviral therapy which is not exploited by currently available drugs. We established high-throughput screening for assembly inhibitors based on competition of small molecules for the binding of a known dodecapeptide assembly inhibitor to the C-terminal domain of HIV-1 CA (capsid). Screening of >70000 compounds from different libraries identified 2-arylquinazolines as low micromolecular inhibitors of HIV-1 capsid assembly. We prepared focused libraries of modified 2-arylquinazolines and tested their capacity to bind HIV-1 CA to compete with the known peptide inhibitor and to prevent the replication of HIV-1 in tissue culture. Some of the compounds showed potent binding to the C-terminal domain of CA and were found to block viral replication at low micromolar concentrations.

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“…15 Percent efficacy of agonists was given relative to the positive control 6. 14a, 16 In the present work, we focused on the (1 and 2), synthetic ligands (3, 4, and 6), and a transrepression-selective ligand (5). transrepressional activity of phenanthridin-6-one, dibenz [b,f ]- [1,4]oxazepin -11-one, 11,12-dihydrodibenz[b,f ]azocin-6-one, and 5,11-dihydro-11-methylene-6H-dibenz[b,e]azepin-6-one derivatives ( Figure 2).…”

Section: Resultsmentioning

confidence: 99%

“…2.3. Synthesis of compounds [16][17][18][19][20][21][22]e]azepin-6-ones 16−22 were prepared via intramolecular Heck reaction as the key step, as shown in Scheme 1. 4-Substituted anilines 11 were monobrominated (12) and vinylated to give compounds 13.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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

et al. 2012

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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 μM but showed no transactivational activity even at 30 μM. 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 LXRα. Next, further structural modification was performed with the guidance of docking simulations with LXRα, focusing on enhancing the binding of the ligands with LXRα 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.

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Discovery and Optimization of a Novel Series of Liver X Receptor‐α Agonists.

Cited by 10 publications

References 1 publication

The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice

The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice

Specific Inhibitors of HIV Capsid Assembly Binding to the C-Terminal Domain of the Capsid Protein: Evaluation of 2-Arylquinazolines as Potential Antiviral Compounds

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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