The discovery of tertiary-amine LXR agonists with potent cholesterol efflux activity in macrophages

Neuroactive steroids act in the peripheral nervous system as physiological regulators and as protective agents for acquired or inherited peripheral neuropathy. In recent years, modulation of neuroactive steroids levels has been studied as a potential therapeutic approach to protect peripheral nerves from damage induced by diabetes. Nuclear receptors of the liver X receptor (LXR) family regulate adrenal steroidogenesis via their ability to control cholesterol homeostasis. Here we show that rat sciatic nerve expresses both LRX␣ and ␤ isoforms and that these receptors are functional. Activation of liver X receptors using a synthetic ligand results in increased levels of neurosteroids and protection of the sciatic nerve from neuropathy induced by diabetes. LXR ligand treatment of streptozotocin-treated rats increases expression in the sciatic nerve of steroidogenic acute regulatory protein (a molecule involved in the transfer of cholesterol into mitochondria), of the enzyme P450scc (responsible for conversion of cholesterol into pregnenolone), of 5␣-reductase (an enzyme involved in the generation of neuroactive steroids) and of classical LXR targets involved in cholesterol efflux, such as ABCA1 and ABCG1. These effects were associated with increased levels of neuroactive steroids (e.g., pregnenolone, progesterone, dihydroprogesterone and 3␣-diol) in the sciatic nerve, and with neuroprotective effects on thermal nociceptive activity, nerve conduction velocity, and Na ϩ , K ϩ -ATPase activity. These results suggest that LXR activation may represent a new pharmacological avenue to increase local neuroactive steroid levels that exert neuroprotective effects in diabetic neuropathy.

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“…All solvents and reagents were HPLC grade (Sigma-Aldrich). GW3965 was synthesized in house as previously described (Marino et al, 2009). …”

Section: Methodsmentioning

confidence: 99%

Activation of the Liver X Receptor Increases Neuroactive Steroid Levels and Protects from Diabetes-Induced Peripheral Neuropathy

Cermenati¹,

Giatti²,

Cavaletti³

et al. 2010

J. Neurosci.

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“…A group at GlaxoSmithKline (GSK) employed parallel solid-phase synthesis to optimize the cell potency of a screening hit to give tertiary amino acid 3 and the corresponding carboxamide, GW6340 ( 35 , Figure ). , Compound 3 has an EC 50 of 190 nM (67%) against LXRα in a Gal4 assay. X-ray structures of 3 bound to both LXRα (PDB ID: ) and LXRβ (PDB IDs: and ) , are publicly available.…”

Section: Medicinal Chemistrymentioning

confidence: 99%

The Medicinal Chemistry of Liver X Receptor (LXR) Modulators

Tice¹,

Noto²,

Fan³

et al. 2014

J. Med. Chem.

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LXRs have been of interest as targets for the treatment of atherosclerosis for over a decade. In recent years, LXR modulators have also garnered interest for potential use in the treatment of inflammation, Alzheimer's disease (AD), dermatological conditions, hepatic steatosis, and oncology. To date, no LXR modulator has successfully progressed beyond phase I clinical trials. In this Perspective, we summarize published medicinal chemistry efforts in the context of the available crystallographic data, druglikeness, and isoform selectivity. In addition, we discuss the challenges that need to be overcome before an LXR modulator can reach clinical use.

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“…The lower value of ΔScore, the higher selectively against LXRβ. As can be seen in Table 1, BDBM27173, BDBM27174 and BDBM50300572 [54] showed favorable binding a nity against LXRβ and poor binding a nity against LXRα, and ΔScore of them were − 8.0 kcal•mol − 1 , -6.1 kcal•mol − 1 and − 3.8 kcal•mol − 1 respectively. These compounds are analogs of GW3965 [55], a tertiary-amine LXR agonist.…”

Section: Exploring Speci C Key Residues Binding With Lxrβmentioning

confidence: 94%

Identifying selective agonists targeting LXRβ from terpene compounds of alismatis rhizoma

Lin

et al. 2021

J Mol Model

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Hyperlipidemia is thought as an important contributor to coronary disease, diabetes and fatty liver. Liver X receptors β (LXRβ) was considered as a validated target for hyperlipidemia therapy due to its role in regulating cholesterol homeostasis and immunity. However, many current drugs applied in clinic are not selectively targeting LXRβ and they can also activate LXRα which activate SREBP-1c worked as activator of lipogenic genes. Therefore, exploiting agonists selectively targeting LXRβ are urgent. Here, computational tools were used to screen potential agonists selectively targeting LXRβ from 112 terpenes of Alismatis Rhizoma. Firstly, structural analysis between selective and nonselective agonists were used to explore key residues of selective binding with LXRβ. Our data indicated that Phe 271 , Ser 278 , Met 312 , His 435 , Trp 457 were important to compounds binding with LXRβ, suggesting that engaging ligand interaction with these residues may provide directions for development of ligands with improved selective pro les. Then, ADMET analysis, molecular docking, MD simulations and calculation of binding free energy and its decomposition were executed to screen the agonists whose bioactivity were favorable from 112 terpenes of Alismatis Rhizoma. We found that two triterpenes 16-hydroxy-alisol B 23-acetate and Alisol M 23-acetate showed favorable ADMET properties and high binding a nity against LXRβ. These compounds could be considered as promising selective agonists targeting LXRβ. Our work provides an alternative strategy for screening agonists selectively targeting LXRβ from Alismatis Rhizoma for hyperlipidemia disease treatment.

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The discovery of tertiary-amine LXR agonists with potent cholesterol efflux activity in macrophages

Cited by 7 publications

References 26 publications

Activation of the Liver X Receptor Increases Neuroactive Steroid Levels and Protects from Diabetes-Induced Peripheral Neuropathy

Activation of the Liver X Receptor Increases Neuroactive Steroid Levels and Protects from Diabetes-Induced Peripheral Neuropathy

The Medicinal Chemistry of Liver X Receptor (LXR) Modulators

Identifying selective agonists targeting LXRβ from terpene compounds of alismatis rhizoma

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