Structure–activity relationship study of non-steroidal NPC1L1 ligands identified through cell-based assay using pharmacological chaperone effect as a readout

Karaki, Fumika; Ohgane, Kenji; Fukuda, Hiromitsu; Nakamura, Masahiko; Dodo, Kosuke; Hashimoto, Yuichi

doi:10.1016/j.bmc.2014.05.022

Cited by 18 publications

(14 citation statements)

References 39 publications

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“…Several steroidal and non-steroidal compounds, which bind to NPC1L1, have pharmacological chaperone activities that correct trafficking defects of NPC1L1 mutants. Recently, it was reported that such compounds bind to sites distinct from both the NTD and the ezetimibe-binding site [18] , [19] . To determine whether fomiroid A directly binds to hNPC1L1, we analyzed the pharmacological chaperone activity of this compound on trafficking of the L1072T/L1168I mutant to the plasma membrane.…”

Section: Resultsmentioning

confidence: 99%

“…Compounds that bind to the second sterol-binding site of NPC1L1, which is distinct from both the NTD and the ezetimibe-binding site, exhibit pharmacological chaperone activity against the NPC1L1 L1072T/L1168I mutant. Normally, this mutant localizes predominantly to the ER, but these pharmacological chaperones re-localize it to the plasma membrane [18] , [19] . We examined the pharmacological chaperone activity of fomiroid A by confocal microscopy ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Several steroidal and non-steroidal compounds have pharmacological chaperone activities that correct trafficking defects of NPC1L1 mutants. Recently, Karaki et al reported that such compounds bind to sites distinct from both the NTD and the ezetimibe-binding site, suggesting the existence of a second sterol-binding site in NPC1L1 [18] , [19] .…”

Section: Introductionmentioning

confidence: 99%

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Fomiroid A, a Novel Compound from the Mushroom Fomitopsis nigra, Inhibits NPC1L1-Mediated Cholesterol Uptake via a Mode of Action Distinct from That of Ezetimibe

et al. 2014

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Hypercholesterolemia is one of the key risk factors for coronary heart disease, a major cause of death in developed countries. Suppression of NPC1L1-mediated dietary and biliary cholesterol absorption is predicted to be one of the most effective ways to reduce the risk of hypercholesterolemia. In a screen for natural products that inhibit ezetimibe glucuronide binding to NPC1L1, we found a novel compound, fomiroid A, in extracts of the mushroom Fomitopsis nigra. Fomiroid A is a lanosterone derivative with molecular formula C30H48O3. Fomiroid A inhibited ezetimibe glucuronide binding to NPC1L1, and dose-dependently prevented NPC1L1-mediated cholesterol uptake and formation of esterified cholesterol in NPC1L1-expressing Caco2 cells. Fomiroid A exhibited a pharmacological chaperone activity that corrected trafficking defects of the L1072T/L1168I mutant of NPC1L1. Because ezetimibe does not have such an activity, the binding site and mode of action of fomiroid A are likely to be distinct from those of ezetimibe.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fomiroid A, a Novel Compound from the Mushroom Fomitopsis nigra, Inhibits NPC1L1-Mediated Cholesterol Uptake via a Mode of Action Distinct from That of Ezetimibe

et al. 2014

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“…We have previously developed LXRs antagonist 1 [ 8 ], retinoic acid receptor-related orphan receptors (RORs) inverse agonist 2 [ 9 ], progesterone receptor (PR) antagonist 3 [ 10 ], and pharmacological chaperones 4 and 5 for Niemann-Pick disease type C1 (NPC1) [ 11 ] and Niemann-Pick type C1-like 1 (NPC1L1) ( Figure 1 ) [ 12 ]. These compounds all contain a phenanthridin-6(5 H )-one skeleton as a cyclized carba-analog of the skeleton of LXRs pan agonist T0901317 ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton

Nishiyama

Fujii

Makishima

et al. 2018

IJMS

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Background: Nuclear receptors (NRs) are considered as potential drug targets because they control diverse biological functions. However, steroidal ligands for NRs have the potential to cross-react with other nuclear receptors, so development of non-steroidal NR ligands is desirable to obtain safer agents for clinical use. We anticipated that efficient lead finding and enhancement of activity toward nuclear receptors recognizing endogenous steroidal ligands might be achieved by exhaustive evaluation of a steroid surrogate library coupled with examination of structure-activity relationships (SAR). Method: We evaluated our library of RORs (retinoic acid receptor-related orphan receptors) inverse agonists and/or PR (progesterone receptor) antagonists based on the phenanthridinone skeleton for antagonistic activities toward liver X receptors (LXRs), androgen receptor (AR) and glucocorticoid receptor (GR) and examined their SAR. Results: Potent LXRβ, AR, and GR antagonists were identified. SAR studies led to a potent AR antagonist (IC50: 0.059 μM). Conclusions: Our approach proved effective for efficient lead finding, activity enhancement and preliminary control of selectivity over other receptors. The phenanthridinone skeleton appears to be a promising steroid surrogate.

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“…Referências desta rota sintética estabelecem uma etapa de proteção do nitrogênio da amida antecedendo a reação de ciclização (BERNARDO et al, 2008;CHENG et al, 2014;FUKUDA et al, 2017;HARAYAMA et al, 2001;KARAKI et al, 2014;PRADO;MICHEL;KOCH, 2006;SMIDRKAL, 1988;TATTON;SIMPSON;DONOHOE, 2014). Proteção de grupos funcionais são realizadas no intuito de aumentar a seletividade da reação e reduzir a formação de subprodutos (WUTS, 2014), embora a reação de Heck (ciclização) seja descrita como uma síntese altamente seletiva e que, na maioria das vezes, não é dificultada pela presença de heteroátomos como nitrogênio, oxigênio e enxofre (JAGTAP, 2017).…”

Section: Proteção Das N-naftil-benzamidasunclassified

Síntese, avaliação biológica e modelagem molecular de potenciais antitumorais análogos da sanguinarina planejados por simplificação molecular

Fernandes¹

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Structure–activity relationship study of non-steroidal NPC1L1 ligands identified through cell-based assay using pharmacological chaperone effect as a readout

Cited by 18 publications

References 39 publications

Fomiroid A, a Novel Compound from the Mushroom Fomitopsis nigra, Inhibits NPC1L1-Mediated Cholesterol Uptake via a Mode of Action Distinct from That of Ezetimibe

Fomiroid A, a Novel Compound from the Mushroom Fomitopsis nigra, Inhibits NPC1L1-Mediated Cholesterol Uptake via a Mode of Action Distinct from That of Ezetimibe

Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton

Síntese, avaliação biológica e modelagem molecular de potenciais antitumorais análogos da sanguinarina planejados por simplificação molecular

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