Investigation of <i>N</i>-Aryl-3-alkylidenepyrrolinones as Potential Niemann−Pick Type C Disease Therapeutics

Cosner, Casey C.; Bourbon, Pauline; Mariani, Christopher J.; Wiest, Olaf; Rujoi, Madalina; Rosenbaum, Anton I.; Huang, Amy Y.; Maxfield, Frederick R.; Helquist, Paul

doi:10.1021/jm900707n

Cited by 30 publications

(28 citation statements)

References 44 publications

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“…The assay is amenable to high throughput screening, allowing libraries of compounds to be investigated for the effect of cholesterol reduction. The technique has already demonstrated some success with our findings that certain pyrrolinones increased cholesterol esterification and decreased LDL uptake in NPC-deficient cells 11. While these initial results are encouraging, the screening process simply identifies compounds that revert the NPC phenotype in terms of cholesterol accumulation.…”

Section: Introductionmentioning

confidence: 86%

Thiadiazole Carbamates: Potent Inhibitors of Lysosomal Acid Lipase and Potential Niemann−Pick Type C Disease Therapeutics

et al. 2010

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Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized at the cellular level by abnormal accumulation of cholesterol and other lipids in lysosomal storage organelles. Lysosomal acid lipase (LAL) has been recently identified as a potential therapeutic target for NPC. LAL can be specifically inhibited by a variety of 3,4-disubstituted thiadiazole carbamates. An efficient synthesis of the C(3) oxygenated/C(4) aminated analogues has been developed that furnishes the products in high yields and high degrees of purity. Common intermediates can also be used for the synthesis of the C(3) carbon substituted derivatives. Herein we tested various thiadiazole carbamates, amides, esters, and ketones for inhibition of LAL. In addition, we tested a diverse selection of commercially available non-thiadiazole carbamates. Our studies show that, among the compounds examined herein, only thiadiazole carbamates are effective inhibitors of LAL. We present a mechanism for LAL inhibition by these compounds whereby LAL transiently carbamoylates the enzyme similarly to previously described inhibition of acetylcholinesterase by rivastigmine and other carbamates as well as acylation of various lipases by orlistat.

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Section: Introductionmentioning

confidence: 86%

Thiadiazole Carbamates: Potent Inhibitors of Lysosomal Acid Lipase and Potential Niemann−Pick Type C Disease Therapeutics

et al. 2010

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“…This assay analyzes whether the compounds affect the transport of free cholesterol from the LSOs to ACAT in the ER. As shown in Figure 2, only compound 1a13 increased ACAT esterification significantly after 18 h treatment of the CT60 cells [46]. The increase in ACAT esterification shown by compound 1a8 was not statistically significant, and all the other 16 compounds caused a decrease of [ 14 C]-oleic acid incorporation into esters as compared to the control.…”

Section: Resultsmentioning

confidence: 86%

“…Nine compounds (1a1, 1a6, 1a10, 1a11, 1a13 [46], 1a14, 2a1, 2a13, 2a15) increased cholesterol efflux to at least 120% of the control value. One compound (1a7) decreased cholesterol efflux.…”

Section: Resultsmentioning

confidence: 94%

“…Moreover, we published data indicating that compound 1a13 increased esterification by ACAT and cholesterol efflux in both NPC mutant and normal cells [46]. Herein, we have retained the data on the LAL inhibitors (1a4, 1a11, 1a14, 2a8, 2a9, 2a13, 2a15) [42] and also on compound 1a13 [46] to give the reader an overall sense of all the processes affected by each compound since only the effect of these chemicals on specific processes was discussed in the previously published work. Recognizing the cellular mechanisms impacted by cholesterol-lowering chemicals could help reveal additional molecular target(s) of these molecules, a difficult task associated with any cell-based screening processes.…”

Section: Resultsmentioning

confidence: 99%

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Cholesterol Pathways Affected by Small Molecules That Decrease Sterol Levels in Niemann-Pick Type C Mutant Cells

2010

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BackgroundNiemann-Pick type C (NPC) disease is a genetically inherited multi-lipid storage disorder with impaired efflux of cholesterol from lysosomal storage organelles.Methodology/Principal FindingsThe effect of screen-selected cholesterol lowering compounds on the major sterol pathways was studied in CT60 mutant CHO cells lacking NPC1 protein. Each of the selected chemicals decreases cholesterol in the lysosomal storage organelles of NPC1 mutant cells through one or more of the following mechanisms: increased cholesterol efflux from the cell, decreased uptake of low-density lipoproteins, and/or increased levels of cholesteryl esters. Several chemicals promote efflux of cholesterol to extracellular acceptors in both non-NPC and NPC1 mutant cells. The uptake of low-density lipoprotein-derived cholesterol is inhibited by some of the studied compounds.Conclusions/SignificanceResults herein provide the information for prioritized further studies in identifying molecular targets of the chemicals. This approach proved successful in the identification of seven chemicals as novel inhibitors of lysosomal acid lipase (Rosenbaum et al, Biochim. Biophys. Acta. 2009, 1791:1155–1165).

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“…Compound D 10 ( Liégault et al, 2009 ). Compound D 4 ( Cosner et al, 2009 ). Compound D 5 ( Murasawa et al, 2012 ).…”

Section: Methodsmentioning

confidence: 99%

Identification of a small molecule inhibitor that stalls splicing at an early step of spliceosome activation

Sidarovich

Will

Anokhina

et al. 2017

eLife

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Small molecule inhibitors of pre-mRNA splicing are important tools for identifying new spliceosome assembly intermediates, allowing a finer dissection of spliceosome dynamics and function. Here, we identified a small molecule that inhibits human pre-mRNA splicing at an intermediate stage during conversion of pre-catalytic spliceosomal B complexes into activated Bact complexes. Characterization of the stalled complexes (designated B028) revealed that U4/U6 snRNP proteins are released during activation before the U6 Lsm and B-specific proteins, and before recruitment and/or stable incorporation of Prp19/CDC5L complex and other Bact complex proteins. The U2/U6 RNA network in B028 complexes differs from that of the Bact complex, consistent with the idea that the catalytic RNA core forms stepwise during the B to Bact transition and is likely stabilized by the Prp19/CDC5L complex and related proteins. Taken together, our data provide new insights into the RNP rearrangements and extensive exchange of proteins that occurs during spliceosome activation.DOI: http://dx.doi.org/10.7554/eLife.23533.001

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Investigation of N-Aryl-3-alkylidenepyrrolinones as Potential Niemann−Pick Type C Disease Therapeutics

Cited by 30 publications

References 44 publications

Thiadiazole Carbamates: Potent Inhibitors of Lysosomal Acid Lipase and Potential Niemann−Pick Type C Disease Therapeutics

Thiadiazole Carbamates: Potent Inhibitors of Lysosomal Acid Lipase and Potential Niemann−Pick Type C Disease Therapeutics

Cholesterol Pathways Affected by Small Molecules That Decrease Sterol Levels in Niemann-Pick Type C Mutant Cells

Identification of a small molecule inhibitor that stalls splicing at an early step of spliceosome activation

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