Design and evaluation of a novel series of 2,3-oxidosqualene cyclase inhibitors with low systemic exposure, relationship between pharmacokinetic properties and ocular toxicity

Fouchet, Marie-Hélène; Donche, Frédéric; Martin, Christelle; Bouillot, Anne; Junot, Christophe; Boullay, Anne-Bénédicte; Potvain, Florent; Magny, Sylvie Demaria; Coste, Hervé; Walker, M; Issandou, Marc; Dodic, N Sinisa

doi:10.1016/j.bmc.2008.04.034

Cited by 16 publications

(15 citation statements)

References 25 publications

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“…Two supporting studies demonstrated that compounds sharing structural similarity to ERG7.153 inhibit lanosterol synthase (Figure S3A). One of these compounds was demonstrated to inhibit lanosterol synthase (Erg7) in C. albicans (Buurman, et al, 2005), while the other was shown to inhibit the human lanosterol synthase, LSS (Fouchet, et al, 2008) (Figure S3A). To genetically confirm that ERG7.153 inhibits Erg7, we tested the individual erg7 heterozygous deletion for the expected compound hypersensitivity to the wild type (Figure S3B).…”

Section: Resultsmentioning

confidence: 99%

Compound Prioritization Methods Increase Rates of Chemical Probe Discovery in Model Organisms

Wallace

Urbanus

Luciani

et al. 2011

Chemistry & Biology

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SUMMARY Pre-selection of compounds that are more likely to induce a phenotype can increase the efficiency and reduce the costs for model organism screening. To identify such molecules, we screened ~81,000 compounds in S. cerevisiae and identified ~7,500 that inhibit cell growth. Screening these growth-inhibitory molecules across a diverse panel of model organisms resulted in an increased phenotypic hit-rate. This data was used to build a model to predict compounds that inhibit yeast growth. Empirical and in silico application of the model enriched the discovery of bioactive compounds in diverse model organisms. To demonstrate the potential of these molecules as lead chemical probes we used chemogenomic profiling in yeast and identified specific inhibitors of lanosterol synthase and of stearoyl-CoA 9-desaturase. As community resources, the ~7,500 growth-inhibitory molecules has been made commercially available and the computational model and filter used are provided.

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Section: Resultsmentioning

confidence: 99%

Compound Prioritization Methods Increase Rates of Chemical Probe Discovery in Model Organisms

Wallace

Urbanus

Luciani

et al. 2011

Chemistry & Biology

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“…As large amounts of cholesterol are required for the elongation of cell fibers, the inhibition of the cholesterol pathway leads to a decreased membrane production and a disturbed fiber cell growth. Recently, the histopathologic findings in hamster and dog associated with the administration of three different OSC inhibitors have been reported (47). Remarkably, dermal and ocular side effects were less pronounced when the dogs were fed a cholesterol rich diet, suggesting that the observed changes were related to the inhibitory effect on the cholesterol biosynthesis and not to the intrinsic toxicity.…”

Section: Oxidosqualene Cyclasementioning

confidence: 96%

“…Several OSC inhibitors have been reported to show in vitro and in vivo potency, exerting profound lipid-lowering effects (47). Moreover, the treatment with OSC inhibitors is not associated with the development of a range of side effects that are reported commonly for HMGR inhibitors, such as gall bladder, as well as testicular and neurological changes.…”

Section: Oxidosqualene Cyclasementioning

confidence: 99%

“…Moreover, the treatment with OSC inhibitors is not associated with the development of a range of side effects that are reported commonly for HMGR inhibitors, such as gall bladder, as well as testicular and neurological changes. However, other toxicological issues have been reported including skin and epididymal changes in the dog, as well as severe cataract formation in dogs and rodents (47). AMO 1618 was identified as a potential OSC inhibitor in metabolic labelling studies according to the distribution profile of radiolabelled sterol intermediates (48).…”

Section: Oxidosqualene Cyclasementioning

confidence: 99%

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Potential role of nonstatin cholesterol lowering agents

et al. 2011

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SummaryAlthough statins, 3b-hydroxy-3b-methylglutaryl coenzyme A reductase (HMGR) inhibitors, have revolutionized the management of cardiovascular diseases by lowering serum low density lipoproteins, many patients suffer from their side effects. Whether the statin side effects are related to their intrinsic toxicity or to the decrease of HMGR main isoprenoid end products, which are essential compounds for cell viability, is still debated. In addition to HMGR, the key and rate limiting step of cholesterol synthesis, many enzymes are involved in this multi-step pathway whose inhibition could be taken into account for a ''nonstatin approach'' in the management of hypercholesterolemia. In particular, due to their unique position downstream from HMGR, the inhibition of squalene synthase, farnesyl diphosphate farnesyltransferase (FDFT1), squalene epoxidase (SQLE), and oxidosqualene cyclase:lanosterol synthase (OSC) should decrease plasma levels of cholesterol without affecting ubiquinone, dolichol, and isoprenoid metabolism. Thus, although FDFT1, SQLE and OSC are little studied, they should be considered as perspective targets for the development of novel drugs against hypercholesterolemia. Here, structurefunction relationships of FDFT1, SQLE, and OSC are reviewed highlighting the advantages that the downstream inhibition of HMGR could provide when compared to the statin-based therapy.2011 IUBMB IUBMB Life, 63(11): 964-971, 2011

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“…Concern about the potential of statins to affect the lens was stimulated by a report of an animal study [8e10], in which dogs were administered high doses of different HMG-CoA reductase inhibitors. In addition, cataract was also detected in experimental animals treated with cholesterol synthesis inhibitors developed before the availability of statins [9,11,12].…”

Section: Introductionmentioning

confidence: 94%

Statin use and risk of cataract: A nested case-control study within a healthcare database

et al. 2016

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Design and evaluation of a novel series of 2,3-oxidosqualene cyclase inhibitors with low systemic exposure, relationship between pharmacokinetic properties and ocular toxicity

Cited by 16 publications

References 25 publications

Compound Prioritization Methods Increase Rates of Chemical Probe Discovery in Model Organisms

Compound Prioritization Methods Increase Rates of Chemical Probe Discovery in Model Organisms

Potential role of nonstatin cholesterol lowering agents

Statin use and risk of cataract: A nested case-control study within a healthcare database

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