Quinuclidine Inhibitors of 2,3-Oxidosqualene Cyclase-Lanosterol Synthase:  Optimization from Lipid Profiles

Brown, George R.; Hollinshead, David M.; Stokes, Elaine S.E.; Clarke, D. S.; Eakin, M. A.; Foubister, Alan J.; Glossop, Steven C.; Griffiths, David E.; Johnson, Michael C.; McTaggart, Fergus; Mirrlees, Donald J.; Smith, Graham J.; Wood, Robin

doi:10.1021/jm990038q

Cited by 25 publications

(20 citation statements)

References 13 publications

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“…Naringenin is the aglycone of naringin, a naturally occurring flavanone glycoside obtained from citrus fruits and grapefruit. Naringenin hypocholesterolemic effect is due to the reduction of both HMGR and acyl CoA: cholesterol O-acyltransferase activities [36] . Discovery of isoflavones as HMGR inhibitors in soy food is very intriguing.…”

Section: Flavonoidsmentioning

confidence: 99%

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

Trapani

Segatto

Pallottini

2013

WJH

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Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of dyslipidemia.© 2013 Baishideng Publishing Group Co., Limited. All rights reserved. Key words: Aging; Cholesterol; HypercholesterolemiaCore tip: The strategies used to reduce plasma cholesterol levels in elderly people are mainly addressed to the inhibition of the rate limiting enzyme of cholesterol biosynthetic pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), in order to increase low density lipoprotein (LDL) receptor membrane exposure and LDL clearance from the circulation. Indeed current therapies are mostly based on the prescription of statins (HMGR inhibitors) that are pretty effective but that exert side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to elderly. Thus, new therapeutic agents should be taken into account.Trapani L, Segatto M, Pallottini V. New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid

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Section: Flavonoidsmentioning

confidence: 99%

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

Trapani

Segatto

Pallottini

2013

WJH

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“…In fact, potentially dose-limiting toxicity might arise from the consequent reduced levels of isoprenoids, ubiquinone, and dolichols. Also the inhibition of enzymes downstream of the lanosterol biosynthesis has the potential to afford toxicity arising from the utilization (in place of cholesterol) of biosynthetic intermediates containing the full sterol ring system (21). As a whole, FDFT1, SQLE, and OSC could be relevant targets for antihypercholesterolemic drugs.…”

Section: Statins: Action Mechanisms and Effectsmentioning

confidence: 99%

“…A variety of OSC inhibitors have been reported bearing amines (49), quinuclidines (21), isoquinolines (50), a lipophilic residue (41). Among others, an interesting compound is U-18666A that inhibits OSC at concentrations higher than 0.5 mM; however, it induces cataracts in rats (51), It was shown to intercalate into a lens lipid model membrane.…”

Section: Oxidosqualene Cyclasementioning

confidence: 99%

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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“…It is worth mentioning here that after a large screening study of 700 quinuclidine derivatives [105] a few compounds were found to inhibit in vivo oxidosqualene cyclase -lanosterol synthase (OSC). These leads were optimized to produce selective OSC inhibitors such as compound 69 or 70 (Fig.…”

Section: Quinuclidine Derivativesmentioning

confidence: 99%

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

Kourounakis

Katselou²,

Matralis³

et al. 2011

CMC

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Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better side-effect profile is expected for these inhibitors. Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8- dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships.

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Quinuclidine Inhibitors of 2,3-Oxidosqualene Cyclase-Lanosterol Synthase: Optimization from Lipid Profiles

Cited by 25 publications

References 13 publications

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

Potential role of nonstatin cholesterol lowering agents

Squalene Synthase Inhibitors: An Update on the Search for New Antihyperlipidemic and Antiatherosclerotic Agents

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