Squalene synthase inhibitors 1998

Rosenberg, Saul H.

doi:10.1517/13543776.8.5.521

Cited by 15 publications

(3 citation statements)

References 28 publications

(26 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…Although many squalene synthase inhibitors have been reported to date (Rosenberg, 1998; Hiyoshi et al ., 2000; Ugawa et al ., 2000), no such drugs have been launched on the market. One of the reasons seems to be toxic acidosis due to overexcretion of farnesol‐derived dicarboxylic acids (Rosenberg, 1998). One squalene synthase inhibitor, zaragozic acid A, caused the excretion of unexpectedly high levels of urinary dicarboxylic acids in rats and dogs (Bostedor et al ., 1997).…”

Section: Discussionmentioning

confidence: 99%

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Lipid‐lowering properties of TAK‐475, a squalene synthase inhibitor, in vivo and in vitro

Nishimoto

Amano

Tozawa

et al. 2003

British J Pharmacology

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1 Squalene synthase is the enzyme that converts farnesyl pyrophosphate to squalene in the cholesterol biosynthesis pathway. We examined the lipid-lowering properties of 1-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid (TAK-475), a novel squalene synthase inhibitor. 2 TAK-475 inhibited hepatic cholesterol biosynthesis in rats (ED 50 , 2.9 mg kg À1 ) and showed lipidlowering effects in beagle dogs, marmosets, cynomolgus monkeys and Wistar fatty rats. 3 In marmosets, TAK-475 (30, 100 mg kg À1 , p.o., for 4 days) lowered both plasma non-high-density lipoprotein (HDL) cholesterol and triglyceride, but did not affect plasma HDL cholesterol. On the other hand, atorvastatin (10, 30 mg kg À1 , p.o., for 4 days) lowered the levels of all these lipids. A correlation between decrease in triglyceride and increase in HDL cholesterol was observed, and TAK-475 increased HDL cholesterol with a smaller decrease in triglyceride than did atorvastatin. 4 TAK-475 (60 mg kg À1 , p.o., for 15 days) suppressed the rate of triglyceride secretion from the liver in hypertriglyceridemic Wistar fatty rats, which show an enhanced triglyceride secretion rate from the liver compared with their lean littermates. 5 In HepG2 cells, TAK-475 and its pharmacologically active metabolite, T-91485, increased the binding of 125 I-low-density lipoprotein (LDL) to LDL receptors. 6 These results suggest that TAK-475 has clear hypolipidemic effects in animals via inhibition of hepatic triglyceride secretion and upregulation of LDL receptors, and that TAK-475 might increase HDL cholesterol by decreasing triglyceride. Thus, TAK-475 is expected to be useful for the treatment of dyslipidemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lipid‐lowering properties of TAK‐475, a squalene synthase inhibitor, in vivo and in vitro

Nishimoto

Amano

Tozawa

et al. 2003

British J Pharmacology

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“…2) [32,36,37]. It is the first enzyme in the cholesterol biosynthetic pathway dedicated to the synthesis of the sterol nucleus and represents an attractive target for antihypercholesterolaemic therapy [38]. Squalene synthase activity is regulated by intracellular cholesterol content while LDL receptors are upregulated after its inhibition.…”

Section: Squalene Synthase (Sqs)mentioning

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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New applications of squalene synthase inhibitors: Membrane cholesterol as a therapeutic target

Kourounakis

Bavavea

2020

Archiv der Pharmazie

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Squalene synthase (SQS) inhibitors, mostly known as antihyperlipidemic agents for controlling blood cholesterol levels, have been increasingly used to study alterations of the cholesterol content in cell membranes. As such, SQS inhibitors have been demonstrated to control cellular activities related to cancer cell proliferation and migration, neuron degeneration, and parasite growth. While the mechanisms behind the effects of cellular cholesterol are still being revealed in detail, the evidence for SQS as a therapeutic target for several seemingly unrelated diseases is increasing. SQS inhibitors may be the next promising candidates targeting the three remaining primary therapeutic areas, beyond cardiovascular disease, which still need to be addressed; their application as anticancer, antimicrobial, and antineurodegenerative agents appears promising for new drug discovery projects underway.

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Squalene synthase inhibitors 1998

Cited by 15 publications

References 28 publications

Lipid‐lowering properties of TAK‐475, a squalene synthase inhibitor, in vivo and in vitro

Lipid‐lowering properties of TAK‐475, a squalene synthase inhibitor, in vivo and in vitro

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

New applications of squalene synthase inhibitors: Membrane cholesterol as a therapeutic target

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