Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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(-1)) and showed lipid-lowering effects in beagle dogs, marmosets, cynomolgus monkeys and Wistar fatty rats. 3. In marmosets, TAK-475 (30, 100 mg kg(-1), 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(-1), 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(-1), 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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PMID:Lipid-lowering properties of TAK-475, a squalene synthase inhibitor, in vivo and in vitro. 1283 59

Although treatment with statins significantly reduces adverse cardiovascular outcomes, several studies have shown that cardiovascular events continue to occur in two thirds of all patients. A logical pharmacologic approach to further reduce cardiovascular disease mortality should be focused on direct modifiers of atherosclerosis or lipid-modifying agents with different mechanism of action than existing drugs against dyslipidemia. Squalene synthase inhibitors can decrease circulating low-density lipoprotein (LDL)-cholesterol by an increased expression of hepatic LDL receptors in a similar manner to statins. Also, depending on their structure, they may possess antiatherosclerotic properties independent of their lipid-modifying effects. This review, following a brief introduction to different classes of squalene synthase inhibitors and representative molecules, presents the accumulating in vitro and in vivo experimental evidence relevant to squalene synthase inhibitors EP2306 and EP2302 and discusses their properties. EP2306 and EP2302 show a similar inhibitory effect in the progression of atherosclerosis in the cholesterol-fed rabbit. Moreover, EP2306 showed a significant long-term antiatherosclerotic effect not shared by simvastatin or their combination in this animal model. EP2302 also showed a favorable effect in the regression of pre-established atherosclerotic lesions. It is reasonable to hypothesize that EP2302, due to its NO-releasing and enhancing properties, could have additional advantages compared to EP2306. Treatment with EP2300 compounds did not adversely affect liver transaminases or cause toxicity on various organs of the cholesterol-fed rabbit. The satisfactory safety profile of EP2300 compounds in this animal model is a promising finding in view of future clinical studies.
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PMID:EP2300 compounds: focusing on the antiatherosclerotic properties of squalene synthase inhibitors. 1975 89

Dyslipidemia is one of the main risk factors leading to atherosclerotic cardiovascular disease (CVD). According to recent treatment guidelines, subjects at substantial risk of CVD should meet more aggressive targets for low-density lipoprotein(LDL)-cholesterol levels. Treatment with statins fails to protect a significant percentage of patients from cardiovascular events despite efficient cholesterol-lowering. Moreover, clinical and epidemiologic data highlight the need of therapies to reduce the residual cardiovascular risk associated with low high-density lipoprotein(HDL)-cholesterol and elevated triglyceride levels. There are several novel agents undergoing preclinical or clinical development for the treatment of dyslipidemia. Squalene synthase inhibitors, antisense oligonucleotides targeting the production of apolipoprotein(apo)B-100, inhibitors of proprotein convertase subtilisin/kexin type 9, microsomal triglyceride transfer protein inhibitors, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor agonists are some of the alternative approaches for lipid-lowering. Moreover, HDL-targeted therapies such as the cholesteryl ester transfer protein inhibitors, HDLderived proteins, and mimetic peptides/lipids can increase HDL-cholesterol levels or improve the antiatherosclerotic properties of HDL. In conclusion, the emergence of agents that act in monotherapy or in combination with available lipid-modifying drugs may allow more effective management of dyslipidemia and, consequently, reduce the burden of CVD.
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PMID:Emerging targets for the treatment of dyslipidemia. 2118 75