Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of primary and secondary prevention studies with HMG-CoA reductase inhibitors(statins) have shown a reduction of cardiac events. However, such cardiac events cannot be completely prevented by antihyperlipidemic drugs there are a number of patients whose hyperlipidemia is resistant to conventional treatment. Furthermore, it is still difficult to observe a regression of atherosclerosis even when patients become normolipidemic after treatment. Thus, many antihyperlipidemic drugs with novel mechanisms are under development and are expected to inhibit progression or rather obtain regression of atherosclerosis in clinical settings. In the current review, inhibitors of cholesterol synthesis such as squalene synthase and squalene epoxidase inhibitors, ileal Na+/bile acid cotransporter(IBAT) inhibitors, and inhibitors of intestinal cholesterol absorption are described.
 ...
PMID:[Trends toward development of other novel antihyperlipidemic drugs]. 1203 3

Accumulation of lipids and cholesterol by macrophages and subsequent transformation into foam cells are key features in development of atherosclerosis. Serum copper concentrations have been shown to be associated with cardiovascular disease. However, the mechanism behind the proatherogenic effect of copper is not clear. We used DNA microarrays to define the changes in gene expression profile in response to copper exposure of human macrophages. Expression monitoring by DNA microarray revealed 91 genes that were regulated. Copper increased the expression of seven cholesterogenic genes (3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase, IPP isomerase, squalene synthase, squalene epoxidase, methyl sterol oxidase, H105e3 mRNA and sterol-C5-desaturase) and low-density lipoprotein receptor (LDL-R), and decreased the expression of CD36 and lipid binding proteins. The expression of LDL-R and HMG CoA reductase was also investigated using real time PCR. The expression of both of these genes was increased after copper treatment of macrophages (P<0.01 and P<0.01, respectively). We conclude that copper activates cholesterogenic genes in macrophages, which may provide a mechanism for the association between copper and atherosclerosis. The effect of copper on cholesterogenic genes may also have implications for liver steatosis in early stages of Wilson's disease.
Atherosclerosis 2003 Jul
PMID:Copper induces the expression of cholesterogenic genes in human macrophages. 1286 Feb 52

Lipid-lowering is established as a proven intervention to reduce atherosclerosis and its complications. This article summarises imminent developments in lipid-lowering therapy, including new statins and cholesterol absorption inhibitors currently undergoing investigation for licensing. It also discusses other therapeutic targets such as squalene synthase, microsomal transfer protein (MTP), acyl-cholesterol acyl transferase (ACAT), cholesterol ester transfer protein (CETP), peroxosimal proliferator activating receptors (PPARs) and lipoprotein (a) (LP(a)), for which compounds have been developed and have at least reached trials in animal models. Lipid-lowering drugs are likely to prove a fast-developing area for novel treatments, as possible synergies exist between new and established compounds for the treatment of atherosclerosis.
 ...
PMID:New lipid-lowering agents. 1466 95

Atherosclerosis is a disease characterized by lipid accumulation in the vascular wall leading to myocardial infarction or stroke. Hypercholesterolemia is an important risk factor and current treatments are largely based on cholesterol lowering. In spite of proven efficacy of existing drugs, like statins, cardiovascular diseases still remain the most common cause of death in industrialised countries. Many new molecular targets are being studied to improve atherosclerosis treatment and reduce the number of deaths. The action on these targets could lead to a decrease of blood cholesterol levels or produce a direct anti-atherosclerotic effect on the vascular wall. A cholesterol lowering effect could be achieved by reducing cholesterol synthesis (squalene synthase inhibitors), intestinal cholesterol absorption as well as intestinal and liver lipoprotein secretion (microsomal transfer protein inhibitors, acyl-coenzyme A-cholesterol acyltransferase inhibitors) or by increasing fecal excretion of bile acids (ileal sodium-dependent bile acid transporter inhibitors). An anti-atherosclerotic effect on the vascular wall could be achieved by reducing the inflammation via activation of peroxisome proliferator activated receptors, or, more particularly, could consist of decreased expression of adhesion molecules and chemoattractant proteins. Increasing the adenosine triphosphate-binding cassette A1 protein and inhibiting acyl-coenzyme A :cholesterol acyltransferase 1 activity could slow down formation of foam cells, which are a hallmark of atherosclerosis. Finally, the cholesterol fraction carried by high density lipoproteins, which is inversely correlated to cardiovascular risk, could be increased by cholesterol ester transfer protein inhibitors. All of these new classes of compounds are currently studied by pharmaceutical companies and are in different phases of development (preclinical or clinical).
 ...
PMID:[Cholesterol metabolism modulators and the future of atherosclerosis therapy]. 1532 20

Lipid lowering is established as a proven intervention to reduce atherosclerosis and its complications. This article summarises novel developments in the lipid-altering therapies under development, including combination therapies, squalene synthase inhibitors, microsomal transfer protein inhibitors, acyl-cholesterol acyl transferase inhibitors, cholesterol ester transfer protein antagonists, peroxisome proliferator-activated receptor agonists, high-density lipoprotein-derived peptides and inflammation inhibitors, which have at least reached trials in animal models. Lipid-altering drugs are likely to to be a fast-developing area for novel treatments as possible synergies exist between new and established compounds for the treatment of atherosclerosis. New agents will have to show significant advantage in tolerability or efficacy over existing agents and have the potential to be used in combination therapy as is well established for bile acid sequestrants, nicotinic acid or fibrates and statins. Any new drugs will also have to be assessed in clinical end-point trials against current compounds with proven outcome benefits.
 ...
PMID:Lipid-lowering therapies in development. 1550 Mar 89

Lipid-lowering is established as proven intervention to reduce atherosclerosis and its complications. This article summarises novel developments in the lipid-altering therapies under development. It also discusses other therapeutic targets, such as squalene synthase, microsomal transfer protein, acyl-cholesterol acyl transferase, cholesterol ester transfer protein, peroxosimal proliferator-activating receptors and lipoprotein (a), for which compounds have been developed and have at least reached trials in animal models. Lipid-altering drugs are likely to prove a fast-developing area for novel treatments, as possible synergies exist between new and established compounds for the treatment of atherosclerosis.
 ...
PMID:Lipid-altering agents: the future. 1560 75

The advent of 3-hydroxy-methylglutaryl Co-enzyme A (HMG-CoA) reductase inhibitors has dramatically improved the treatment of dyslipidaemia and the prevention of atherosclerosis over the past 10 years. Similar but less marked benefit had previously been demonstrated for fibrates and bile acid sequestrants, which were first introduced over 30 years ago and are still in use. The discovery that fibrates are ligands for peroxisome proliferator activated receptors (PPARs) may lead to innovations in the future. However, most of the compounds now undergoing clinical trials are either HMG-CoA reductase inhibitors or bile acid sequestrants, which is indicative of the current emphasis on lowering low density lipoprotein (LDL) cholesterol. Drugs in an earlier stage of development include inhibitors of squalene synthase, which have yet to fulfil their initial promise, and of acylcholesterolacyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). Most of the earlier ACAT inhibitors were poorly absorbed, but compounds with better bioavailability hold considerable promise by virtue of their ability to inhibit ACAT in liver and arterial wall macrophages. MTP inhibitors have the potential to drastically reduce apolipoprotein B (apoB) secretion, but safety issues could negate this advantage. Thus, despite the impact of statins, the development of new lipid-modulating drugs continues to be a dynamic field of research.
 ...
PMID:New prospects for lipid-lowering drugs. 1599 63

We investigated the effects of EP2306 and EP2302, two novel 2-biphenylmorpholine derivatives, on squalene synthase activity in rabbit and human liver microsomes, lipid biosynthesis, low-density lipoprotein (LDL) receptor expression and LDL protein uptake as well as apoB secretion in HepG2 cells. Both EP2306 and EP2302 inhibited squalene synthase activity dose-dependently. In rabbit liver microsomes, the IC50 values were 33 microM for EP2306 and 0.6 microM for EP2302 whereas in human liver microsomes, they were 63 microM for EP2306 and 1 microM for EP2302. Both EP2300 compounds inhibited cholesterol production by HepG2 cells dose dependently with IC50 values of 13.3 microM for EP2306 and 3 microM for EP2302. Furthermore, both EP2300 compounds and simvastatin significantly reduced triglyceride synthesis and apoB secretion and increased LDL receptor expression and LDL uptake in HepG2 cells. In summary, we have shown that EP2300 compounds are potent inhibitors of squalene synthase activity in rabbit and human liver microsomes and also they are effective inhibitors of cholesterol and triglyceride biosynthesis in HepG2 cells. These results suggest that EP2306 and EP2302 might prove to be useful for lipid-lowering and treatment of atherosclerosis in vivo.
 ...
PMID:Pharmacological characterization in vitro of EP2306 and EP2302, potent inhibitors of squalene synthase and lipid biosynthesis. 1654 96

Atherosclerosis is a disease characterized by lipid accumulation in the vascular wall leading to myocardial infarction or stroke. Hypercholesterolemia is an important risk factor and current treatments are largely based on cholesterol lowering. In spite of proven efficacy of existing drugs, like statins, cardiovascular diseases still remain the most common cause of death in industrialised countries. Many new molecular targets are being studied to improve atherosclerosis treatment and reduce the number of deaths. The action on these targets could lead to a decrease of blood cholesterol levels or produce a direct anti-atherosclerotic effect on the vascular wall. A cholesterol lowering effect could be achieved by reducing cholesterol synthesis (squalene synthase inhibitors), intestinal cholesterol absorption as well as intestinal and liver lipoprotein secretion (microsomal transfer protein inhibitors, acyl-coenzyme A-cholesterol acyltransferase inhibitors) or by increasing fecal excretion of bile acids (ileal sodium-dependent bile acid transporter inhibitors). An anti-atherosclerotic effect on the vascular wall could be achieved by reducing the inflammation via activation of peroxisome proliferator activated receptors, or, more particularly, could consist of decreased expression of adhesion molecules and chemoattractant proteins. Increasing the adenosine triphosphate-binding cassette A1 protein and inhibiting acylcoenzyme A:cholesterol acyltransferase 1 activity could slow down formation of foam cells, which are a hallmark of atherosclerosis. Finally, the cholesterol fraction carried by high density lipoproteins, which is inversely correlated to cardiovascular risk, could be increased by cholesterol ester transfer protein inhibitors. All of these new classes of compounds are currently studied by pharmaceutical companies and are in different phases of development (preclinical or clinical).
 ...
PMID:[Cholesterol metabolism modulators in future drug therapy for atherosclerosis]. 1659 6

EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide] inhibits squalene synthase and lipid biosynthesis and possesses antioxidant properties. We hypothesized that EP2306 can effectively modify circulating lipids and reduce atherosclerosis in the cholesterol-fed rabbit. Animals were fed a high-cholesterol diet for 4 weeks followed by 4 (phase 1 and 2) or 12 weeks (phase 3) of drug treatment while on high-cholesterol diet. In phase 1, the dose-effect relationship of EP2306 on lipids and atherosclerosis was established, and its most effective dose was determined (2 mg/kg). This dose reduced significantly total cholesterol (512 +/- 96 mg/dl before versus 320 +/- 124 mg/dl after treatment, p < 0.05) and atherosclerotic lesions compared with control animals. In phase 2, the effects of 2 mg/kg EP2306, 2.5 mg/kg simvastatin, and their combination were assessed. Although no significant effect on lipid parameters was observed, there was a significant reduction (35 +/- 5%, p < 0.05) of atherosclerotic lesions in animals treated with EP2306, a similar reduction with simvastatin, and a further reduction (48 +/- 7%, p < 0.05) when the two agents were combined. In animals treated for 12 weeks with the drugs (phase 3), only EP2306 significantly reduced atherosclerotic lesions by more than 50%, whereas simvastatin alone or in combination with EP2306 had no effect. Treatment with EP2306 did not adversely affect liver transaminases or cause any histopathological changes on various organs of the animals. In conclusion, we have shown that EP2306 inhibits atherosclerosis in vivo, indicating potential as a novel therapeutic agent for coronary artery disease and other atherosclerosis-related disorders.
 ...
PMID:EP2306 [2-(4-biphenyl)-4-methyl-octahydro-1,4-benzoxazin-2-ol, hydrobromide], a novel squalene synthase inhibitor, reduces atherosclerosis in the cholesterol-fed rabbit. 1780 77


1 2 3 Next >>