Cholesterol, 25-hydroxy-, inhibition

The statins lower cholesterol by inhibiting the en zyme 3 hydroxy 3 methylglutaryl coenzyme A reduc tase which is required for the biosynthesis of meva Ionic acid (see Section 26 10) Mevalonic acid is an obligatory precursor to cholesterol so less mevalonic acid translates into less cholesterol... 

Monobactams have been investigated as p-lactamase inhibitors <98CHE1308, 98CHE1319>. The ketene-imine route to P-lactams was used to obtain 1,3,4-trisubstituted derivatives with high trans selectivity. The enolate from 4-hydroxy-y-lactone reacted with the imine (Ar CH NAr ) to give 59, vdiich cyclized in the presence of lithium chloride at low temperature to yield 60. The compounds were assayed for cholesterol absorption inhibition and 61 (R = = OH, R = F) was found to be a potent inhibitor of 3-hydroxy-3-... 

The lithium amides 98, prepared from 4-hydroxy—lactone and imines, rearranges in the presence of lithium chloride at low temperature to form -lactams 99 (Scheme 52) with cholesterol absorption inhibition properties <1999JOC3714, CHEC-III(2.01.3.10.10)69>. 

Cerivastatin is a competitive inhibitor of HIVIG-CoA reductase, which is responsible for the conver sion of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis by cerivastatin reduces the level of cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors. 

Background It is well known that hypercholesterolemia is a major risk factor in the progression of atherosclerosis, the major cause of cardiovascular diseases. Statins are widely used to treat hypercholesterolemia. The mechanism of action of these drugs is to reduce the endogenous production of cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase. Atorvastatin (ATV, Lipitor) is one of the top-selling prescribed oral medications. The only known adverse effect is skeletal muscle toxicity (myopathy) that may be related to the formation of the lactone of the acidic side chain on the molecule. 

Derivatives of cholesterol which inhibit the biosynthesis of cholesterol in aortic smooth muscle, presumably by suppressing the activity of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, also effect a corresponding decrease in the levels of glycosylated lipid intermediates with an apparent inhibition of the biosynthesis of glycoproteins. ... 

Of the cholesterol-lowering medications available to date, statins are currently the first choice for treating patients with hypercholesterolemia. They lower serum LDL cholesterol concentrations by 24-50% (Knopp, 1999) by blocking the synthesis of cholesterol through inhibition of the action of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase in the fiver. 

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

A class of cholesterol lowering drugs that inhibit 3-hydroxy-3-methylglutary 1-CoA reductase, the rate-limiting enzyme step in cholesterol biosynthesis. 

Unlike heliantholysin and congeners, the toxicity of metridiolysin is not prevented by sphingomyelin, but is inhibited by cholesterol in low concentration, as well as by certain related sterols (23). In addition, metridiolysin is activated by thiols such as dithiothreitol, and is reversibly inactivated by compounds having an affinity for SH-groups, such as p-hydroxy-mercuribenzoate. A third notable feature is that the action of metridiolysin on membranes involves, or is associated with, the formation of 33 nm rings demonstrable by electron microscopy of negatively stained preparations. 

Starvation elicits mobilization of triglycerides from the adipose tissue and inhibits the endogenic cholesterol synthesis owing to the low activity of hydroxy-methylglutaryl-CoA reductase. The latter process provides the possibility for the active production of ketone bodies in the liver. 

It has been found that the 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) inhibitors statins (atorvastatin, pravastatin, and cerivastatin), widely prescribed cholesterol-lowering agents, are able to inhibit phorbol ester-stimulated superoxide formation in endothelial-intact segments of the rat aorta [64] and suppress angiotensin II-mediated free radical production [65]. Delbose et al. [66] found that statins inhibited NADPH oxidase-catalyzed PMA-induced superoxide production by monocytes. It was suggested that statins can prevent or limit the involvement of superoxide in the development of atherosclerosis. It is important that statin... 

Which of the following drugs recommended for the lowering of blood cholesterol inhibits the synthesis of cholesterol by blocking 3-hydroxy-3-me thy 1 glutary 1-coenzyme A (HMG-CoA) reductase ... 

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interrupting the conversion of HMG-CoA to mevalonate, the rate-limiting step in de novo cholesterol biosynthesis. Reduced synthesis of LDL and enhanced catabohsm of LDL mediated through LDL-Rs appear to be the principal mechanisms for lipid-lowering effects. 

The therapeutic class that uniquely exemplifies lactone prodrugs are the statins, i.e., the cholesterol-lowering agents that act by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34). This microsomal enzyme catalyzes conversion of HMG-CoA to mevalonate, an important rate-limiting step in cholesterol biosynthesis. Cholesterol synthesis occurs mainly... 

Hydroxy-3-methylglutaryl (HMG)-CoA reductase on the smooth endoplasmic reticulum (SER) is the rate-limiting enzyme. Insulin acth"ates the enzyme (dephosphorylation), and glucagon inhibits it. Mevalonate is the product, and the statin drugs competitively inhibit the enzyme. Cholesterol represses the expression o the HMG-CoA reductase gene and also increases degradation of the enzyme. 

Mitotane (Lysodren) produces selective atrophy of the zona fasciculata and zona reticularis, which results in a decrease in the secretion of 17-hydroxy corticosteroids. Direct inhibition of cholesterol side-chain cleavage and 11 (3/18-hydroxylase activities has also been demonstrated. Mitotane is capable of inducing remission of Cushing s disease, but only after several weeks of therapy and at the price of severe gastrointestinal distress. Moreover, more than half of patients relapse following cessation of therapy. Other side effects include lethargy,... 

Thieno[2,3-. ]pyridine derivatives, 155, can be successfully used as replacements for the hexahydronaphthalene ring found in naturally occurring 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors <2001BML1285>. These compounds also display significant inhibition of cholesterol biosynthesis in vivo. 

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