Cholesterol Lowering Dmgs

Cholesterol lowering drugs are indicated for the prevention and treatment of atherosclerosis. There are three families of these dmgs inhibitors of HMG-CoA reductase (statins), inhibitors of cholesterol transport protein, and inhibitors of cholesteryl ester transfer protein (CETP). They are important drugs from an economical point of view. Among them, several are fluorinated. 

1 HMG-CoA Reductase Inhibitors Statins inhibit HMG-CoA reductase, the enzyme synthesizing mevalonic acid (a key step in cholesterol biosynthesis). These drugs are indicated to treat hypercholesterolemia and to reduce LDL cholesterol. 

SUN-8075 is also a propanolol derivative, but it does not act as a S-blocker it is a dual Na+/Ca + channel blocker and channel inhibitor. It is being studied in Phase I clinical trials as a therapeutic agent for acute stroke. 

Ketanserine, a 5-HT2 serotonin peripheral receptor antagonist, is being marketed for the treatment of hypertension. 

A vasopressin V2 receptor antagonist, lixivaptan, is currently being developed (Phase 11) for the treatment of hyponatremia. This agent blocks the effect of the antidiuretic hormone arginine-vasopressin. 

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The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

Therapeutic profile It is a lead candidate compound for development by Kowa, Japan, as a cholesterol-lowering dmg. 

Biological Diels-Alder reactions are known but uncommon. One example occurs in the biosynthesis of the cholesterol-lowering dmg lovastatin (trade name Mevacor) isolated from the bacterium Aspergillus terreus. The key step is... 

Today, the association of aromaticity with fragrance has long been lost, and we now use the word aromatic to refer to the class of compounds that contain six-membered benzene-like rings with three double bonds. Many naturally occurring compounds are aromatic in part, including steroids such as estrone and well-known pharmaceuticals such as the cholesterol-lowering dmg ator-vastatin, marketed as Lipitor. Benzene itself causes a depressed white blood cell count (leukopenia) on prolonged exposure and should not be used as a laboratory solvent. 

Hersmans Y. Cholesterol-lowering agents and cardiac glycosides. In Levy RH, Thummel KE, Trager WF, et al., eds. Metabolic Dmg Interactions. Philadelphia Lippincott Williams and Wilkins, 2000 379-390. 

Ezetimibe is a newer dmg that inhibits cholesterol absorption by the G1 tract it reduces LDLc modestly as monotherapy and is used in combination therapy with simvastatin (marketed as Vytorin) to achieve good cholesterol lowering and minimizing... 

Bliznakov, E.G., Coenzyme QIO, lipid-lowering dmgs (statins) and cholesterol a present day Pandora s box, J. Am. Nutraceut. Assoc., 5, 32, 2002. 

Ten years later, Taylor et al. [84] published a study on the effects of Upo-some encapsulation on the pharmacokinetics in humans of sodium cromoglycate, a water-soluble antiasthmatic/antiallergenic compound. The dmg was formulated in dipalmitoylphosphatidylcholine/cholesterol (DPPC/CH) (1 1 molar ratio) liposomes and administered as a nebulized aerosol. The researchers demonstrated that, compared with drug administered in solution, the liposomally encapsulated dmg achieved a lower C ax and prolonged plasma half-life, indicating that the liposomes were controlling dmg delivery. 

Since the rodent effects of PPs ate mediated via PPARa and humans appear to be non-responsive to these adverse effects, species differences in PPARa expression levels provide a plausible explanation for the lack of hitman response. However, humans do respond to PPs by altering etqtression of enzymes that regulate serum cholesterol and lipid homeostasis. " In addition, human liver does contain a functional PPARa although the expression of PPARa in humans is around 10-fold lower when compared with responsive species such as rat and mouse."" "" In total, these data support a quantitative hypothesis whereby PPARa expression in humans is sufficient to mediate the beneficial effects of hypolipidaemic dmgs via regulation of genes for enzymes and lipid transporters. 

Lovastatin is rapidly metabolised, which is undesirable for any dmg likely to be chronically administered. In order to achieve once-daily dosing, steric hindrance around the ester carbonyl was increased by the introduction of an extra methyl group close to the ester bond in order to reduce the rate of esterase hydrolysis. This resulted in formation of simvastatin, a highly successful lipid-lowering agent. Simvastatin (like lovastatin) is inactive until metabolised in the liver to form its active metabolite mevinolinic acid (Fig. 8.48). Part of mevino-linic acid is stmcturally similar to the HMG portion of HMG-GoA, the substrate for HMG-CoA reductase, and hence competes with it for the active site of the enzyme. This reduces the amount of mevalonic acid which is produced. Mevalonic acid is a precursor of cholesterol. 

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