Statins total synthesis

The statine 12 was prepared by Claisen condensation of valine with methyl acetate followed by stereoselective reduction of the /J-keto ester, following precedents as in Jouillie s total synthesis [38] of tamandarin. The Boc group... 

All other statins, which entered the market, are produced by total synthesis (Fig. 5.153). Fluvastatin is marketed as the racemate. After the Lipobay scandal, cerivastatin was withdrawn from the market worldwide in 2001, due to reports of fatal rhabdomyolysis associated with renal failure. The reasons behind these toxicities were a too narrow therapeutic window (effective dose compared to toxic dose) and the drug interaction with fibrates, especially with gemfibrozil. 

In 2005, Kambourakis et al. reported the biocatalytic reduction of a-alkyl-1,3-diketones and a-alkyl-/l-ketoesters by employing isolated NADPH-dependent ketoreductases (KREDs). The corresponding optically pure single keto alcohols and hydroxy esters were obtained in quantitative yields (Scheme 3.9). The same group had previously reported the total synthesis of a new class of triterpene derivatives with anti-HIV activity, statin and statin analogues, based on a diastereoselective reduction of a 2-alkyl-substituted 3-ketoglutarate by a KRED. The results are summarised in Scheme 3.9. 

Asymmetric Hydrogenation of Keto Esters in the Total Synthesis Statins ° are effective inhibitors of 3-... 

Andrushko N, Andrushko V, Tararov V, Korostylev A, Konig G, Bomer A. Highly stereoselective hydrogenations-as key-steps in the total synthesis of statins. Chirality 2010 22 (5) 534-541. 

Endocrine effects Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Small declines in total testosterone with no commensurate elevation in LH have been noted with the use of fluvastatin. Pravastatin showed inconsistent results with regard to possible effects on basal steroid hormone levels atorvastatin, lovastatin, rosuvastatin, and simvastatin did not reduce basal plasma cortisol concentration or basal plasma testosterone concentration or impair adrenal reserve. Appropriately evaluate patients who display clinical evidence of endocrine dysfunction. Exercise caution when administering HMG-CoA reductase inhibitors with drugs that affect steroid levels or activity, such as ketoconazole, spironolactone, and cimetidine. 

Despite inhibition of HMG-CoA reductase by statins, cells compensate by increasing enzyme expression several fold. However, the total body cholesterol is reduced by 20-40% due to increased expression of LDL-receptors after statin administration this enhances LDL (the major cholesterol carrying lipoprotein) clearance from serum with a net reduction of serum cholesterol (Chapter 20). Individuals who lack functional LDL-receptors (homozygous familial hypercholesterolemia. Chapter 20) do not benefit from statin therapy. However, statin therapy is useful in the treatment of heterozygous familial hypercholesterolemia. Since HMG-CoA reductase plays a pivotal role in the synthesis of many products vital for cellular metabolism, inhibitors of the enzyme may have toxic effects. Monitoring of liver and muscle function may be necessary to detect any toxicity of statin drug therapy. A decreased risk of bone fractures with statin therapy has been observed in subjects age 50 years or older, who are being treated for hypercholesterolemia. The mechanism of action of statins in bone metabolism may involve inhibition of prenylation... 

Ezetimibe is the first compound approved for lowering total and LDL-C levels that inhibits cholesterol absorption by enterocytes in the small intestine. It lowers LDL-C levels by 15-20% and is used primarily as adjunctive therapy with statins. Ezetimibe does not affect intestinal triglyceride absorption. In human subjects, ezetimibe reduced cholesterol absorption by 54%, precipitating a compensatory increase in cholesterol synthesis, which can be inhibited with a cholesterol synthesis inhibitor such as a statin. The consequence of inhibiting intestinal cholesterol absorption is a reduction in the incorporation of cholesterol into chylomicrons. The reduced cholesterol content... 

In spite of a multitude of total syntheses of statins, those which occur naturally are obtained on an industrial scale by fermentation, and in the case of simvastatin, by partial synthesis. Only those statins containing a nitrogen heterocycle are obtained by total syntheses. [391] Hereafter, selected representative examples are presented. 

Lovastatin (mevinolin) is a bioactive secondary metabohte from mushrooms, which belongs to statins. Statins are inhibitors of the HMG-CoA reductase, the liver rate-limiting enzyme important to the synthesis of cholesterol (Chen et al. 2012). Mevinolin was detected in some species of edible mushrooms, like oyster mushroom Pleurotus ostreatus. Dietary intake of P. ostreatus can positively influence the lipid profile in laboratory animals and in humans by lowering the total cholesterol and triglyceride concentration in the serum (Schneider etal. 2011). In animal studies, dried mushrooms and extracts oiP ostreatus markedly increased a favorable fraction of cholesterol— the HDL-cho-lesterol (Schneider et o/. 2011). 

Statins are drugs that reduce serum cholesterol levels by inhibiting the enzyme that catalyzes the formation of a compound needed for the synthesis of cholesterol. As a consequence of diminished cholesterol synthesis in the liver, the liver forms more LDL receptors—the receptors that help clear LDL (the so-called bad cholesterol) from the bloodstream. Studies show that for every 10% that cholesterol is reduced, deaths from coronary heart disease are reduced by 15% and total death risk is reduced by 11%. 

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