Synthetic statins

There are currently marketed four naturally derived statins (lovastatin, pravastatin, simvastatin, and rosuvas-tatin) and two synthetic statins (atorvastatin and fluvas-tatin). The structure of these statins is shown in Fig. 2. 

Simvastatin is a semi-synthetic statin that is produced from the natural statin lovasta-tin7 Both are potent antihypercholesterolemic agents with simvastatin differing from lovastatin by just one additional methyl substituent residing on the 2-(5)-methylbutyrate side chain (Figure 1.6). 

Rosuvastatin (Crestor ) is the most recent HMG-CoA reductase inhibitor to be widely approved for the treatment of hypercholesterolemic patients. It has established an impressive record of clinical efficacy and is often prescribed to patients that do not respond well to earlier HMG-CoA reductase inhibitors (Schuster, 2003). This fully synthetic statin, developed by Astra-Zeneca and Shionogi Research Laboratories, has been shown to potently inhibit cholesterol biosynthesis in rat hepatocytyes (IC50 =1.12 nM). By comparison, pravastatin (5) was > 100-fold less active in the same assay (IC50 =198 nM) (Hirai et al., 1993 Watanabe et al., 1997). 

Another promising route was reported in patent and open hterature by both DSM and Diversa [13, 14]. This route employs a 2-deoxy-D-ribose 5-phosphate aldolase (DERA) that catalyzes a tandem aldol addition in which two equivalents of acetaldehyde (AA) are added in sequence to chloroacetaldehyde (CIAA) to produce a lactol derivative that is similar to the 3,5-dihydoxy side chain of synthetic statins (Figure 6.2e). Diversa screened environmental libraries for novel wild-type DERAs and identified an enzyme that was both tolerant to increased substrate concentrations and more active than DERA from E. coli in the target reaction [13]. 

Scheme 6.2 Key precursors to synthetic statins by derivatization of lactol 1.

The research teams of Merck, Sharpe and Dohme (USA) were the first to succeed in finding a synthetic statin analogue that contained a biphenyl moiety [2] instead of a decalin ring (Fig. 4.4). 

At approximately the same time, fluvastatin was discovered as having an indole ring. This was the first synthetic statin launched in 1994. 

Synthetic statins are important lipid regulating drugs for the treatment of atherosclerosis and other diseases related to hyperlipidaemia, especially coronary heart disease. As the pharmacophore, all synthetic statins contain a saturated or partially unsaturated syn-3,5-dihydroxy C7-carboxylate. An important building block for the synthesis of the side chain is represented by 4-chloro-3-hydroxybutanoate esters (CHBE). Both enantiomers can be obtained by enzyme-catalyzed reduction of the (1-keto ester. The group of Kataoka and Shimizu found that an aldehyde reductase of Sporobolomyces salmonicolor [161] and a carbonyl reductase of Candida... 

Following the success of lovastatin, a number of other statins were developed (Figure 12.3). Simvastatin, a semisynthetic derivative of lovastatin, was first approved for marketing in Sweden in 1988 and then later worldwide. Pravastatin, isolated from Nocardia autotropica, was approved in 1991. The purely synthetic statins fluvastatin (1994), atorvastatin (1997), cerivastatin (1998), rosuvastatin (2003), and pitavastatin (2009) soon followed. Cerivastatin was subsequently pulled from the market in 2001 because of postmarketing surveillance reports which revealed 52 deaths that were attributed to rhabdomyolysis and resulting renal failure [61]. 

Due to the exceedingly high market value and the requirement for high chemical and stereochemical purity (>99.5% ee, >99% de) immense and competitive efforts have been invested in the production of synthetic statins. Pharmaceutical, chemical and biotech companies have recently developed various chemoenzymatic strategies employing different biocatalysts en route to building blocks used for the stereoselective synthesis ofthe dihydroxyhexanoate side chain (Scheme 4.17) [62]. 

Figure 35.18 Synthetic statins. Atorvastatin (Lipitor) and rosuvastatin (Crestor) are completely synthetic drugs that inhibit HMG-CoA reductase.

Compactin and lovastatin are natural statins used clinically under the trade names Zocor and Mevacor . Atorvastatin (Lipitor) , a synthetic statin, is now the most popular statin. Lipitor has greater potency and a longer half-life than natural statins have, because its metabolites are as active as the parent drug in reducing cholesterol levels. Therefore, smaller doses of the drug may be administered. The required dose is reduced further because Lipitor is marketed as a single enantiomer. In addition, it is more lipophilic than compactin and lovastatin, so it has a greater tendency to remain in the endoplasmic reticulum of the liver cells, where it is needed. 

Statins are the secondary metaboKtes of a number of different filamentous fungi. Their medical importance and commercial value stem from their ability to inhibit the enzyme (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Since this enzyme catalyzes a key step in the endogenous cholesterol biosynthetic pathway, statins have become the widely used an-tihypercholesterolemic drugs. Along with some synthetic statins, the most prominent examples are lovastatin, mainly from Aspergillus terreus, and mevastatin produced by Penicillium citrinum, which was the first statin to be discovered [92, 93]. 

Statins can be classified as natural statins and synthetic statins. Lavastatin, simvastatin, and pravastatin are the first three natural statins to reach the market. Lavastatin and pravastatin are natural products isolated from fermentation broths, while simvastatin is a semisynthetic statin derived from lavastatin. Fluvastin was the first truly synthetic statin brought to the market by Sandoz pharmaceutical company (now part of Novartis), and it was obtained by replacing the hexahydro-naphthalene core stiucture of the natural statins with the indole nucleus [5]. It was the discovery of fluvastin that opened up the opportunity of more potent synthetic statins including atorvastatin, the most prescribed drug in the world. 

Natural, semi-synthetic and totally synthetic statins for the treatment of hypercholesterolemia. 

Today, HMG-CoA reductase inhibitors (statins) have worldwide sales of approximately 20 billion, led by Atorvastatin 47 and Crestor 48 (Rosuvastatin) (Figure 4.15) The synthetic statins share the chiral 3, 5-dihydroxy acid side chain, which is essential for activity and represents the synthetic challenge for the preparation of these drugs [80]. 

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