Statins mevastatin

Rosuvastatin calcium (56 Crestor ) Mevastatin Statin NP-derived Microbial Dyslipidemia Inhibits ttie rate-limiting step in hie formation of endogenous cholesterol by HMG-CoA reductase 215-217, 492-495... 

Inhibition by drugs The statin drugs, including simvastatin, lovastatin, and mevastatin, are structural analogs of HMG CoA, and are reversible, competitive inhibitors of HMG CoA reductase (Figure 18.7). They are used to decrease plasma cholesterol levels in patients with hypercholesterolemia.1... 

The statins include atorvastatin, bervastatin, cerivastatin, crilvastatin, dalvastatin, fluvastatin, glenvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin,... 

Research groups in Japan [1] have screened over 8000 microbial extracts for their ability to produce an inhibitor of sterol synthesis in vitro. These studies led to the isolation of mevastatin from cultures of Penicillium citrinum. Mevastatin (Fig. 4.2) served as the lead-molecule for seven statins which currently are among the best-selling drugs. 

Lovastatin was the first statin to be developed, and was isolated from the fungus Aspergillus terreus. It was launched in 1987 by Merck, Sharpe and Dohme (USA), and is a two-fold more potent methyl-homologue of mevastatin (Fig. 4.3). 

Pravastatin was obtained by the microbiological hydroxylation of mevastatin. It is a ring-opened derivative which is much more hydrophilic than lovastatin and simvastatin. Lovastatin, simvastatin and pravastatin all share the decalin (hexahy-dronaphthalene) ring of natural origin. These drugs represent the first generation of statins. 

The first "statin" was discovered by Endo and coworkers at Sankyo in Tokyo in 1976. After testing over 8,000 microbial extracts, they found a compound, named mevastatin (ML-236B) (Figure 9), from Penicillium citrinum which showed specific inhibition of HMG CoA reductase and functioned in vivo, lowering serum cholesterol levels. Further development of mevastatin was curtailed because inhibition of cholesterol biosynthesis was not restricted to the liver. The compound enters the lens and adrenals, where it blocks the essential biosynthesis of cholesterol. The same compound was also isolated by a team at the Beecham Research Laboratories in Brockham Park, Surrey. Whilst screening for antifungal activity, they isolated the compound, which they named compactin, from Pencillium brevicompactum, but apparently failed to recognise it as a potent inhibitor of HMG CoA reductase. 

Many attempts have been made to find cholesterol biosynthesis inhibitors for development as hypocholesterolemic agents. Microbial secondary metabolites have been used as valuable natural sources in the development of novel cholesterol biosynthesis inhibitors. Mevastatin and lovastatin were isolated from the fungi, Penicillium citrinum and Aspergillus terreus, respectively, as potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which is involved in the rate-limiting step of cholesterol synthesis in mammals. These findings have led to the development of statins , which are drugs of choice in the treatment of hypercholesterolemia. 

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]. 

Prompted by the success with lovastatin, Merck developed the semisynthetic statin simvastatin, which differs from the former by an additional methyl group in its side-chain. Pravastatin was the first statin to be marketed by Sankyo in 1989. It is obtained from mevastatin by microbial hydroxy-lation. The efficacy of these statins differs in patients very little from that of lovastatin. 

Endo, A., M. Kuroda andY Tsujita,/. Antibiotics, 29,1976,1346-1348. (Discovery of mevastatin - the first statin)... 

Statins are Lovastatin (1), Mevastatin -naturally-occurring compound found in red yeast rice, and Pravstatin. Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis i) Improving endothelial function ii) Modulate inflammatory responses, iii) Maintain plaque stability, and iv) Prevent thrombus formation. 

Figure 8 Chemical structures of statins. HMG-CoA analog is highlighted with a dashed circle. Lovastatin and mevastatin are natural statins of fungal origin. Simvastatin and pravastatin are chemically modified derivatives of lovastatin and mevastatin, respectively. Fluvastatin, atorvastatin, cerivastatin (withdrawn from clinical use in 2001), pitavastatin and rosuvastatin are fully synthetic compounds (Schachter, 2005).

The discovery of these early statins paved the way for the worldwide development of other drugs based on the statin chemical structure (Figure 8.2). Sankyo and Merck directed their later efforts at manufacturing synthetic analogs. Many different statins are currently available for therapeutic use, but lovastatin and mevastatin remain the only fermentation-derived statins. The lovastatin biosynthetic pathway in A. terreus is well understood. This pathway was the first example of a polyketide synthetic pathway in which two fungal type I polyketide synthases work in combination to produce a product (Hendrickson et al., 1999 Kennedy et al., 1999). Since then several statins, including simvastatin, pravastatin, fluvastatin and atorvastatin, have been approved in many countries and are currently used by millions. 

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