Simvastatin discovery

Simvador (Simvastatin) Discovery Miarmaceuticals Ltd UK Summary ofproduct characteristics, July 2003... 

Sim vador (Simvastatin). Discovery Pharm aceuticals Ltd. UK Summary of product characteristics, July 2003. 

Subsequently, a second, closely related molecule—lovastatin—was discovered by scientists at Merck in the United States in another fungal fermentation broth and by Sankyo in Japan. Lovastatin, marketed as Mevacor in the United States, proved both safe and efficacious for the intended nse and was the first statin to be approved for human use. Several others, some mentioned above, followed. The history of discovery and development of HMGR inhibitors has been pnUed together by Jonathan Tobert, who led the lovastatin and simvastatin clinical development effort at Merck. ... 

The discovery of compactin and lovastatin prompted efforts to develop derivatives with improved biological properties (163, 164). Modification of the methylbutyryl side chain of lovastatin led to a series of new ester derivatives with varying potency and, in particular, introduction of an additional methyl group a to the carbonyl gave a compound with 2.5 times the intrinsic enzyme activity of lovastatin (165). The new derivative, named simvastatin (124), was the second HMG-CoA reductase inhibitor to be marketed by Merck. Both lovastatin and simvastatin are prodrugs and are hydrolyzed to their active open-chain dihydroxy acid forms in the liver (166). A third compound, pravastatin (125), launched by Sankyo and Squibb in 1989, is the open hy-droxyacid form of compactin that was first identified as a urinary metabolite in dogs. Pravastatin is produced by microbial biotransformation of compactin. 

This key discovery prompted further efforts to develop improved cholesterol lowering agents. For example, chemical modifications of the methylbutyryl sidechain gave simvastatin (having twice the potency of lovastatin) (Figure 10) which is also marketed by Merck. Pravastatin, marketed by Sankyo and Bristol Myers Squibb, is the 6-hydroxy open hydroxyacid derivative produced by microbial biotransformation of mevastatin (Figure 10). ... 

If this endogenous production of cholesterol could be reduced, it would be of significant therapeutic use. With the discovery of the mevinic acids almost 15 years ago, an enzyme inhibitor for an enzyme participating in cholesterol biosynthesis, namely HMG-CoA reductase, was found for the first time. Today lovastatin, simvastatin, and pravastatin are standard components of the battery of pharmaceuticals. 

Commercial evidence also supports the case for natural products. Of the 20 best-selling non-protein drugs in 1999, nine were either derived from or developed as the result of leads generated by natural products (e.g., simvastatin, lovastatin, ciprofloxacin, clarithromycin and cyclosprin) with combined annual sales of greater than US 16 billion. Newer developments based on natural products include the antimalarial drug artemisinin, and the anticancer agents taxol, docetaxel and camptothecin. In addition to the historical success in drug discovery, natural products are likely to continue to be sources of new commercially viable... 

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. 

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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