Discovery and development of statins

The discovery of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors, called statins, was a breakthrough in the prevention of hypercholesterolemia and related diseases. Hypercholesterolemia is considered to be one of the major risk factors for atherosclerosis which often leads to cardiovascular, cerebrovascular and peripheral vascular diseases.^[1] The statins inhibit cholesterol synthesis in the body and that leads to reduction in blood cholesterol levels, which is thought to reduce the risk of atherosclerosis and diseases caused by it.^[2]

History

In the mid-19th century, a German

In the 1970s the Japanese microbiologist Akira Endo first discovered natural products with a powerful inhibitory effect on HMGR in a fermentation broth of Penicillium citrinum, during his search for antimicrobial agents. The first product was named compactin (ML236B or mevastatin). Animal trials showed very good inhibitory effect as in clinical trials, however in a long term toxicity study in dogs it resulted in toxic effects at higher doses and as a result was believed to be too toxic to be given to humans. In 1978, Alfred Alberts and colleagues at Merck Research Laboratories discovered a new natural product in a fermentation broth of Aspergillus terreus, their product showed good HMGR inhibition and they named the product mevinolin, which later became known as lovastatin.^[2][3][4]

The cholesterol controversy began in the early promotion of statins.^[2]

Mechanism

Statins are a competitive

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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|alt=Statin pathway edit]]

Statin pathway edit

1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Statin drug design

The ideal statin should have the following properties:^[6]

• High affinity for the enzyme active site
• Marked selectivity of uptake into hepatic cells compared with non-hepatic cells
• Low systemic availability of active inhibitory equivalents
• Relatively prolonged duration of effect.

One of the main design objectives of statin design is the selective inhibition of HMGR in the liver, as cholesterol synthesis in non-hepatic cells is needed for normal cell function and inhibition in non-hepatic cells could possibly be harmful.^[7]

The statin pharmacophore

The essential structural components of all statins are a dihydroxyheptanoic acid unit and a ring system with different

The statins differ with respect to their ring structure and substituents. These differences in structure affect the pharmacological properties of the statins, such as:^[6]

• Affinity for the active site of the HMGR
• Rates of entry into hepatic and non-hepatic tissues
• Availability in the systemic circulation for uptake into non-hepatic tissues
• Routes and modes of metabolic transformation and elimination

Statins have sometimes been grouped into two groups of statins according to their structure.^[9]

Type 1 statins Statins that have substituted

• Lovastatin (Figure 2)
• Pravastatin
• Simvastatin

Type 2 statins Statins that are fully synthetic and have larger groups linked to the HMG-like moiety are often referred to as type 2 statins. One of the main differences between the type 1 and type 2 statins is the replacement of the butyryl group of type 1 statins by the fluorophenyl group of type 2 statins. This group is responsible for additional polar interactions that causes tighter binding to the HMGR enzyme. Statins that belong to this group are:^[9]

• Fluvastatin (Figure 3)
• Cerivastatin
• Atorvastatin
• Rosuvastatin

Lovastatin is derived from a fungus source and simvastatin and pravastatin are chemical modifications of lovastatin and as a result do not differ much in structure from lovastatin.^[7] All three are partially reduced napthylene ring structures. Simvastatin and lovastatin are inactive lactones which must be metabolized to their active hydroxy-acid forms in order to inhibit HMGR.^[7] Type 2 statins all exist in their active hydroxy-acid forms. Fluvastatin has indole ring structure, while atorvastatin and rosuvastatin have pyrrole and pyrimidine based ring structure respectively. The lipophilic cerivastatin has a pyridine-based ring structure.

HMGR statin binding site

Studies have shown that statins bind reversibly to the HGMR enzyme. The affinity of statins for HGMR enzyme is in the nanomolar range, while the natural substrate's affinity is in the micromolar range.

With the recent elucidation of the structures of the catalytic portion of human HMGR enzyme complexed with six different statins by a series of crystallography studies, new possibilities have opened up for the rational design and optimization of even better HGMR inhibitors.^[15]

A new study using comparative molecular field analysis (CoMFA) to establish