Discovery and development of statins

Fig 1. The statin pharmacophore

The essential structural components of all statins are a dihydroxyheptanoic acid unit and a ring system with different substituents. The statin pharmacophore is modified hydroxyglutaric acid component, which is structurally similar to the endogenous substrate HMG CoA and the mevaldyl CoA transition state intermediate (Figure 1). The statin pharmacophore binds to the same active site as the substrate HMG-CoA and inhibits the HMGR enzyme. It has also been shown that the HMGR is stereoselective and as a result all statins need to have the required 3R,5R stereochemistry.[8]

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

Fig.2 Lovastatin, a type 1 statin

Fig.3 Fluvastatin, a type 2 statin

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

Type 1 statins Statins that have substituted decalin-ring structure that resemble the first statin ever discovered, mevastatin have often been classified as type 1 statins due to their structural relationship. Statins that belong to this group are:[9]

• 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.

Fig 4. HMG-CoA Reductase binding with rosuvastatin

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.[10] Studies have shown that statins use the conformational flexibility of the HMGR enzyme that causes a shallow hydrophobic groove that the statins exploit and is used to accommodate their hydrophobic moieties.[11] The specificity and the tight binding of statins is due to orientation and bonding interactions that form between the statin and the HMGR enzyme.[9] Polar interactions are formed between the HMG-moiety and residues that are located in the cis loop of the enzyme. These polar interactions are between Ser⁶⁸⁴, Asp⁶⁹⁰, Lys⁶⁹¹ and Lys⁶⁹² (Figure 4). The terminal carboxylate of the HMG moiety forms a salt bridge with the cationic Lys⁷³⁵ of the enzyme. In addition to the polar interaction, Lys⁶⁹¹ participates in a hydrogen bonding network with Glu⁵⁵⁹, Asp⁷⁶⁷ and the O5 hydroxyl group of the hydroxyglutartic acid component of the statins. Van der Waals interactions are formed between the hydrophobic side chains of the enzyme, which involve the Leu⁵⁶², Val⁶⁸³, Leu⁸⁵³, Ala⁸⁵⁶ and Leu⁸⁵⁷ and the statins.[9] Type 2 statins form polar interaction between the fluorine atom on the fluorophenyl group and the guanidinium group of Arg⁵⁹⁰.[11] In addition to these interactions atorvastatin and rosuvastatin also form unique hydrogen bonds between Ser⁵⁶⁵ residue and either a carbonyl oxygen atom (atorvastatin) or a sulfone oxygen atom (rosuvastatin). A unique polar interaction between the Arg⁵⁶⁸ side chain and the electronegative sulfone group on rosuvastatin makes it the statin that has the greatest number of bonding interactions with HGMR.[9]

All statins have the same pharmacophore so the difference in their pharmacodynamic effect is mostly based on the substituents. The activity of each statin is dependent on the binding affinity of the compound for the substrate site and the length of time it binds to the site.[5] Type 2 statins have unique fluorophenyl group that causes additional polar interaction between the enzyme and the statins, which results in a tighter binding to the enzyme. The newest statin, rosuvastatin has a unique polar methane sulfonamide group, which is quite hydrophilic and confers low lipophilicity. The sulfonamide group forms a unique polar interaction with the enzyme. As a result, rosuvastatin has superior binding affinity to the HMGR enzyme compared to the other statins, which is directly related to its efficiency to lower LDL cholesterol.[6]

Lipophilicity of the statins is considered to be quite important since the hepatoselectivity of the statins is related to their lipophilicity. The more lipophilic statins tend to achieve higher levels of exposure in non-hepatic tissues, while the hydrophilic statins tend to be more hepatoselective. The difference in selectivity is because lipophilic statins passively and non-selectively diffuse into both hepatocyte and non-heptatocyte, while the hydrophilic statins rely largely on active transport into hepatocyte to exert their effects.[5][12] High hepatoselectivity is thought to translate into reduced risk of adverse effects.[7] It has been reported that the organic anion transporting polypeptide (OATP) is important for the hepatic uptake of hydrophilic statins such as rosuvastatin and pravastatin.[5][12] OATP-C is expressed in liver tissue on the basolateral membrane of hepatocytes and is considered to be a potential contributor for the low IC₅₀ for rosuvastatin in hepatocytes. Of the marketed statins, cerivastatin was the most lipophilic and also had the largest percentage of serious adverse effects due to its ability to inhibit vascular smooth muscle proliferation and as a result was voluntarily removed from the market by the manufacturer.[5]