The discovery ofHMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors, calledstatins, was a breakthrough in the prevention ofhypercholesterolemia and related diseases. Hypercholesterolemia is considered to be one of the major risk factors foratherosclerosis which often leads tocardiovascular,cerebrovascular and peripheral vascular diseases.[1] The statins inhibitcholesterol 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]
In the mid-19th century, a Germanpathologist namedRudolf Virchow discovered thatcholesterol was to be found in theartery walls of people that died from occlusive vascular diseases, likemyocardial infarction. The cholesterol was found to be responsible for the thickening of the arterial walls and thus decreasing the radius in the arteries which leads in most cases tohypertension and increased risk of occlusive vascular diseases.[2]
In the 1950s theFramingham heart study led by Dawber revealed the correlation between high blood cholesterol levels andcoronary heart diseases. Following up from that study the researchers explored a novel way to lower blood cholesterol levels without modifying the diet and lifestyle of subjects suffering with elevated blood cholesterol levels. The primary goal was to inhibit the cholesterol biosynthesis in the body. HenceHMG-CoA reductase (HMGR) became a natural target. HMGR was found to be therate-limitingenzyme in the cholesterol biosynthetic pathway. There is no build-up of potentially toxic precursors when HMGR is inhibited, because hydroxymethylglutarate is water-soluble and there are alternative metabolic pathways for its breakdown.[2][3]
In the 1970s the JapanesemicrobiologistAkira Endo first discoverednatural products with a powerful inhibitory effect on HMGR in a fermentation broth ofPenicillium citrinum, during his search forantimicrobial agents. The first product was namedcompactin (ML236B ormevastatin).Animal trials showed very good inhibitory effect as inclinical 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 ofAspergillus terreus, their product showed good HMGR inhibition and they named the productmevinolin, which later became known aslovastatin.[2][3][4]
The cholesterol controversy began in the early promotion of statins.[2]
Statins are a competitiveantagonists of HMG CoA, as they directly compete with theendogenous substrate for theactive site cavity of HMGR. Statins are also noncompetitive with the cosubstrate NADPH (nicotinamide adenine dinucleotide phosphate).[5] By blocking the HMGR enzyme they inhibit the synthesis of cholesterol via themevalonate pathway. The end result is lowerLDL (Low Density Lipoprotein),TG (Triglycerides) and total cholesterol levels as well as increasedHDL (High Density Lipoprotein) levels inserum.[2][3][4]
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
The ideal statin should have the following properties:[6]
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 essential structural components of all statins are a dihydroxyheptanoic acid unit and a ring system with differentsubstituents. The statinpharmacophore is modified hydroxyglutaric acid component, which is structurally similar to the endogenous substrate HMG CoA and the mevaldyl CoAtransition 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 isstereoselective 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 thepharmacological properties of the statins, such as:[6]
Statins have sometimes been grouped into two groups of statins according to their structure.[9]
Type 1 statinsStatins that have substituteddecalin-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]
Type 2 statinsStatins 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 thebutyryl 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]
Lovastatin is derived from afungus 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 inactivelactones which must bemetabolized to their active hydroxy-acid forms in order to inhibit HMGR.[7] Type 2 statins all exist in their active hydroxy-acid forms. Fluvastatin hasindole ring structure, while atorvastatin and rosuvastatin havepyrrole andpyrimidine based ring structure respectively. Thelipophilic cerivastatin has apyridine-based ring structure.[citation needed]
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 shallowhydrophobic 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 terminalcarboxylate of the HMG moiety forms asalt bridge with the cationic Lys735 of the enzyme. In addition to the polar interaction, Lys691 participates in ahydrogen 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 thefluorineatom on the fluorophenyl group and the guanidinium group of Arg590.[11] In addition to these interactions atorvastatin and rosuvastatin also form uniquehydrogen bonds between Ser565 residue and either acarbonyloxygen atom (atorvastatin) or asulfone 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 theirpharmacodynamic 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 methanesulfonamide group, which is quitehydrophilic and confers lowlipophilicity. 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 bothhepatocyte 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 ofadverse 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 thebasolateral membrane of hepatocytes and is considered to be a potential contributor for the lowIC50 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]
| Cerivastatin | Simvastatin | Fluvastatin | Atorvastatin | Rosuvastatin | Pravastatin | |
|---|---|---|---|---|---|---|
| Log D Class | 1,50–1,75 | 1,50–1,75 | 1,00–1,25 | 1,00–1,25 | -0,25–(-0,50) | -0,75–(-1,0) |
All statins aremetabolized by the liver, which causes their low systemicbioavailability.[13] Lovastatin and simvastatin are administered in their lactone forms, which is more lipophilic than their free acid forms, and therefore they have to be activated byhydrolysis to the activeanionic carboxylate form.[8][13]Cytochrome P450(CYP) isoenzymes are involved in theoxidative metabolism of the statins, withCYP3A4 andCYP2C9isoenzymes being the most dominant. CYP3A4 isoenzyme is the most predominant isoform involved in metabolism of lovastatin, simvastatin, atorvastatin and cerivastatin.[8][13] CYP2C9 isoenzyme is the most predominant isoform involved in metabolism of Fluvastatin, but CYP3A4 andCYP2C8 isoenzymes also contribute to the metabolism of Fluvastatin.[13] Rosuvastatin is metabolized to a small degree by CYP2C9 and to a lesser extent byCYP2C19 isoenzymes. Pravastatin is not metabolized by CYP isoenzymes to any appreciable extent.[6][8][13] The statins that have the ability to be metabolized by multiple CYP isoenzymes may therefore avoid drug accumulation when one of the pathways is inhibited by co-administered drugs.[13]
| Drug | Reduction in LDL-C (%) | Increase in HDL-C (%) | Reduction in TG (%) | Reduction in TC (%) | Metabolism | Protein binding (%) | T1/2 (h) | Hydrophilic | IC50 (nM)[6] |
|---|---|---|---|---|---|---|---|---|---|
| Atorvastatin | 26 – 60 | 5 – 13 | 17 – 53 | 25 – 45 | CYP3A4 | 98 | 13–30 | No | 8 |
| Lovastatin | 21 – 42 | 2 – 10 | 6 – 27 | 16 – 34 | CYP3A4 | >95 | 2 – 4 | No | NA |
| Simvastatin | 26 – 47 | 8 – 16 | 12 – 34 | 19 – 36 | CYP3A4 | 95 – 98 | 1 – 3 | No | 11 |
| Fluvastatin | 22 – 36 | 3 – 11 | 12 – 25 | 16 – 27 | CYP2C9 | 98 | 0,5 – 3,0 | No | 28 |
| Rosuvastatin | 45 – 63 | 8 – 14 | 10 – 35 | 33 – 46 | CYP2C9 | 88 | 19 | Yes | 5 |
| Pravastatin | 22 – 34 | 2 – 12 | 15 – 24 | 16 – 25 | Sulfation | 43 – 67 | 2 – 3 | Yes | 44 |
With the recent elucidation of the structures of thecatalytic portion of human HMGR enzyme complexed with six different statins by a series ofcrystallography 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 establishthree-dimensional quantitative structure-activity relationship (3D QSAR), while searching for novel active pharmacophores as potentially potent HGMR inhibitors, was recently published. Using this novel technique researchers were able to screen for compounds with high screening scores. In addition to the conventional statin-like compounds with HMG-like moiety, eight additional compounds with completely different pharmacophore structure were found. This structure-basedvirtual screening procedure is considered promising for rational quest and optimization of potential novel HGMR inhibitors.[15]
