Statin development



The discovery of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors, called 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

More than 100 years ago a German cholesterol was to be found in the artery walls of people that died from occlusive vascular diseases, like myocardial 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 to hypertension and increased risk of occlusive vascular diseases.[2]

In the 1950´s the Framingham heart study led by Dawber revealed the correlation between high blood cholesterol levels and coronary 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. Hence HMG-CoA reductase (HMGR) became a natural target. HMGR was found to be the rate-limiting enzyme 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 1970´s the Japanese microbiologist Akira Endo first discovered lovastatin.[2][3][4]

Mechanism

Statins are a competitive TG (Triglycerides) and total cholesterol levels as well as increased HDL (High Density Lipoprotein) levels in serum).[2][3][4]

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 stereoselective and as a result all statins need to have the required 3R,5R stereochemistry.[8]

Differences in statin structure

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 elminination

   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]

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]

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 pyridine-based ring structure.

HMGR statin binding site

  Studies have shown that statin 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 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]

Structure-activity relationship (SAR)

All statins have the same pharmacophore so the difference in their 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 it’s efficiency to lower LDL cholesterol.[6]

Lipophilicity

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 due to the fact that 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 it’s ability to inhibit vascular smooth muscle proliferation and as a result was voluntarily removed from the market by the manufacturer.[5]

Comparison of lipophilicity of HMG-CoA Reductase Inhibitors at pH 7,4[5]
Cerivastatin Simvastatin FluvastatinAtorvastatin 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)

Metabolism

All statins are (CYP2C19 isoenzymes. Pravastatin is not metabolized by CYP isoenzymes to any appreciable extent.[6][8][13] The statins who 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]

Comparative pharmacology of statins

Comparative efficiency and pharmacology of the statins.[14]
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

Future research

With the recent elucidation of the structures of the 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 virtual screening procedure is considered promising for rational quest and optimization of potential novel HGMR inhibitors.[15]

References

  1. ^ Christians, Uwe; Jacobsen, Wolfgang & Floren, Leslie C. (October 1998), " ", Pharmacology and Therapeutics 80 (1): 1-34,
  2. ^ a b c d e Tobert, Jonathan A. (July 2003), " ", Nature Reviews Drug Discovery 2: 517-526,
  3. ^ a b c Endo, Akira (1992), " ", Journal of Lipid Research 33: 1569-1580,
  4. ^ a b Endo, Akira (2004), " ", International Congress Series 1262: 3-8,
  5. ^ a b c d e f White, C. Michael (2002), " ", The Journal of Clinical Pharmacology 42: 963-970,
  6. ^ a b c d e McTaggart, Fergus (2003), " ", Atherosclerosis Supplements 4: 9-14,
  7. ^ a b c d Hamelin, Bettina A. & Turgeon, Jacques (January 1998), " ", Trends in Pharmacological Sciences 19: 26-37,
  8. ^ a b c d Roche, Victoria F. (2005), " ", American Journal of Pharmaceutical Education 69 (4): 546-560,
  9. ^ a b c d e f Istvan, Eva S. & Deisenhofer, Johann (May 2001), " ", Science Magazine 292: 1160-1164,
  10. ^ Moghadasian, Mohammed H. (May 1999), " ", Life Sciences 65 (13): 1329-1337,
  11. ^ a b Istvan, Eva S. (December 2002), " ", American Heart Journal 144 (6): 27-32,
  12. ^ a b Pfefferkorn, Jeffrey A.; Song, Yuntao & Sun, Kuai-Lin et al. (June 2007), " ", Bioorganic & Medicinal Chemistry Letters 17: 4538-4544,
  13. ^ a b c d e f Corsini, Alberto; Bellosta, Stefano & Baetta, Roberta et al. (1999), " ", Pharmacology & Therapeutics 84: 413-428,
  14. ^ Vaughan, Carl J. & Gotto, Jr., Antonio M. (June 2004), " ", Circulation, Journal of the American heart association 110: 886-892,
  15. ^ a b Zhang, Qing Y.; Wan, Jian & Xu, Xin et al. (November 2006), " ", Journal of Combinatorial Chemistry 9 (1): 131-138,
 
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