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Statins: Powerful Inhibitors of Cholesterol Biosynthesis. H. O. Cholesterol: What is it? 1. Cholesterol is a fatty steroid made primarily in the liver of most animals and humans. It is an integral component in the synthesis of hormones, can also be found in cell walls of animals and humans.

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Statins powerful inhibitors of cholesterol biosynthesis l.jpg

Statins: Powerful Inhibitors of Cholesterol Biosynthesis


Cholesterol what is it 1 l.jpg

H

O

Cholesterol: What is it?1

Cholesterol is a fatty steroid made primarily in the liver of most animals and humans. It is an integral component in the synthesis of hormones, can also be found in cell walls of animals and humans.

Isolated cholesterol is a white, flaky solid that is insoluble in aqueous environments.

Cholesterol


Two types of transportation for cholesterol l.jpg
Two types of transportation for cholesterol

In order to transport the steroid through blood, cholesterol is attached to a set of proteins called lipoproteins. There are two types of lipoproteins: high density and low density lipoproteins.

HDL: High-density lipoproteins –collectcholesterol particles as they travel through blood vessels and deposits them in the liver where they are transferred to bile acids and disposed off.

LDL: Low-density lipoproteins –deposits on the walls of blood vessels, and over time, builds up into cholesterol plaque and blocks blood vessels, especially arteries that feed blood to the heart.

1. The liver manufactures, secretes and removes LDL cholesterol from the body. To remove LDL cholesterol from the blood, there are special LDL receptors on the surface of liver cells.

2. LDL receptors remove LDL cholesterol particles from the blood and transport them inside the liver. A high number of active LDL receptors on the liver surfaces is necessary for the rapid removal of LDL cholesterol from the blood and low blood LDL cholesterol levels.

A deficiency of LDL receptors is associated with high LDL cholesterol blood levels.

Diets that are high in cholesterol diminish the activity of LDL receptors!!!!


Biological role 1 l.jpg
Biological Role:1

  • It is an important component of cell linings

  • It helps in the digestion of lipids

  • It is a key component in the building of hormones

  • Hypercholestraemia: High blood cholesterol

  • Usually a result of high LDL/low HDL cholesterol levels

  • Leads to

    • narrowing of artery walls (atherosclerosis)

    • decreased blood and oxygen supply to heart

    • heart attack

    • death

  • Coronary heart disease1: Leading cause of death in western

    countries.


  • Slide6 l.jpg
    Initial treatment of hypercholesteraemia was directed toward limiting LDL-cholesterol levels through:

    Low-cholesterol diet

    and regular exercise.

    Exercise burns fat so it is not

    coverted to cholesterol which the

    Body will have to dispose off.

    • This approach was not very successful because high blood

    • cholesterol is also hereditary (Familial Hypercholestraemia (FH))1 and a chronic condition. People with FH have defective or nonexistent LDL receptors and need rigorous, long-term treatment.

    • Scientific Approach:

    • Know and understand how the body makes cholesterol

    • Find a way to effectively control cholesterol levels with

    • minimum adverse effects


    The mevanolate pathway 2 l.jpg

    19 steps

    H

    O

    H

    O

    lanosterol cholesterol

    The Mevanolate Pathway2

    The biosynthesis of cholesterol and isoprenoids (agroup of compounds responsible for cell fluidity and cell proliferation)

    5-pyrophosphomevalonate

    isopentenyl pyrophosphate

    geranyl pyrophosphate

    farnesyl pyrophosphate

    squalene

    2,3-oxidosqualene


    In 1976 l.jpg
    In 1976……..

    • ML-236A, ML-236B, ML-236C: metabolites isolated from a fungus (Penicillium citrinum) were found to reduce serum cholesterol levels in rats.

    • This work was done by Akira Endo, Masao Kuroda and Yoshio Tsujita at the Fermentation Research Laboratories, Tokyo, Japan.3

    Preliminary experiments showed that these fungal metabolites had no effect on mevanolate or other steps in the biosynthetic pathway.

    This led to the speculation that their action was somewhere between the mevanolate and the HMG-CoA

    β


    Target hmg coa reductase hmgr l.jpg
    Target: HMG-CoA Reductase (HMGR)

    • The enzyme that catalyzes the conversion of HMG-CoA to mevanolate.

    • This reaction is the rate-determining step in the synthetic pathway.

    3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)


    Results l.jpg
    RESULTS

    • Rats received oral dose of test compounds (5 mg/kg suspended in 0.5 mL of saline)

    • Control group received 0.5 mL of saline

    • Of the 3 substances tested, ML-236B had the highest level of hypocholesterolemic activity.

      Amounts required for 50% inhibition

      ML-236A 0.18 µg/mL

      ML-236B 0.01 µg/mL

      ML-236C 0.08 µg/mL


    Statins l.jpg

    lovastatin

    compactin

    Statins

    • ML-236B was later called compactin(6-demethylmevinolin or mevastatin). A related fungal metabolite called lovastatin (mevinolin) was also found to be another good inhibitor of HMG-CoA reductase. Lovastatin was isolated from Aspergillus terreus.

    Today, there are two classes of statins:

    Natural Statins: Lovastatin(mevacor),

    Compactin, Pravastatin (pravachol), Simvastatin (Zocor).

    Synthetic Statins: Atorvastatin (Lipitor),

    Fluvastatin (Lescol).

    Statins are competitive inhibitors of

    HMG-CoA reductase. They are bulky and

    literally get “stuck” in the active site.

    This prevents the enzyme from binding

    with its substrate, HMG-CoA.

    Ester side-chain


    Making the synthetic statins l.jpg
    Making the synthetic statins

    Lovastatin and compactin can be made in the lab in multistep syntheses.

    This allowed scientists to study the structural-activity relationship of statins. The lactone was found to be the business end of the drugs.4


    Modification of lovastatin l.jpg
    Modification of Lovastatin

    • Since statins are competitive inhibitors, an increase in the amount of HMG-CoA will reduce the effectiveness of the drugs.

    • New drug design approaches are geared towards making lovastatin analogs that will have longer interaction with the enzyme –increase duration of drug occupancy of active site.

    • Structural modification: i. making ether side-chain analogs

      (Lee, et. al. 1982) ii. homologation of the lactone ring

      iii. converting lovastatin to mevanolate analog (changing stereochemistry at the hydroxy- bearing carbon in the lactone)



    Slide15 l.jpg

    • Purpose is to develop a lactone homolog that is compatible with the complex and sensitive structural features of lovastatin.

    • As in the case of making the ether analogs, the hydroxy-bearing carbon had to be protected


    Slide16 l.jpg

    iii. converting lovastatin to mevanolate analog (placing a methyl group at the hydroxy-bearing carbon in the lactone)6

    • The hydroxy-bearing carbon in HMG-CoA and mevanolate have a methyl group. This substituent is lacking in lovastatin

    • Purpose is to investigate the biological consequence of this methyl group

    • 16 and 11 are epimers: diastereomers that differ in configuration at only one stereogenic center.


    Results17 l.jpg
    Results methyl group at the hydroxy-bearing carbon in the lactone)

    • Mevanolate and lactone modifications: no biological test and results have been report.

    • Results from ether analogs (Lee, et. al. in 1991)5

      i. The ethers were tested against their ester analogs

      ii. Compactin was used as standard and assigned a relative potency of 100

    In vitro HMG-CoA reductase inhibitory activity

    showed that absence of the carbonyl has

    detrimental effect on the inhibitory strength.

    General conclusion: side-chain ether analogs are

    weaker inhibitors of HMGR than their

    Corresponding ether analog.

    The role of the ester group in the synthetic

    pathway is still under investigation.


    Conclusions l.jpg
    Conclusions methyl group at the hydroxy-bearing carbon in the lactone)

    • Coronary heart disease, a condition caused by hypercholestraemia is a major leading cause of death in most western countries.

    • The discovery of natural statins (lovastatin and compactin) lead to innovative approaches to treatment of high cholesterol.

    • These natural statins have also served as templates for making synthetic statins, most of which are on the market today.

    • With understanding of the SAR of statins and their interactions with HMGR (bonding nature, etc), we can improve the effectiveness of these drugs and limit side-effects.


    References l.jpg
    References methyl group at the hydroxy-bearing carbon in the lactone)

    • Lee, D. Cholesterol and the heart. http://www.medicinenet.com/cholesterol/ (Sept 2004).

    • Diwan, J. J. Cholesterol Synthesis. http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm (Sept 2004).

      3.Endo, A.; Kuroda, M.; Tsujita, Y. J. Antibio. (Tokyo) 1976, 29, 1346-1348.

      4.Istvan, E. S. American Heart Journal 2002, 144, S27-32.

      5.Lee, T. J.; Holtz, W. J.; Smith, R. L.; Alberts, A. W.; Gilfillan, J. L. J Med Chem 1991, 34, (8), 2474-7.

      6. Lee, T. J. H., W. J.; Smith, R. L. Journal of Organic Chemistry 1982, 47, (24), 4750.


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