statins powerful inhibitors of cholesterol biosynthesis
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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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cholesterol what is it 1

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
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
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
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

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
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
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
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

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
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
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

homologation of the lactone ring6

  • 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

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
Results
  • 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
Conclusions
  • 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
References
  • 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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