Inhibition of Cholesterol Biosynthesis

1
Inhibition of Cholesterol Biosynthesis

• By Peter Riedell
• Medicinal Chemistry
• Dr. Buynak
• April 6, 2006

2
What is Cholesterol?

• Molecule found within all cells of the body
• Insoluble in aqueous medium
• Functions in many different roles within body
• Cell signaling
• A component of the cell membrane
• Synthesis of hormones

3
Two Types of Cholesterol

• Cholesterol must be transported via attachment to
  a protein ? lipoproteins
• Two classes of lipoproteins
• HDL- High density lipoproteins- capture
  cholesterol particles as they travel through
  blood vessels and deposit them in the liver
• Known as good cholesterol
• LDL- Low density lipoproteins- transport
  cholesterol throughout the body from the liver to
  other places where it is needed
• Known as bad cholesterol

4
Hypercholesterolemia

• Hypercholesterolemia? high blood cholesterol
• Most commonly the result of high LDL and low HDL
  cholesterol levels
• Leads to atherosclerosis? narrowing of artery
  walls
• Leads to decreased oxygen supply to parts of body
• If vessels leading to the heart then results in a
  heart attack
• If vessels leading to the brain then results in
  an aneurysm

5
How Atherosclerosis Occurs
6
Treatment Options

• Initial treatments for hypercholesterolemia
  focused on changing a patients behavior
• Diet- low in cholesterol and saturated/total fat
• Exercise- prevents fat from being converted to
  cholesterol
• Options not very effective
• Low compliance
• Some patients have familial hypercholesterolemia
  (FH) in which LDL receptors are defective or
  ineffective
• It was necessary to search for a new way to lower
  serum cholesterol

7
Cholesterol Biosynthesis Pathway

• Around 80 of cholesterol synthesized in liver
• Rest acquired from dietary sources
• Synthesis pathway elucidated in 1964

5-pyrophosphomevalonate
isopentenyl pyrophosphate
geranyl pyrophosphate
farnesyl pyrophosphate
squalene
2,3-oxidosqualene
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Early Inhibitors of Cholesterol Synthesis

• Searched microbes for natural inhibitors of
  cholesterol synthesis
• Hoped that certain microbes would produce
  inhibitors as a weapon to fight against others
  who needed sterols for growth
• Penicillium citrinum - found to produce
  metabolites which lowered serum cholesterol in
  rats
• Further experiments showed that metabolites had
  no apparent effect on mevalonate or any of the
  other steps in the pathway

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Inhibitors of HMG-CoA Reductase

• Metabolites found to inhibit the enzyme HMG-CoA
  Reductase- the rate limiting step in the
  synthesis of cholesterol

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Mevastatin and Lovastatin

• Mevastatin or compactin was found to a potent
  inhibitor of the HMG-CoA Reductase enzyme
• Antagonist
• Reversible
• Competitive
• Enzyme has 10,000 fold higher affinity for
  mevastatin than for HMG-CoA
• Lovastatin
• Isolated from related microbe Aspergillus terreus
• Similar in structure and behavior to mevastatin

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Similarities to HMG-CoA

• Similar in HMG-CoA binding region
• Lactone portion is active center and binds to HMG
  binding site
• Hydrophobic region interacts with adjacent
  hydrophobic pocket in enzyme
• Kinetic studies show that spatial arrangement
  between lactone and ring important
• Both are prodrugs
• Enzymatically hydrolyzed to active hydroxyl-acid
  in vivo

Mevastatin and Lovastatin
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Classes of Statins

• Two classes of statins
• Natural statins
• Include Lovastatin (mevacor), Compactin
  (mevastatin), Pravastatin (pravachol),
  Simvastatin (Zocor)
• Synthetic statins
• Include Atorvastatin (Lipitor), Fluvastatin
  (Lescol).

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Synthesizing Synthetic Statins

• Synthesis of novel statins begins with the
  synthesis of mevastatin
• Then modify ester linkage, hydrophobic region,
  changed stereochemistry of active hydroxy, and
  modified lactone ring to attain novel drug

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Additional Uses and Benefits

• Additional cardiovascular health benefits
• Stabilize plaques, promote new vessel formation,
  and reduces the vascular inflammatory process
• Other potential benefits
• Improvement of fracture risk in osteoporosis
• Retard the pathogenesis of Alzheimers disease
• Reduce incidence of failure in organ transplant

15
Side Effects

• Adverse side effects are rare
• Most important are liver and muscle toxicity
• Muscle side effects include
• myopathy - abnormal disease of the muscle tissue
• Rhabdomyolysis - breakdown of the muscle fiber
• Occurs in 1 in 1000 patients
• Other minor side effects include fever and malaise

16
References

• Cholesterol. http//en.wikipedia.org/wiki/Choleste
  rol (Mar 2006).
• Fallon, F.L., Odle, T. Hypercholesterolemia.
  http//www.healthatoz.com/healthatoz/Atoz/ency/hyp
  ercholesterolemia.jsp (Mar 2006).
• Lee, D. Cholesterol and the heart.
  http//www.medicinenet.com/cholesterol/ (Mar
  2006).
• Istvan, E. S. American Heart Journal 2002, 144,
  S27-32.
• Auer, J., Berent, R., Weber, T., and Eber, B.
  Curr. Med. Chem. 2002, 9, 1831-1850.
• Pillarisetti, S., Alexander, C.W., and Saxena, U.
  Curr. Med. Chem. 2004, 2, 327-334.
• Endo, A. J. of Lipid Research. 1992, 33,
  1569-1582.
• Luo, J., and Chen, A.F. Curr. Med. Chem. 2003,
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• Istvan, E.S.,  Deisenhofer, J. Science. 2001,
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