Inhibition of Cholesterol
Biosynthesis
By Peter Riedell
Medicinal Chemistry
Dr. Buynak
April 6, 2006
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
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
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

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If vessels leading to the heart then results in a heart attack
If vessels leading to the brain then results in an aneurysm
How Atherosclerosis Occurs
Treatment Options

Initial treatments for hypercholesterolemia focused
on changing a patient’s behavior

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Options not very effective
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Diet- low in cholesterol and saturated/total fat
Exercise- prevents fat from being converted to cholesterol
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
Cholesterol Biosynthesis Pathway
Around 80% of cholesterol synthesized in liver

Rest acquired from dietary sources

Synthesis pathway elucidated in 1964

HO
C
H2C
CH2
C

O
2NADP
+ HSCoA
HO
C
H2C
O
SCoA
O
geranyl pyrophosphate
farnesyl pyrophosphate
CH3
CH2
C
isopentenyl pyrophosphate
HMG-CoA
HMG-CoA
Reductase
+

C
O
O
2NADPH
5-pyrophosphomevalonate
CH3
H2
C OH
mevalonate
squalene
2,3-oxidosqualene
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
Inhibitors of HMG-CoA Reductase

Metabolites found to inhibit
the enzyme HMG-CoA
Reductase- the rate limiting
step in the synthesis of
cholesterol
HO
C
H2C
CH3
CH2
C

O
C
H2C
O
HMG-CoA
HMG-CoA
Reductase
2NADP+
+ HSCoA
HO

SCoA
O
O
2NADPH
C
CH3
CH2
C
O
H2
C OH
mevalonate
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
Similarities to HMG-CoA

Similar in HMG-CoA
binding region



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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
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).
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
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 Alzheimer’s disease
Reduce incidence of failure in organ transplant
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
References
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Cholesterol. http://en.wikipedia.org/wiki/Cholesterol (Mar 2006).
Fallon, F.L., Odle, T. Hypercholesterolemia.
http://www.healthatoz.com/healthatoz/Atoz/ency/hypercholeste
rolemia.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, 10, 15931601.
Istvan, E.S., Deisenhofer, J. Science. 2001, 292, 1160-1164.