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Inhibition of Cholesterol Biosynthesis

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

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Inhibition of Cholesterol Biosynthesis

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  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 patient’s 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

  8. 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

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

  10. 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

  11. 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

  12. 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).

  13. 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

  14. 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

  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/Cholesterol (Mar 2006). • Fallon, F.L., Odle, T. Hypercholesterolemia. http://www.healthatoz.com/healthatoz/Atoz/ency/hypercholesterolemia.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, 1593-1601. • Istvan, E.S.,  Deisenhofer, J. Science. 2001, 292, 1160-1164.

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