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 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.