Lovastatin Medicinal Chemistry

Lovastatin drug

1. Ajit Kumar Yadav Msc Biomedical science Delhi University LOVASTATIN

2. Lovastatin Introduction In 1978, Merck isolated a closely related structure (to Mevastatin a potent Inhibitor of HMGR) called mevinolin from the fermentation broth of Aspergillus terreus . The drug was marketed in 1987 as lovastatin and it revolutionized the treatment of hypercholesterolaemia (high cholesterol levels). Statins are classified into Class I and Class II Statin based on their Hydrophobic moiety. Lovastatin is a class I statin. It is a naturally occurring compound found in low concentrations in food such as oyster mushrooms , red yeast rice, etc. Polar head group Lactone ring Hydrophobic Moiety Fig.- Lovastatin Decalin ring

3. Lovastatin Patent Lovastatin was first approved for sale by Merck Frosst Canada Ltd. Under the brand name MEVACOR and is used for the treatment of elevated blood cholesterol. The application for the 380 patent was filed in Canada on June 11, 1980 and issued on January 31,1984 to Merck & Co.

4. Property Name Property Value Molecular Weight 404.5 g / mol LogP 4.3 Hydrogen Bond Donor Count 1 Hydrogen Bond Acceptor Count 5 Rotatable Bond Count 7 Topological Polar Surface Area 72.8 Ų Heavy Atom Count 29 Formal Charge Defined Atom Stereocenter Count 8 Chemical and Physical Properties Lovastatin Polar head group Lactone ring Hydrophobic Moiety Fig.- Lovastatin Decalin ring

5. Physical Properties White Crystalline solid Melting Point = 174.5 °C Boiling Point = 559.2 °C at 760 mmHg Solubiliity - - Insoluble in water - Very soluble in Chloroform, soluble in dimethyl formamide, slightly soluble in  acetone and ethanol. Uv Spectra - UV max at 231 , 238, 247 nm Lovastatin

6. Lovastatin Drug indicated for Diseases Lovastatin is a commonly used  as cholesterol  lowering agent Hypercholesterolemia (High cholesterol level) Dyslipidaemia ( an abnormal amount of lipids i.e. average to moderately elevated total-C and LDL-C, and below average HDL-C .) Lovastatin also indicated to reduce the risk of myocardial infarction, unstable angina and clinical atherosclerosis. Besides a cholesterol lowering agent, there is growing evidence that statins have immunomodulatory activities .

7. Lovastatin Mechanism of action for Lovastatin —Pharmacodynamics The rate limiting step in biosynthesis of cholesterol pathway is the reduction of b - hydroxy - b - methylglutaryl -coenzyme A (HMG-CoA) to mevalonate by HMG-CoA reductase.

8. Lovastatin The statins work by acting as competitive inhibitors. They mimic the natural substrate (HMG-SCoA) and compete with it in order to bind to the active site of HMG-SCoA Reductase. T he statins contain an extra hydrophobic region which can form additional hydrophobic interactions with a hydrophobic binding region present in the enzyme . This allows the statins to bind more strongly. Fig. – Structural Comparison of HMG-SCoA with Statins HMG- SCoA Statin There is one other interesting feature about the statins. They are actually more similar to the first intermediate mevaldyl CoA than to the substrate. Assuming that mevaldyl CoA is less stable than the substrate, this implies that the statins bear some resemblance to the transition state leading to mevaldyl CoA. Consequently, they would be expected to have a stronger binding interaction than the natural substrate and are likely to be acting as transitionstate Analogues. Facts

9. Lovastatin The polar head-group of the statins binds in a similar fashion as the substrate. There is also no other hydrophobic region into which the statins could Bind. Thus , the statins are effective inhibitors because they can take advantage of the enzyme’s flexibility and essentially create their own binding site. Cholesterol

10. Lovastatin Volume of Distribution Lovastatin is able to cross the blood-brain barrier and placenta. Biological Half Life Lovastatin half-life is reported to be of 13.37 hours. The elimination half-life of the hydroxy acid form of lovastatin is reported to be of 0.7-3 hours Pharmacokinetics Absorption Lovastatin Cmax was found to be 3.013ng/mL with a Tmax of 3.36 hours. Plasma concentrations of total radioactivity peaked at 2 hours and declined rapidly to about 10% of peak by 24 hours post dose. Absorption of lovastatin, estimated relative to an intravenous reference dose averaged about 30% of an oral dose.

11. Lovastatin Lovastatins are lactone Prodrugs. They are administered orally and pass unchanged into the liver where the lactone ring is hydrolyzed to the active hydroxy- heptanoic acid form of the drug . metabolized by the microsomal hepatic enzyme system (Cytochrome P-450). Metabolism

12. Lovastatin Following an oral dose of 14C-labeled lovastatin to man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug excreted in bile, together with unabsorbed drug. Route of Elimination The major active metabolites present in human plasma are the beta- hydroxy acid of lovastatin, its 6'-hydroxy, 6'-hydroxymethyl , and 6'-exomethylene derivatives.

13. Lovastatin Myopathy ( as muscle pain , tenderness or weakness with   high creatine   kinase level in blood.) Rhabdomyolysis with or without acute renal failure H epatic failure Testicular atrophy The median lethal dose of lovastatin is higher than 15 g/m2. Toxicity  Lovastatin, like other inhibitors of  HMG-CoA  reductase, causes :--

14. Lovastatin References:- An Introduction to Medicinal Chemistry by Graham L. Patrick Medicinal Chemistry - Gareth Thomas https:// pubchem.ncbi.nlm.nih.gov/compound/Lovastatin www.go.drugbank.com Thank you