Mainly focuses on drugs obtained from natural resources such as lovastatin and dicoumarol covering its history, extraction and structure activity relationship to give new modified drug molecules.

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Department of Pharmaceutical Chemistry
Bharati Vidyapeeth University (Deemed to be),
Poona College of Pharmacy, Erandwane, Pune-411038
Presented By
Ms. Pooja Dhamade
M.Pharm (Sem I)
Research Guide
Dr. (Mrs.) Deepali Bansode
Associate Professor
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SR.
NO
CONTENTS
1. AIM AND OBJECTIVE
2. INTRODUCTION
3. ANTIHYPERLIPIDEMIC DRUGS
4. ANTICOAGULANT DRUGS
5. SUMMARY
6. REFERENCES

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• Aim : To study the naturally occuring compounds as a lead for the
synthesis and development of new potent pharmaceuticals.
• Objective :
1) The present study focuses on history, extraction, isolation and
biosynthetic pathway of the naturally occuring compounds from
two classes i.e. antihyperlipidemic drugs and anticoagulant drugs.
2) It also focuses on the structure activity relationship of the above
mentioned class of compounds and some synthetic drugs available
in market.
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AIM AND OBJECTIVES

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INTRODUCTION
• Cardiovascular diseases or Heart diseases is a general name for
category of diseases, disorders and conditions that affect the heart
and blood vessels.

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• Hypercholesterolemia is the presence of high levels of cholesterol in the
blood. Since cholesterol is insoluble in water, it is transported in the blood
plasma within protein particles (lipoproteins). Lipoproteins are classified by
their density: very low density lipoprotein (VLDL), intermediate density
lipoprotein (IDL), low density lipoprotein (LDL) and high density
lipoprotien (HDL). Elevated levels of LDL-cholesterol are associated with
an increased risk of atherosclerosis and coronary heart disease.
• Statins also known as HMG-CoA reductase inhibitors, are a class
of lipid-lowering medications that reduce illness and mortality in those
who are at high risk of cardiovascular disease. Statins are effective in
lowering LDL cholesterol. Lovastatin is the natural product as a lead for
new pharmaceuticals.
ANTIHYPERLIPIDEMIC DRUGS
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Lovastatin

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 1970 - Dr. Akira Endo, (Japan biologist) posited that perhaps a fungus exists
which produces a chemical that inhibits HMG-CoA reductase, thereby depriving
nearby bacteria of cholesterol without damaging its own cell wall.
 1973 - After testing 6,000 fungal broths, Endo discovered compactin (ML236B or
mevastatin), an HMG-CoA reductase inhibitor in the fermentation broth of the
fungus Penicillium citrinum. Animal trials and later clinical trials of compactin
demonstrated good effect in lowering plasma cholesterol levels.
 1978 - Alberts, Chen and others at Merck discovered a potent inhibitor of HMG-
CoA reductase in a fermentation broth of Aspergillus terreus and named this
compound mevinolin (later named lovastatin).
 1987 September 1st - Lovastatin became the first statin to be approved in USA
by Food and Drug Administration.
HISTORY
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• Natural statins are produced by direct fermentation of fungi.
• Many fungi such as M. purpureus, M. pilosus, A. terreus, A. flavipes, A.
fischeri, etc have been reported to produce lovastatin.
• Lovastatin is a secondary metabolite during the secondary phase
(idiophase) of fungi growth.
• A.terreus was commercialized for manufacture of high quantity of
lovastatin. It is a filamentous ascomycota, a soil fungus.
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EXTRACTION AND ISOLATION

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BIOSYNTHETIC PATHWAY OF LOVASTATIN
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MECHANISM OF ACTION
• Statins block the conversion of HMG-CoA to mevalonic acid in the mevalonate
pathway.
• The major rate-limiting step in this pathway is regulated by the activity of the
enzyme 3-hydroxy-3- methylglutaryl-coenzyme A reductase, which catalyses the
conversion of HMG-CoA to mevalonic acid.
• Statins act as reversible and competitive inhibitors. The statins reduce total
cholesterol level in serum, especially the low-density lipoprotein levels.
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STRUCTURE ACTIVITY RELATIONSHIP
Important structural features :
• Lactone, bicyclic ring and ethylene bridge
• Size and shape of ring.
• The presence of a side chain ester moiety is crucial for inhibitory potency.
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• Side chain modification - Additional branching
at the α carbon of the acyl moiety enhances
potency and efficacy. Eg. Simvastatin. It is
lipophilic in nature.
• Lactone ring modification - It is more
hydrophillic and has less side effects. Eg.
Pravastatin

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• Bicyclic system modification - By replacement with substituted aromatic ring
system. Bicyclic ring when replaced with other lipophilic ring its potency
increases. Eg. Atorvastatin, Fluvastatin, Pitavastatin, Rosuvastatin (newest and
most potent statin).
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USES
Primary hyperlipidemia
Myocardial infarction.
Unstable angina.
Coronary revascularization procedures.
Coronary Heart Disease.
Secondary hypercholesterolemia.
CONTRAINDICATIONS
Hypersensitivity.
Active liver disease.
Pregnancy and lactation.
WARNINGS
Myopathy/Rhabdomyolysis (injury or death of muscle tissue).
Liver Dysfunction.
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• Atorvastatin - Storvas, Atorva, Tonact, Aztor, Lipicure (10, 20 mg tabs.)
• Lovastatin - Rovacor, Lostatin, Lovacard, Aztatin, Lovameg (10, 20 mg
tabs.)
• Rosuvastatin - Rosuvas, Rozavel, Crestor, Razel, Roseday (5, 10, 20 mg
tabs.)
• Simvastatin - Simvotin, Zocor, Zosta, Simcard, Simvofix (5, 10, 20 mg tabs.)
• Pravastatin - Pravator
• Fluvastatin - Lescol Xl
SOME MARKETED FORMULATIONS

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ANTICOAGULANT DRUGS
• Thrombosis is the formation of a blood clot inside a blood vessel,
obstructing the flow of blood through the circulatory system. When a blood
vessel is injured, the body uses thrombocytes and fibrin to form a blood
clot to prevent blood loss. Thrombosis may occur in veins (venous
thrombosis) or in arteries (arterial thrombosis). Venous thrombosis leads to
congestion of the affected part of the body, while arterial thrombosis affects
the blood supply and leads to damage of the tissue supplied by that artery.
• Anticoagulants commonly known as blood thinners, are chemical
substances that prevent or reduce coagulation of blood (inhibit the
coagulation cascade) thus prolonging the clotting time. Dicoumarol is the
natural product as a lead for new pharmaceutical.
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HISTORY
 1920's - In North Dakota and in Alberta, Canada a new disease of cattle
involving fatal bleeding showed up known as "sweet clover disease".
 It was recognized by Schofield and Roderick that the disease was
reversible.
 1931 - Roderick emphasized that the delayed or abolished coagulability
of the blood was due to a "prothrombin" deficit.
 June 28, 1939 - After working all night, Link and Campbell identified it
as Dicoumarol.
 1941 - These haemorrhagic properties were shown by Stahmann,
Huebner & Link .
 1942 - Marketed under the name dicumarol.
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EXTRACTION
AND
ISOLATION
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BIOSYNTHETIC PATHWAY OF DICOUMAROL
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MECHANISM OF ACTION
• Dicoumarol is a competitive inhibitor of vitamin K epoxide reductase; thus, it
inhibits vitamin K recycling and causes depletion of active vitamin K in blood. This
prevents the formation of the active form of prothrombin and several other coagulant
enzymes, and inhibits blood clotting.
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STRUCTURE ACTIVITY RELATIONSHIP
• Dicoumarol or bishydroxycoumarin show slow and erratic onset of action. Thus
synthetic compounds with longer duration of action and fast onset of action were
needed.
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• Acenocoumarol - Rapid acting
drug.
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• 4-hydroxy coumarin residue substitution at 3rd
position increases activity.
• Warfarin - S (levorotatory) form is 3-5* more
potent than R (dextrorotatory) form. Showed
increased duration of action.
AcenocoumarolPhenprocoumon
4-hydroxycoumarin

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USES
Deep vein thrombosis (along with heparin).
Oral anticoagulant.
Pulmonary embolism.
Myocardial infarction.
Cerebrovascular disease.
CONTRAINDICATIONS
Low vitamin K levels.
Anaemia.
Liver disease.
Pregnancy, etc.
WARNINGS
Hemorrhage.
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• Dicoumarol - Dicoumarol (50 mg tab.)
• Warfarin - Coumadin, Uniwarfin (1, 2, 5 mg tabs), WARF-5 (5 mg
tab.)
• Acenocoumarol/Nicoumalone - Acitrom (1, 2, 4 mg tabs.)
• Some newer anticoagulants - Dabigatran, Rivaroxaban, Apixaban,
Edoxaban.
SOME MARKETED FORMULATIONS

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SUMMARY
• In the present seminar, two major categories of drugs namely
lovastatin as antihyperlipidemic and dicoumarol as anticoagulant
were focused as lead due to their natural occurance.
• It covered following key points such as their history, isolation,
extraction, biosynthetic pathway, mechanism of action and structure
activity relationship.
• It also covered the development of newer synthetic and more potent
pharmaceticals from the above mentioned two drugs along with
some of their marketed formulations.

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• KD Tripathi, Essentials of Medical Pharmacology, 7th edition, Jaypee Brothers Medical Publishers.
• Thomas L. Lemke, David A Williams, Victoria F Roche, S William Zito, Foye’s Principles of medicinal
chemistry, 7th edition, , Lippincott Williams and Wilkin.
• Grundy SM, History of Statins.
• Tobert JA, LOVASTATIN AND BEYOND, 2003(July).
• Mevacor D, Mevacor T. TABLETS MEVACOR.
• Harbinson M, Statins : in the beginning, 2009.
• Jahromi MF, Liang JB, Ho YW, Mohamad R, Goh YM, Shokryazdan P, Lovastatin Production by
Aspergillus terreus Using Agro-Biomass as Substrate in Solid State Fermentation,2012.
• Subhan M, Faryal R, Macreadie I, Exploitation of Aspergillus terreus for the Production of Natural
Statins, 2016.
• Lee T, Synthesis, SARs and therapeutic potential of HMG- CoA reductase inhibitors, 1987(November).
• Ndo BAE, Review : A historical perspective on the discovery of statins, 2010.
• Junod SW, Statins : A Success Story Involving FDA , Academia and Industry, 2007(April).
• Manzoni MM,Biosynthesis and biotechnological production of statins by filamentous fungi and
application of these cholesterol-lowering drugs, 2002.
• Sweet cloyer determination dicoumarol, 1970.
• Bellis BYDM, Stoker MSSADJR, The Biosynthesis of Dicoumarol, 1967.
• Lin Y, Shen X, Yuan Q, Yan Y, Precursor 4-hydroxycoumarin, Nat Commun, 2013(May).
• Sequels I, The Discovery of Dicumarol and Its Sequels, 1959.
REFERENCES

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