medicinal chemistry

1. ANTIHYPERLIPIDEMIC
AGENTS
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2. INTRODUCTION
• Hyperlipidemia is a condition in which there are high levels of lipid or
fat in the blood.
• Pharmacological agents which reduces the concentration of plasma
lipids are known as antihyperlipidemic agents.
• Arthersclerosis is a condition characterised by the build up of fats ,
cholesterol and other substances in the artery walls. This condition
involving arterial damage may lead to ischemic heart disease ,
myocardial infarction , and cerebral vascular accidents.
• Lipids are transported in the plasma as lipoproteins.An increase in
the plasma concentration of these substances is termed
hyperlipidemia.
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3. INTRODUCTION
• Lipoproteins are macromolecules consisting of lipid substances non-
covalently bound with protein and carbohydrates.
• Lipoproteins consist of a central core of hydrophobic lipid encased in more
hydrophilic coat of polar substances- phospholipid , free cholesterol , and
associated protein ie.apoprotein.
• According to the apoprotein and lipid core , lipoproteins are classified into
four types
 High density lipoprotein ( HDL )
 Low density lipoprotein ( LDL )
 Very low density lipoprotein ( VLDL )
 Chylomicros
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6. NORMAL RANGES
• LDL- 70-130 mg/dl ( lower numbers are better )
• HDL - > 50 mg/dl ( higher numbers are better )
• Total cholesterol - < 200mg /dl ( lower numbers are better )
• Triglycerides – 10-150 mg/dl ( lower numbers are better )
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7. CLASSIFICATION
1. HMG CoA REDUCTASE INHIBITORS - LOVASTATIN, SIMVASTATIN , MEVASTATIN
, PRAVASTATIN , FLUVASTATIN , ATORVASTATIN,CERIVASTATIN.
2. FIBRIC ACID DERIVATIVES – CLOFIBRATE , FENOFIBRATE,GEMFIBROZIL,
CIPROFIBRATE, BENZAFIBRATE.
3. BILE ACID SEQUESTRANTS – CHOLESTYRAMINE , COLESTIPOL.
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8. CLASSIFICATION
4.INHIBITION OF LDL OXIDATION - PROBUCOL .
5.PYRIDINE DERIVATIVES – NICOTINIC ACID , NICOTINAMIDE.
6.MISCELLANEOUS AGENTS – β-SITOSTEROL , DEXTROTHYROXINE
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9. HMG-CoA REDUCTASE INHIBITORS (STATINS)
• Statins are most effective cholesterol lowering drugs.
• Statins lower total cholesterol and LDL particles.
• These are competitive inhibitors.
• HMG-CoA has a conformation similar to the lactone moiety of statins
, resuting in binding at the same site without any productive effect.
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10. SAR OF STATINS
 STATIN PHARMACOPHORE
All statins conists of two specific structural component , a
dihydroxyheptanoic acid unit and a ring system with lipophilic
substituents .
Dihydroxyheptanoic acid component is essential to HMGR – inhibiting
activity.
Since they bind to the same active site , the structure of the statin HMGR
inhibitors resembles the endogenous substrate , HMG CoA.
All statins contain a modified hydroxyglutaric acid component that mimics
the 3-hydroxyglutaryl unit of both the substrate ( HMG CoA ) and the
mevaloyl CoA transition state intermeiates.
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11. SAR
• Statins that are active and intact contain a free acidic functional
group ,mimics the free COOH of HMG CoA.
• These compounds exist as anions at pH 7.4 and this is critical to their
ability to compete for the HMGR active site .
• Compounds that have their carboxylic acid group tied up in a lactone
are prodrugs.
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13. BIOSYNTHETIC PATHWAY OF CHOLESTEROL
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14. MECHANISM OF ACTION
• All the statins hydrolyse in vivo to hydroxyl carboxylic acid and inhibit
HMG CoA reductase found in the liver.
• This enzyme is the rate-limiting catalyst for the irreversible
conversion of HMG CoA to mevalonic acid in the synthesis of
cholesterol.
• The binding of the dihydroxypentanoic acid portion of the statins to
the HMG reductase mimics that of the endogenous substrate HMG
CoA .
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15. LOVASTATIN
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IUPAC NAME : 2-Methyll butanoic acid -
1,2,3,7,8,8a – hexahydro – 3,7 – dimethyl –
8 – [ 2 – ( tetrahydro – 4 – hydroxy – 6 –
oxo – 2H – pyran – 2 – yl ) ethyl ] – 1 –
naphthalenyl ester

16. BRAND NAMES
• Mevacor
• Advicor ( As a combination with niacin )
• Atlocor
• Altoprev
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17. USES
• Antihyperlipoproteinemic agent
• Prevention of cardiovascular diseases
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18. NIACIN
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IUPAC NAME : Pyridine -3 carboxylic acid

19. BRAND NAMES
• Niaspan
• Niacor
• Niacin
• Slo-Niacin
• Nicotinex
• Niacinol
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20. USES
• It is used to lower triglycerides and cholesterol
• Artherosclerosis
• Treatment and prevention of niacin deficiency and conditions like
pellagra
• Hyperlipoproteinemia
• Depression
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21. PELLEGRA
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22. CLOFIBRATE
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IUPAC NAME : Ethyl-2-(p-choro phenoxy )-
2-methyl propionate

23. BRAND NAMES
Atromid - S
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24. USES
• Drug of choice in the treatment of type 3
hyperlipoproteinemias.
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25. EZETIMIBE
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IUPAC NAME : ( 3R,4S)-1-(4-Fluorophenyl)-3-( ( 3S)-3-( 4-
Flurophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl

26. BRAND NAMES
• Ezedoc
• Ezetrol
• Ezentia
• Ezerem
• Ezetib
• Mibe
• Zetica
• Lipezet
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27. USES
• Used as anticholesteremic agent
• Used alone or in combination with statins or fibrates
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28. THANK YOU
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