anti hyperlipidemic agents
DESCRIPTION
ABOUT ANTIHYPERLIPIDEMIC AGENTSTRANSCRIPT
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ANTI HYPERLIPIDEMIC AGENTS
ANILA . K.ALEXANDERDEPARTMENT OF PHARMACEUTICAL CHEMISTRY
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Hyperlipidemia is the term used to describe elevated plasma levels of lipids usually in the form of lipoproteinLipoprotein consist of a central core of hydrophobic lipid (triglycerides or cholesteryl esters) enclosed in a more hydrophilic coat of polar substance
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LIPID LOWERING DRUGS
Acts either by reduce production of lipoprotein or by increasing their removal from blood . Main aim is to decrease plasma cholesterol
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CLASSIFICATION
HMG COA reductase inhibitorsFibric acid derivativeBile acid sequesterantInhibition of LDL oxidationMiscellaneous agents
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HMG COA REDUCTASE INHIBITORS
Fungal derived productPotent competitive inhibitor of β - hydroxy β – methyl glutaryl CoA (HMG CoA) reductase enzymeCHEMISTRYCommonly called statinsLactones ring of statin is structurally similar to HMG CoA
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Fermentation derived inhibitor
R1R2 R3 Source
Mevastatin
Lovastatin
simvastatin
O
OOH
O
OOH
O
OOH
H
H
H
CH3
CH3 CH3
Pencillinium sps
Aspergillus sps
Semisynthetic sps
GENERAL STRUCTURE
R3
CH3
R1
OC
O
CH3R
2
CH3
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SYNTHETIC INHIBITORS
F
O
OOH
N
CH3
CH3
CH3
Dalvastatin
F
COONa
OH
OH
N
CH3
CH3
HFluvastatin
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MEC
HAN
ISM
OF
ACTI
ON
Reversible inhibitor of HMG CoA reductase enzyme cause reduction in intracellular pool of cholesterol.
Increase in the No: of LDL receptor on cell surface. Cause catabolism and clearance of
circulating LDL
2HMGRIS inhibit LDL production by inhibiting the hepatic synthesis of VLDL
Inhibition of cholesterol biosynthesis
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SARCommon features for all HMGRIS
OH
COOH1
OH
H
H2C
2
3
4 5
67
1. 3,5 dihydro carboxylate is essential.
2. Lactone containing prodrug require in vivo hydrolysis.
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3. Altering distance between C5 and ring diminishes the activity
R3
CH3
OC
O
CH3H
CH3
O
OOH
1
2
3
45
Mevastatin
O
OOH
Lovastatin & Mevastatin
COONa
OH
OH
Pravastatin
COONa
OH
SCoA
O
CH3
HMG CoA substrate
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4. A double bond between C6 and C7 can either increase or decrease activity 5. Ethyl group provide optimal activity for drugs contain some heterocyclic ring (pyrrole ring in atorvastatin)
F
COONa
OH
OH
N
O
NH
CH3
CH3
H
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6. Ethenyl group is optimal for drugs with
other ring system E.g. Indole in
fluvastatin and pyrimidine in rosuvastatin
F
COONa
OH
OH
N
CH3
CH3
HFluvastatin F
COONa
OH
OH
NN
NCH3 S
O
O CH3
CH3
CH3
HRosuvastatin
CH4
CH4
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RING A SUBCLAS Decalin ring is essential for
binding to active site of enzyme
Replacement with cyclohexane cause 10,000 fold decrease in activity
R3
CH3
C7O
C
O
CH3R
2
CH3
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Stereo chemistry of ester side chain is not essential for activity
R3
CH3
C7O
C
O
CCH3
R2
CH2
CH3
Conversion of ester to ether results in decrease in activity
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Methyl substitution at R2 position increase activityi.e., simvastatin is more potent than lovastatin
H3C
CH3
H2COC
O
CH3CH3
CH3
O
OOH
SimvastatinH3C
CH3
H2COC
O
CH3H
CH3
O
OOH
Lovastatin
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β hydroxyl group at R1 position increase
hydrophilicityE.g. Pravastatin
OH
CH3
H2COC
O
CH3
CH3
OH
H
OH
COONa
H
Pravastatin
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Ring B subclass
Substituent's W, X, Y can be Carbon or Nitrogen n= 0 /1 i.e., 5 or 6 membered heterocyclic ring.Para –fluoro phenyl is non coplanar with central aromatic ring ( co- planarity cause loss of activity).R substitution with aryl gps , hydrocarbon chains, amides or sulphonamides enhances lipophilicity and inhibitory activity.
F
X
Y
W
CH3
CH3
n
R
Ring B
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SYNTHESIS Simvastatin is a semisynthetic derivativeof Lovastatin is produced via multistage fermentation process which originate from the culture of aspergillus terreus Mechanism of action
H3C
CH3
H2COC
O
CH3R
CH3
O
OOH
R= CH3Lovastatin
Mevastatin R=H
Invivo
hydrolysis
H3C
CH3
H2COC
O
CH3R
CH3
OH
OHCOOH
H
Active form
SCoA
OH
OHCOOH
H
CH3
(Mimic)
HMG CoA reductaseOH
OHCOOH
H
CH3
SCoA
O
OHCOOH
CH3
HMG CoA Intermediate
HMG CoA reductase
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COMPOUND R1 R2
CLOFIBRATE Cl C2H5
FENOFIBRATE
BENZOFIBRATEH
Cl C
O
HC
CH3
CH3
Cl C
O
NCH3
CH3
FIBRIC ACID DERIVATIVEAnalogues of phenoxy
isobutyric acid R1 O
CH3
CH3
COOR2
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SAR Isobutyric acid is essential for activity
Fenofibrate , an ester (prodrug) requires invivo
hydrolysis
HC
CH3
CH3
C O
CH3
CH3
COOHCl
O
{Aromatic ring} - O- {Spacer group} C
CH3
COOH
CH3
Chlorine increase half life
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Mechanism of actionStimulation of Peroxisome
Proliferator Activated receptors [PPARs]
Activate fatty acid oxidation and inhibition of triglyceride synthesis
Reduce expression of apo C III and enhance action of lipoprotein
lipase enzyme
Significantly reduce VLDL
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Cl OH + CH3
CCH3
O
+ CHCl3
P.chloro PhenolAcetone Chloroform
NaOH/H+
Reflux
Cl O
CH3
C
CH3
COOH
Clofibric acid
CH3 CH2 OH /H+
Esterification
Cl O
CH3
C
CH3
COOCH2-CH3
Clofibrate
CLOFIBRATESynthesis
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BENZOFIBRATE
OCl CO CH2CH2NH C
CH3
CH3
COOH
SYNTHESIS
Cl COCl
P.chloro Phenol
+ OHCH2CH2NH2
N
-HCl
Cl CO OHCH2CH2NH
ClOC Cl
Benzoylation
-HCl
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OOCCl CO CH2CH2NH Cl
C
CH3
CH3
Br COOC2H5
Alpha Bromo ethyl esterCondensation
BrOC Cl
_
OCl CO CH2CH2NH C
CH3
CH3
COOC2H5
KOHHydrolysis C2H5OH
OCl CO CH2CH2NH C
CH3
CH3
COOH
-
Benzofibrate
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BILE ACID SEQUECTRANTS (BAS)/CholesterolAbsorption Inhibitors.
Chemically they are anion – exchange resin
Non systemicdrugsDrugs include Cholestyramine Colestipol colesevelam
CHEMISTRY
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CH CH2 CH2
CH2 N+
CH3
CH3
CH3
HCCH2 Cl-
n
CHOLESTYRAMINE
COLESTIPOL
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Acts by binding bile acids within the intestinal lumen
Interfering with reabsorption and enhancing fecal excretion
Upregulation Of cholesterol 7a-hydroxylase activity
Increased hepatic conversion of cholesterol to bile acid
MEC
HAN
ISM
OF
ACTI
ON
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The liver's increased requirement for
cholesterol is partially met through the hepatic
removal of circulating LDLc through
upregulation of hepatic LDL receptor
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LDL OXIDATION INHIBITORS
PROBUCOL
OH
C
CH3
CH3CH3
S
OH
C
CH3
CH3 CH3
S
CH3 CH3
CCH3
CH3
CH3
CCH3
CH3
CH3
PROBUCOL 4,4' isopropylidendithio bis [ 2,6 di t butyl phenol]
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OH
C
CH3
CH3 CH3
SHCCH3
CH3
CH3
2,6 di t- butyl 4 phenol
CH3
CCH3
O
Acetone
+ OH
C
CH3
CH3CH3
SH CCH3
CH3
CH3
+
OH
C
CH3
CH3CH3
S
OH
C
CH3
CH3 CH3
S
CH3 CH3
CCH3
CH3
CH3
CCH3
CH3
CH3
PROBUCOL
Synthesis
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MISCELLANEOUS AGENTS
NICOTINIC ACIDHORMONE REPLACEMENT
THERAPYESTROGEN MODULATORSPLANT STEROLS
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NICOTINIC ACID
Mechanism of action• Decrease mobilization of free
fatty acids from adipose tissue, resulting in reduced plasma FFA levels
• Enhance clearence of VLDL
N
COOH
Nicotinic acid (niacin)
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PLANT STEROL
Nonabsorbable cholestrol analogue E.g. βsitosterol and sitostanolAble to inhibit intestinal absorption of
cholestrol
OH
H
H H
H
CH3CH
CH3
CH3CH3
Cholestrol
OH
H
H H
H
CH3HC
CH3
CH3CH3
CH3
OH
H
H H
H
CH3CH
CH3
CH3CH3
CH3
sitostanolB sitosterol
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HORMONE REPLACEMENT THERAPY
HRT directly stimulates LDL receptor activity, leading to reductions in total cholesterol and LDLc levels.
Moderate increases in HDLc levels
Decrease in HDL and LDL oxidation
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ESTROGEN MODULATORS.Along with the cardioprotective
effects of estrogen, the lipid effects of estrogen include moderate decreases in LDLc, increases in HDLc, and a decrease in LDL and HDL oxidation
The effects are modulate through binding of estrogen to its nuclear estrogen receptor
E.G Tamoxifen, Torimefene
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CH3
ON
CH3
CH3 ON
CH3
CH3
Cl
Tamoxifen Torimefene
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REFERENCE
• Burgers medicinal chemistry, Volume 3
Pg:no 339 – 374• Foye’s principles of medicinal
chemistry Thomas. L Lemke et.al Pg:no 815 – 840
• Text book of medicinal chemistry Volume 2 K. Ilango , P. Valentina Pg:no 275 - 284