ANTI HYPERLIPIDEMIC AGENTS
ANILA . K.ALEXANDERDEPARTMENT OF PHARMACEUTICAL CHEMISTRY
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
LIPID LOWERING DRUGS
Acts either by reduce production of lipoprotein or by increasing their removal from blood . Main aim is to decrease plasma cholesterol
CLASSIFICATION
HMG COA reductase inhibitorsFibric acid derivativeBile acid sequesterantInhibition of LDL oxidationMiscellaneous agents
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
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
SYNTHETIC INHIBITORS
F
O
OOH
N
CH3
CH3
CH3
Dalvastatin
F
COONa
OH
OH
N
CH3
CH3
HFluvastatin
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
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.
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
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
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
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
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
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
β hydroxyl group at R1 position increase
hydrophilicityE.g. Pravastatin
OH
CH3
H2COC
O
CH3
CH3
OH
H
OH
COONa
H
Pravastatin
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
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
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
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
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
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
BENZOFIBRATE
OCl CO CH2CH2NH C
CH3
CH3
COOH
SYNTHESIS
Cl COCl
P.chloro Phenol
+ OHCH2CH2NH2
N
-HCl
Cl CO OHCH2CH2NH
ClOC Cl
Benzoylation
-HCl
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
BILE ACID SEQUECTRANTS (BAS)/CholesterolAbsorption Inhibitors.
Chemically they are anion – exchange resin
Non systemicdrugsDrugs include Cholestyramine Colestipol colesevelam
CHEMISTRY
CH CH2 CH2
CH2 N+
CH3
CH3
CH3
HCCH2 Cl-
n
CHOLESTYRAMINE
COLESTIPOL
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
The liver's increased requirement for
cholesterol is partially met through the hepatic
removal of circulating LDLc through
upregulation of hepatic LDL receptor
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]
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
MISCELLANEOUS AGENTS
NICOTINIC ACIDHORMONE REPLACEMENT
THERAPYESTROGEN MODULATORSPLANT STEROLS
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)
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
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
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
CH3
ON
CH3
CH3 ON
CH3
CH3
Cl
Tamoxifen Torimefene
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