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