ABOUT ANTIHYPERLIPIDEMIC AGENTS

1. ANILA . K.ALEXANDER
DEPARTMENT OF PHARMACEUTICAL
CHEMISTRY

2. Hyperlipidemia is the termused to describe elevated
plasma levels of lipids usually in the form of
lipoprotein
Lipoprotein consist of a central core of hydrophobic
lipid (triglycerides or cholesteryl esters) enclosed in
amore hydrophilic coat of polar substance

3. LIPID LOWERING DRUGS
Acts either by reduce production of lipoprotein or by
increasing their removal from blood . Main aim is to
decrease plasma cholesterol

4. CLASSIFICATION
HMG COA reductase inhibitors
Fibric acid derivative
Bile acid sequesterant
Inhibition of LDL oxidation
Miscellaneous agents

6. HMG COA REDUCTASE INHIBITORS
Fungal derived product
Potent competitive inhibitor of β - hydroxy β –
methyl glutaryl CoA (HMG CoA) reductase
enzyme
CHEMISTRY
Commonly called statins
Lactones ring of statin is structurally similar to
HMG CoA

7. Fermentation derived
inhibitor
R1
O
R2 R3 Source
Mevastatin
Lovastatin
simvastatin
HO O
O
HO O
O
HO O
O
H
H
H
CH3
CH3 CH3
Pencillinium sps
Aspergillus sps
Semisynthetic sps
GENERAL STRUCTURE
R
3
CH3
R
1
O
C
H3C
R
2
H3C

8. SYNTHETIC INHIBITORS
F
HO O
O
N
CH3
Dalvastatin
CH3
CH3
F
COONa
HO
OH
N
CH3
CH3
Fluvastatin H

9. MECHANISM OF ACTION
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

10. SAR
Common features for all HMGRIS
1. 3,5 dihydro carboxylate is essential.
2. Lactone containing prodrug require in vivo
hydrolysis.
COOH
1
OH
HO
H
H2C
2
3
4 5
6
7

11. HO O
3. Altering distance between C5 and ring diminishes the activity
R
O
3
HO O
1
CH3
O
C
H3C
H
H3C
O
2
3
4
5
Mevastatin
O
Lovastatin & Mevastatin
COONa
HO
OH
Pravastatin
COONa
HO
SCoA
O
H3C
HMG CoA substrate

12. 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
HO
OH
N
O
NH
CH3
CH3
H

13. 6. Ethenyl group is optimal for drugs with other
ring system
E.g. Indole in fluvastatin and pyrimidine in
rosuvastatin
F
COONa
HO
OH
N
CH3
CH3
Fluvastatin H
F
COONa
HO
OH
N N
N
H3C S
CH3
CH3
O
H
O CH3
Rosuvastatin
CH4

14. RING A SUBCLAS
Decalin ring is essential for binding to active site of
enzyme
2
R
O
C
3
CH3
C7
O
H3C
R
H3C
Replacement with cyclohexane cause 10,000
fold decrease in activity

15. Stereo chemistry of ester side chain is not essential
for activity
R
O
3
CH3
C7
O
C
C
H3C
R
2
CH2
H3C
Conversion of ester to ether results in decrease in activity

16. Methyl substitution at R2 position increase activity
i.e., simvastatin is more potent than lovastatin
H3C
HO O
CH3
H2C
O
O
C
H3C
CH3
H3C
O
Simvastatin
H3C
HO O
CH3
H2C
O
O
C
H3C
H
H3C
O
Lovastatin

17. β hydroxyl group at R1 position increase hydrophilicity
E.g. Pravastatin
HO
COONa
CH3
H2C
O
O
C
H3C
H3C
HO
H
OH
H
Pravastatin

18. Ring B subclass
F
X
Y
W
CH3
CH3
n
R
Ring B
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.

19. 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
HO O
CH3
H2C
O
O
C
H3C
R
H3C
O
Lovastatin R= CH 3
Mevastatin R=H
Invivo
hydrolysis
H3C
CH3
H2C
O
O
C
H3C
R
H3C
OH
HO
COOH
H
Active form
OH
SCoA
HO
COOH
H
H3C
(Mimic)
HMG CoA reductase
OH
HO
COOH
H
H3C
O
SCoA
HO
COOH
H3C
HMG CoA
Intermediate
HMG CoA reductase

20. FIBRIC ACID DERIVATIVE
Analogues of phenoxy isobutyric acid
CH3
COMPOUND R1 R2
CLOFIBRATE Cl C2H5
FENOFIBRATE
BENZOFIBRATE
CH3
H
O
Cl C
HC
CH3
O
Cl C
N
CH3
CH3
R1 O
CH3
COOR 2

21. SAR
Isobutyric acid is essential for
activity
{Aromatic ring} - O- {Spacer group} C
Fenofibrate , an ester
(prodrug) requires invivo
hydrolysis
HC
CH3
CH3
Cl C O
COOH
CH3
CH3
O
CH3
COOH
CH3
Chlorine increase half

22. Mechanism of action
Stimulation 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

23. Cl OH + H3C
C
CH3
O
+ CHCl 3
P.chloro Phenol
Acetone Chloroform
NaOH/H
+
Ref lux
Cl O
CH3
C
CH3
COOH
Clof ibric acid
H3C CH2 OH /H
+
Esterification
Cl O
CH3
C
CH3
COOCH 2-CH3
Clof ibrate
CLOFIBRATE
Synthesis

24. BENZOFIBRATE
CH3
Cl CO NH CH2 CH2 O C
CH3
COOH
SYNTHESIS
Cl COCl
P.chloro Phenol
+ H2N CH2 CH2 OH
N
-HCl
Cl CO NH CH2 CH2 OH
-HCl
Benzoylation
ClOC Cl

25. Cl CO NH CH2 CH2 OOC Cl
CH3
Br C
COOC 2H5
Condensation Alpha Bromo ethyl ester
CH3
_
BrOC Cl
CH3
Cl CO NH CH2 CH2 O C
CH3
COOC 2H5
Hydrolysis C2H5OH
KOH
CH3
Cl CO NH CH2 CH2 O C
CH3
COOH
-
Benzof ibrate

26. BILE ACID SEQUECTRANTS (BAS)/Cholesterol
Absorption Inhibitors.
 Chemically they are anion – exchange
resin
Non systemicdrugs
Drugs include
Cholestyramine
Colestipol
colesevelam
CHEMISTRY

27. CH CH2 CH2
CH3
CH2 HC +
Cl
CH2 N
CH3
CH3
-
n
CHOLESTYRAMINE
COLESTIPOL

28. 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
MECHANISM OF ACTION

29. The liver's increased
requirement for cholesterol is
partially met through the
hepatic removal of circulating
LDLc through upregulation of
hepatic LDL receptor

30. LDL OXIDATION INHIBITORS
PROBUCOL
OH
H3C C
CH3
CH3
S
HO
H3C C
CH3
CH3
S
H3C CH3
C
CH3
CH3
H3C
C
H3C
H3C
CH3
PROBUCOL 4,4' isopropylidendithio bis [ 2,6 di t butyl phenol]

31. C SH
HO
H3C C
CH3
CH3
H3C
H3C
CH3
2,6 di t- butyl 4 phenol
Synthesis
+ OH
H3C
C
CH3
O
Acetone
H3C C
CH3
CH3
HS
C
CH3
CH3
H3C
+
OH
H3C C
CH3
CH3
S
HO
H3C C
CH3
CH3
S
H3C CH3
C
CH3
CH3
H3C
C
H3C
H3C
CH3
PROBUCOL

32. MISCELLANEOUS AGENTS
NICOTINIC ACID
HORMONE REPLACEMENT THERAPY
ESTROGEN MODULATORS
PLANT STEROLS

33. NICOTINIC ACID
N
COOH
Nicotinic acid (niacin)
Mechanism of action
• Decrease mobilization of free fatty acids
from adipose tissue, resulting in reduced
plasma FFA levels
• Enhance clearence of VLDL

34. PLANT STEROL
Nonabsorbable cholestrol analogue
E.g. βsitosterol and sitostanol
Able to inhibit intestinal absorption of cholestrol
HO
H
H
H3C CH3
CH3
H H
CH
H3C
Cholestrol
HO
H
H
CH3
H H
HC
CH3
CH3
H3C
CH3
HO
H
H
H3C CH3
CH3
H H
CH
H3C
CH3
sitostanol
B sitosterol

35. 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

36. 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

37. CH3
O
N
H3C
N
H3C
H3C O
H3C
Cl
Tamoxifen Torimefene

38. 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