Hyperlipidemia refers to elevated plasma lipid levels, usually in the form of lipoproteins containing a hydrophobic lipid core enclosed by a hydrophilic coat. Lipid-lowering drugs act by reducing lipoprotein production or increasing their removal from blood to decrease plasma cholesterol levels. These drugs include HMG-CoA reductase inhibitors (statins), fibric acid derivatives, bile acid sequestrants, LDL oxidation inhibitors, and miscellaneous agents such as nicotinic acid. Statins are the most potent class and work by competitively inhibiting HMG-CoA reductase to reduce intracellular cholesterol levels and increase LDL receptor expression and clearance of LDL from blood.

2. Hyperlipidemia is the term used 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 a more
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
 HMGCOAreductaseinhibitors
 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 HMGCoA

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

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

9. MECHANISM
OF
ACTION
Reversible inhibitor of HMG
CoAreductase 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
COO
H
1
H
O
O
H
H
2
2
3
4 5
6
H
7
C
1.3,5 dihydro carboxylate is essential.
2.Lactone containing prodrug require in vivo
hydrolysis.

11. 3. Altering distance between C5 and ring diminishes the activity
R
3
CH3
O
C
O
H
H3C
O
O
HO
1
2
3
4
5
H3C
Mevastatin
O
O
HO
Lovastatin &M
evastatin
HO
COONa
OH
Pravastatin
HO
COONa
SCoA
H3C
O
HM
GCoA 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
CH3
N
CH3
NH
O
HO
COONa
OH
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
H
Fluvastatin
F
HO
COONa
OH
N
N
N
H3C S
O
O CH3
CH3
CH3
H
Rosuvastatin

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

15. Stereo chemistry of ester side chain is not
essential for activity
R
3
CH3
C7
O
C
O
C
H C
3
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
CH3
H2C
O
C
O
H C
3
CH3
H C
3
O
O
HO
Simvastatin
H3C
CH3
H2C
O
C
O
H3C
H
H3C
O
O
HO
Lovastatin

17. β hydroxyl group at R1 position increase hydrophilicity E.g.
Pravastatin
CH3
H2C
O
C
O
H C
3
H3C
H
HO
COONa
OH
H
Pravastatin
HO

18. 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
CH3
W
CH3
n
R
Ring B

19. SYNTHESIS
Simvastatin is a semisynthetic derivativeof Lovastatin is produced via multistage
fermentation process which originate from the culture of
Mechanism of action
H3C
CH3
H2C
O
C
aspergillus terreus
O
H C
3
R
H3C
O
O
HO
Lovastatin
M
evastatin
R=CH 3
R=H
Invivo
hydrolysis
H3C
CH3
H2C
O
C
O
H C
3
R
H3C
OH
HO
COOH
H
Activeform
HO
COOH
OH
H
H C
3
(Mimic)
HM
GCoAreductase
HO
COOH
OH
H
H3C
O
HO
COOH
H3C
SCoA
HM
GCoA
SCoA
Intermediate
HM
GCoAreductase

20. COMPOUND R1 R2
CLOFIBRATE Cl C2H5
FENOFIBRATE
BENZOFIBRATE
H
Cl C
O
HC
C H 3
C H 3
Cl
O
C N
CH3
CH3
FIBRIC ACID DERIVATIVE
R1 O
CH3
Analogues of phenoxy isobutyric acid
CH3
COOR 2

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

22. Mechanism of action
Stimulation of Peroxisome ProliferatorActivated
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
+
P.chloro Phenol
Acetone
CHCl 3
Chloroform
NaOH/H
+
Reflux
Cl O C
CH3
COOH
CH3
Clofibric acid
H3C CH 2 OH /H
+
Esterification
Cl
CH3
COOCH 2-CH 3
O C
CH3
Clofibrate
CLOFIBRATE
Synthesis

24. BENZOFIBRATE
O
Cl CO NH CH2 CH2
CH3
CH3
C COOH
SYNTHESIS
Cl COCl
P
.chloro Phenol
+ OH
H2N CH2 CH2
N
-HCl
Cl CO OH
2
2
NH CH CH
ClOC Cl
Benzoylation
-HCl

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

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

27. CH CH 2 CH 2
CH3
CH2 HC
CH3
+ -
CH2 N CH3 Cl
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 LDLreceptor

30. LDL OXIDATION INHIBITORS
PROBUCOL
S
HO
CH3
H3C C CH3
S
H3C CH3
C
CH3
CH3
OH
H3C C CH3
H3C
C
H C
3
H3C
CH3
PROBUCOL
CH3
4,4' isopropylidendithio bis [ 2,6 di t butyl phenol]

31. HO
H3C C CH3
SH
C
H C
3
H C
3
CH3
H C
3 CH3
O
C
Acetone
+
CH3
HS C
CH3
CH3
OH
H3C C CH3
H3C
+
CH3
S
CH3
HO
H3C C CH3
S
H3C CH3
CH3
CH3
OH
H3C C CH3
H3C
C
CH3
2,6 di t- butyl 4 phenol
H3C
H3C
CH3
C
PROBUCOL
Synthesis

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

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

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

35. HORMONE REPLACEMENT THERAPY
HRT directly stimulates LDLreceptor
activity, leading to reductions in total
cholesterol and LDLc levels.
 Moderate increases in HDLc levels
Decrease in HDLand LDLoxidation

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
H3C O
N
H3C
H3C
Cl
Tamoxifen Torimefene

38. REFERENCE
• Burgers medicinal chemistry,
Volume 3
Pg:no 339 – 374
• Foye’s principles of medicinal
chemistry Thomas. LLemke et.al
Pg:no 815 – 840
• Text book of medicinal chemistry
Volume 2 K. Ilango , P. Valentina
Pg:no 275 - 284