This document discusses statins, which are cholesterol-lowering drugs. It notes that excess cholesterol can cause cardiovascular issues. Statins work by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. The first identified statin was mevastatin from a fungus. Later statins included lovastatin, simvastatin, and pravastatin. Newer "type II" statins like atorvastatin and rosuvastatin are easier to synthesize. Statins bind competitively to HMG-CoA reductase, forming additional interactions beyond the natural substrate. Rosuvastatin forms unique bonds and is the most potent statin. Statins' main mechanism is reducing

1. STATINS AS
ANTICHOLESTEROLAGENTS
Patrick: An Introduction
to Medicinal Chemistry 6e
Case Study 1

2. 1. Cholesterol
Notes
•Important in biosynthesis and cell membrane structure
•Excess cholesterol leads to cardiovascular disease
•Fatty molecule transported round blood supply by low-density
and high-density lipoproteins (LDLs and HDLs)
•LDLs carry cholesterol to cells
•HDLs carry cholesterol from cells to liver
•Mortality is associated with high levels of LDLs or low levels of
HDLs
•Cholesterol can cause fatty plaques in arteries leading to a risk
of artherosclerosis, clot formation, stroke and heart attack

3. 2. Target for statins
Notes on statins
•Inhibit an enzyme in the biosynthetic pathway to cholesterol
•Prevent synthesis of cholesterol within cells
•Target the enzyme catalysing the rate limiting step in the
biosynthetic pathway
•Cholesterol can still be obtained from the diet
O CH3 O
O
S
HO
SH
CoA
CH3
O
O
HO
HO
( S ) - H M G - C o A
( R ) - M
+ 2 H
H M G - C o A r
2NADPH 2 N A D P
Target enzyme

4. 3. Catalytic mechanism
Notes
•Involves two hydride transfers
•Two molecules of cofactor required (NADPH)
O
R S CoA
O
R S CoA
H
M eval dyl - C
oA
NADPH
NADP
+H
R H
M eval dehyde
+ C
oA
SH
N
A
D
PH + H OH
R H
H
O
NADP
Melvaldyl-CoA Melvaldehyde
+ CoASH
NADPH + H+
NADP+
+H+
NADPH
NADP+

5. 3. Catalytic mechanism
Substrate binding
H-bond
H-bond
H-bond
Ionic
O CH3 O
O
S
O
CoA
H
-

6. Notes
•Lys, His, Glu, and Asp are involved in the reaction mechanism
•Histidine acts as an acid catalyst
•Lysine stabilises the negatively charged oxygen of mevaldyl-CoA and the
transition state leading to it
•Lowers activation energy for first step
3. Catalytic mechanism
N
Lys-691
H H
H
O
R S CoA
H
-b
ond
H
NH
N
H
His-866
Mevaldehyde
O
R H
N
Lys-691
H H
H
H-bond
NH
N
His-866
SH CoA
Mevaldyl-CoA
O
R S CoA
H
N
Lys-691
H H
H
H-bond
Ionic

7. Glu-559
O O
H
Notes
•Glutamic acid acts as an acid catalyst
•An aspartate residue stabilises Glu-559 and Lys-691
3. Catalytic mechanism
Glu-559
O O
N
Lys-691
H H
H
Asp-767
O
O
H
N
Lys-691
H H
H
O
R H
H
-b
ond
(from NADPH)
H
Mevalonate
OH
R H
N
Lys-691
H H
H
H-bond
Glu-559
O O
H
O
R H
H
N
Lys-691
H H
H
H-bond
Ionic

8. 4. Identification of a Lead Compound
Notes
•Identified by screening compounds produced by microorganisms
•Microbes lacking HMGR might produce HMGR inhibitors to inhibit
microbes which do have HMGR - chemical warfare
•Compactin (Mevastatin) isolated from Penicillium citrinum
•10,000 x higher affinity for enzyme than substrate
•Never reached the market
O
O
O
O
HO
H
H Compactin (Mevastatin)
IC50 = 23 nM

9. 5. Type I Statins
Notes
•Lovastatin isolated from Aspergillus terreus
•First statin to be marketed (Merck; 1987)
•Revolutionised treatment of hypercholesterolaemia
•Simvastatin introduced in 1988 as semi-synthetic analogue of lovastatin
• Pravastatin derived from compactin by biological transformation (1991)
O
O
OH
CO2H
HO
H
H
HO
Lovastatin
IC50 = 24 nM
O
O
O
O
HO
H
H
H
O
O
O
O
HO
H
H
Me
Simvastatin
IC50 = 24 nM
Pravastatin
IC50 = 1900 nM

10. Polar ‘head’
R'
O
OH
CO2H
HO
H
H
R''
O
R
5. Type I Statins
Notes
•General structure of type I statins contains a polar head and a hydrophobic
moiety including a decalin ring
•Lovastatin and simvastatin are prodrugs where a lactone ring is hydrolysed
to give the polar head
Hydrophobic
moiety
Decalin ring

11. R'
O
OH
CO2H
HO
H
H
R''
O
R
5. Type I Statins
Disadvantages of Type I statins
•Various side effects
•Difficult to synthesise
•Large number of asymmetric centres
*
*
*
*
*
*
*
*
* = Asymmetric centres Hydrophobic
moiety
Decalin ring
Polar ‘head’

12. 6. Type II Statins
Notes
•Synthetic agents
•Contain larger hydrophobic moiety with no asymmetric centres
•Easier to synthesise
•Fluvostatin (1994), atorvastatin (1997), cerivastatin (1998),
rosuvastatin (2003)
Fluvastatin
IC50 = 28 nM
Atorvastatin
IC50 = 8 nM
Cerivastatin
IC50 = 10 nM
OH
CO2H
HO
N
F
H
N
OH
CO2H
HO
H
F
O
NH
OH
CO2H
HO
N
O
H3C
F
H

13. OH
CO2H
HO
H
N
F
OH
CO2H
HO
N N
N
S CH3
F
H3C
O
O
H
Rosuvastatin
IC50 = 5 nM
Pitavastatin
IC50 = 6.8 nM
Notes
•Type II statins share a number of similar features (‘me too
drugs’)
•Rosuvastatin is the most potent - related to sulphonamide group
•Cerivastatin is the most hydrophobic
•Pravastatin and rosuvastatin are the least hydrophobic
6. Type II Statins

14. Notes
•Statins with lower hydrophobic character target liver cells and
have lower side effects
•Less hydrophobic statins do not cross cell membranes easily
•Liver cells have transport proteins for statins, whereas other
cells do not
•Majority of cholesterol synthesis takes place in liver cells
•Side effects thought to be due to inhibition of HMGR in other
cells, such as muscle cells
•Common side effect is myalgia (muscle pain)
•Rhabdomyolysis = severe muscle toxicity which can be fatal
•Cerivastatin withdrawn in 2001 due to rhabdomyolysis and 50
fatalities
6. Type II Statins

15. 7. Statins - Mechanism of action
Notes
•Competitive inhibitors of HMGR
•Polar head group mimics the natural substrate (HMG-SCoA)
•Same binding interactions for polar head group as natural
substrate
•Hydrophobic moiety forms additional binding interactions
•Binds more strongly than natural substrate, but does not
undergo reaction - no leaving group
O CH3 O
O
S
HO
CoA
HM G - S Co A
SCoA
CO2
HO
CH3
O
=
Hydrophobic group
OH
CO2
HO
H
H
Statins
Statins

16. 7. Statins - Mechanism of action
Notes
•Statins are closer mimics of the first reaction intermediate
mevaldyl CoA
•Statins likely to bear a resemblance to the transition state for the
first stage of the reaction mechanism
•Can be viewed as transition-state analogues
Statins
Mevaldyl CoA

17. Atorvastatin
8. Statins - Binding interactions
Notes
•Polar head group binds in similar manner to substrate
•Hydrophobic moiety does not bind to the pocket for SCoA
•Enzyme is flexible and alters shape to accommodate statins
•Hydrophobic pocket is created to bind the hydrophobic moiety
vd
w
Ion-dipole
bond
H-bond

18. Methylethyl
substituent
Atorvastatin
vd
w
Ion-dipole
bond
H-bond
8. Statins - Binding interactions
The methylethyl substituent of Type II statins binds to the same
region of the binding site as the decalin ring of type I statins

19. Fluorophenyl
substituent
Atorvastatin
vd
w
Ion-dipole
bond
H-bond
8. Statins - Binding interactions
•Arg-590 forms an important polar interaction with the
fluorophenyl substituent
•The planar guanidium group is also stacked over the
phenyl ring

20. Amide group
Atorvastatin
vd
w
Ion-dipole
bond
H-bond
8. Statins - Binding interactions
•Amide group forms an additional hydrogen bonding
interaction with Ser-565
•Additional interaction not formed with other statins
other than rosuvastatin

21. Sulphone group
H-bond
Rosuvastatin
8. Statins - Binding interactions
Notes
•Rosuvastatin forms additional H-bonding interactions
•Sulphone oxygen forms a hydrogen bonding interaction with Ser 565
•Sulphone group also interacts uniquely with Arg-568
•Explains why rosuvastatin is the most potent statin
•Sulphone group important for binding as well as for selectivity
vdw
Ion-dipole
bond

22. 9. Other mechanisms of action for statins
Notes
•Statins inhibit HMGR in liver cells
•HMGR inhibition lowers cholesterol levels in liver cells
•Causes an increase in the synthesis of hepatic LDL receptors
•Increases the number of LDL receptors in the cell membrane of
liver cells
•Increases the amount of LDL-cholesterol cleared from the
plasma
•Crucial to the effectiveness of statins