Medicinal Chemistry

CARDIOVASKULAR DRUGS

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 2. Parenteral Anticoagulants
A. Heparin
• Chemistry and Mechanisms: It is a polymeric
mixture of sulfated mucopolysaccharides.
• It is highly negatively charged at physiological
pH. Can be neutralized by basic molecules
such as protamine.
• Heparin is synthesized as a normal product of
many tissues including the lung, intestine, and
the liver.
• Commercial preparations are derived from
bovine lung or porcine intestinal extracts
(average molecular wt. 15,000-20,000).

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 Heparin - Structure
Average molecular wt of 12,000 daltons (40 glucose units) with the
following structure:

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 Heparin binds to antithrombin III (ATIII)
and enhances its proteolytic activity

Active clotting factors Active clotting factors

(IIa, IXa, Xa, XIa, XIIa, XIIIa (IIa, IXa, Xa, XIa, XIIa, XIIIa

Rapid AT III +
Slow AT III heparin
(1000x)

Inactive factors Inactive factors

A. No Heparin B. With Heparin 4

Heparin mechanism of action

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Cont….

Mechanism of action of heparin, low-molecular-weight heparin (LMWH), and fondaparinux,

a synthetic pentasaccharide.
A. Heparin binds to antithrombin via its pentasaccharide sequence. T
his induces a conformational change in the reactive center loop of antithrombin that
accelerates its interaction with factor Xa. To potentiate thrombin inhibition, heparin must
simultaneously bind to antithrombin and thrombin.
Only heparin chains composed of at least 18 saccharide units, which corresponds to
a molecular weight of 5400, are of sufficient length to perform this bridging function.
With a mean molecular weight of 15,000, all of the heparin chains are long enough to do this.
B. LMWH has greater capacity to potentiate factor Xa inhibition by antithrombin than
thrombin because, with a mean molecular weight of 4500–5000, at least half of the LMWH
chains are too short to bridge antithrombin to thrombin.
C. The pentasaccharide only accelerates factor Xa inhibition by antithrombin because the
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pentasaccharide is too short to bridge antithrombin to thrombin.
 Mechanism of action of Heparin
• Heparin binds to antithrombin III and
enhances its proteolytic activity by 1000-fold.
• Heparin has a direct anticoagulant activity
(can inhibit clotting in vitro).
• Heparin releases lipoprotein lipase from
vascular beds, which accelerate clearing of
lipoproteins from the plasma.

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 Pharmacokinetic and
Pharmacological Effects (Heparin)
• Heparin must be given parenterally by slow
infusion or deep subcutaneous injection. It
is not injected IM due to the potential of
hematoma
• Heparin is metabolized in the liver by
heparinase to smaller molecular-weight
compounds, which are excreted in the urine.

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B. Hirudin and Related Drugs
• Hirudin is a natural anticoagulant
obtained from Hirudo medicinalis, the
medicinal leech.
• It is a direct inhibitor of thrombin.
• These drugs are undergoing clinical
trials for the treatment of unstable
angina and acute MI.

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10
Hirudo medicinalis

anatomy

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Hirudin

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Antiplatelet agents
 Antiplatelet agents

 Predominantly prevent arterial thrombosis

 In acute setting of MI & ischaemic stroke
 Secondary prevention of vascular events
 Primary prevention when 10 yr risk >15% and
BP controlled
BEBERAPA OBAT
1. Klopidogrel
mekanisme yaitu menghambat reseptor purinergik
yang terletak pada trombosit.

2. Aspirin
Menghambat sintesis tromboksan didalam trombosit dan
prostaksiklin dipembuluh darah dengan menghambat
secara irrefersible enzim siklo oksigenase(COX) dengan
mengasetilasi enzim tersebut.
Antiplatelet drug targets

 Prostaglandin
synthesis
 ADP binding
 GPIIb/IIIa
receptor
 Cyclic AMP
 Antiplatelet agents

Aspirin

inhibits cyclo-oxygenase
 thromboxane A2 synthesis
inhibits both COX 1 and COX 2 irreversibly
Aspirin

 Pros -
Inexpensive
Proven efficacy

 Cons –
Intolerance
Limited potency
Adverse effects

 GI ulceration 6-31%
 Haemorrhage
 Bronchospasm
 Interstitial nephritis, papillary necrosis, proteinuria,
renal failure
 Reye’s syndrome in children CI <16yrs
 Dangerous in overdose
The Cardiac Glycosides
Cardio-active Glycosides

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 What are they used for?
• Cardiac glycosides are cardiotonic drugs
• Used in the treatment of congestive heart
failure and cardiac arrhythmia

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 Why use Cardiac Glycosides?
Starling Curve • Decompensation 
contractions get weaker

• In heart failure:
- Decompensation occurs
well below the
pericardium limit

• Increase contractile strength of failing heart by 50-100%

• Drugs have little effect on a healthy heart
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Structure features:

• Steroidal nucleus must be present.

• 3b-OH group involved in glycosidic
linkage.
• 14b-OH group at C-14.
• A/B ring junction cis
• B/C ring junction trans
• C/D ring junction cis R1
• Additional oH groups at C-5, C-11 R
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and C-16 may be present. 17
C
• The presence of lactone ring: D
H R2
16

A H OH
3
B
sug-O 5
H
R3 24
• According to the type of lactone ring O
Cardiac Glycosides are classified into: O
– Cardinolides:
They are C-23 containing 5-membered
unsaturated lactone ring
e.g. Digitalis & Strophanthus 17

O
– Bufadienolides:
They are C-24 containing 6-membered
unsaturated lactone ring
O
e.g. Squill

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 The Sugar Part:
• The glycosides usually contain 3 to 4 sugars attached at C-3 OH.

• Beside Glucose and Rhamnose they usually contain

deoxysugars.

CHO CHO CHO CHO

CH OH HO CH CH2 CH2
HO CH HO CH CH OH CH OCH3
CH OH CH OH CH OH CH OH
CH OH CH OH CH OH CH OH
CH2OH CH3 CH3 CH3
Glucose Rhamnose Digitoxose Cymarose
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 The Cardinolides
1- Digitalis Glycosides

• Scrophulariaceae
• Known as “foxglove”
• The most important species includes:

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Digitalis purpurea

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Digitalis lanata

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 Digitalis contain three major aglycones:

O
O
R1

12 17
R1=R2=H Digitoxigenin
16 R2 R1=H, R2=OH Gitoxigenin
R1=OH, R2=H Digoxigenin

OH
3

HO 5

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Digitoxigenin derived Glycosides: (Glycosylation at 3 OH)
Lanatoside A -Ac (Alkaline hydr.) Purpurea glycoside A
DX-DX-DX(Ac)-Gl DX-DX-DX-Gl
-Gl (Enzymatic Hydr.) -Gl (Enzymatic Hydr.)

Acetyl-digitoxin Digitoxin
DX-DX-DX(Ac) -Ac (Alkaline hydr.) DX-DX-DX

Gitoxigenin derived Glycosides: (Glycosylation at 3 OH)

Lanatoside B -Ac (Alkaline hydr.) Purpurea glycoside B
DX-DX-DX(Ac)-Gl DX-DX-DX-Gl
-Gl (Enzymatic Hydr.) -Gl (Enzymatic Hydr.)

Acetyl-gitoxin Gitoxin
DX-DX-DX(Ac) -Ac (Alkaline hydr.) DX-DX-DX

Digoxigenin derived Glycosides: (Glycosylation at 3 OH)

LanatosideC -Ac (Alkaline hydr.) Deacetyl lanatoside C (Deslanoside)
DX-DX-DX(Ac)-Gl DX-DX-DX-Gl
-Gl (Enzymatic Hydr.) -Gl (Enzymatic Hydr.)

Acetyl-digoxin Digoxin
-Ac (Alkaline hydr.) 31
DX-DX-DX(Ac) DX-DX-DX
 2- Strophanthus Glycosides
• Apocyanaceae
• Strophanthus vine seeds – Africa
• Obtained from Strophanthus kombé
• The used part is the seeds.
• The common aglycone is K-strophanthidin

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33
 O
O

12 17

CHO 16

OH
3

O
OH 5 K-Strophanthidin

Cymarose Cymarin

b-Glucose K-Strophanthin b

-Glucose K-Strophanthoside 34
 Bufadienolides
1- Squill Glycosides
• Liliceae
• Urginea bulbs (squill) – Europe, India
• Convallaria leaves (lily of the valley) – also produces a
volatile oil perfume
• They have 6-membered lactone ring.
• Obtained from Squill bulbs.
• Aglycone contains only two hydroxyl groups at
C-3 and C-14.

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36
 O

12 17
16

OH
3

O 5
Scillaridin A

Rhamnose Proscillaridin A

b-Glucose Scillarin A

Glucoscillarin A
b-Glucose 37
Physical and Chemical properties of cardiac
glycosides:

• Solubility:
– Glycosides are soluble in water and alcohols.
– Increase number of sugars increase water solubility.
– Aglycones soluble in CHCl3 and EtOAc.

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• Stability:
– Acid hydrolysis:
• Split sugars from the aglycone first.
– Enzymatic hydrolysis:
• Split sugars stepwise starting from the terminal sugar.
– Elevated temperature:
• Cause dehydration by removal of C-14 OH group to give
inactive anhydro-form

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 O O
O O

High temperature

OH

Sug-O Sug-O
Anhydro-form

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 Dehydration of Gitoxin with another OH at C-16 give a
fluorescent compound used as test for Gitoxin

O O
O O

OH
H2SO4
OH

HO HO
Anhydro-form

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