Medicinal Chemistry

of Cardiovascular
Drugs I

1. Assoc. Prof. Dr Fazlin Mohd Fauzi

2. Head of Department
3. Pharmacology & Pharmaceutical Chemistry
Learning Outcome

1. Describe the SAR of drugs that affect the cardiovascular system

2. Apply (1) to the pharmacology and pharmacotherapeutics of
drugs related to the cardiovascular system
Lecture Outline
• Diuretics
• Cardiac glycosides
• Organic nitrates
• Calcium channel blockers
• Peripheral sympatholytics
• Agents affecting the Renin-Angiotensin
Pathway
• Statins
• Anticoagulants
• Antiplatelets
DIURETICS
Diuretics
Targets the kidney whose function include:
• Maintaining a balance between electrolytes and water
• Excrete hydrophilic metabolites

Diuretics:
• Increase urine flow rate à increase excretion of electrolytes and water WITHOUT
affecting reabsorption of proteins, vitamins, glucose and amino acids
• Decrease in extracellular fluid (ECF) volume
Low molecular weight compounds

Highly water soluble à not likely to be reabsorbed

Act on proximal convoluted tubule and descending

loop of Henle à freely permeable to water

osmosis or locally high concentrations of solute in the

nephron drags in water and associated electrolytes

i.e. mannitol (given parenterally), isosorbide (orally)

 Isosorbide

Mannitol
 Infrequently used as diuretics - low
efficacy and the early development of
Carbonic tolerance.

anhydrase Played an important role in the

inhibitors development of other major classes of
diuretics that are currently largely used.

They act at the proximal convoluted

tubule
CH3COHN SO2NH2 CH3CON SO2NH2

Acetazolamide
Methazolamide

SO2NH2
H2NO2S SO2NH2

Ethozxolamide
Dichlorphenamide
Inhibit the luminal membrane bound
Na+/Cl- co-transport system located at the
distant convoluted tubule
Hence the reabsorption of Na+ and Cl- are
blocked

Responsible for urinary loss of 5-8% of

filtered Na+

Other electrolytes are also excreted i.e. K+

(causing hypokalaemia)
 • Thiazide diuretics are weakly acidic with a
benzothiadiazine-1,1-dioxide nucleus
Loss of double bond between C3 and
Electron withdrawing group at C6 i.e. C4 increases diuretic activity ten-fold
CF3 and Cl needed for diuretic
activity. CF3 is more lipophilic than Cl 4
5 Substitution at C3 with lipophilic
hence has a longer duration of action
group increase diuretic potency i.e
6 3 haloalkyl, aralkyl, tioether

H2NO2S 8
2
Alkyl substitution (decrease
1 polarity) at N2 increase
Sulfonamide at C7 is required for
diuretic activity duration of action
• Thiazide-like diuretics do not contain the benzothiadiazine ring but are a group of
structurally diverse sulfonamide derivatives that has the same activity and side effect
profile as thiazide diuretics

QUINAZOLINONE

QUINAZOLINONE

PHTHALIMIDINE

INDOLINES
Acting at the thick ascending Henle’s
loop – loop diuretics

Highest capacity for Na+ reabsorption (20-

25%) – high ceiling diuretics
Patient counselling point

Inhibits the Na+/K+/2Cl- symporter –

excretion of these ions

Drugs in this class are classified by the

similarity of their pharmacological action
rather than their structural similarity
 Furosemide
An electron withdrawing
group needed at C4 i.e. Cl

5
6
4

H2NO2S 3 1
2

Sulfonamide group seen before in

thiazide diuretics Acidic group i.e. carboxylic acid
A prerequisite for the high ceiling required at C1 – makes Furosemide a
diuretic effect stronger acid than thiazide diuretics
Bumetanide

A phenoxy group has

replaced the usual Cl 5 The amine group has now
or CF3 4 move from C6 to C5
6

3 1

H2NO2S 2

The minor changes from Furosemide results in a compound with similar

mode of action to Furosemide but marked increase in diuretic potency
Torsemide

Sulfonylurea instead of the usual sulfonamide

Ethacrynic acid
Notice anything different?

Chloride on C2 and C3 for

optimal diuretic activity

Oxyacetic acid positioned para to α,β –

unsaturated carbonyl for optimal diuretic
activity
Hypokalaemic effect of thiazide and loop
diuretics

Both diuretics increase Na+ delivery

to the distal segment of the distal
tubule/ collecting duct

This stimulates the aldosterone-

sensitive sodium pump to increase
sodium reabsorption in exchange
for potassium and hydrogen ions.
 • Antagonizes the effect of aldosterone at the
collecting duct

• Aldosterone - promotes the retention of water

Potassium- and salt, and excretion of K+ and H+ ions i.e.
Spironolactone
sparring
diuretics • Also blocks sodium channel at the luminal
membrane i.e. triamterene and amiloride

• Do not increase excretion of K+ -

hyperkalaemia
Spironolactone
γ-lactone ring on C-17

Aldosterone Spironolactone

Interaction of C-7–unsubstituted agonists, such as aldosterone, with a methionine residue in

the MR ligand binding domain is important for receptor activation and subsequent
transcription. However, this interaction is sterically hindered by C-7 substituents on
aldosterone antagonists
Eplerenone
9α,11 α -epoxy - 20- to 40-fold lower
affinity for the MR than spironolactone

similar to the diuretic spironolactone, though it is much

more selective for the mineralocorticoid receptor in comparison (i.e.
does not possess any antiandrogen, progestogen, or estrogenic effects)
Triamterene and amiloride

Triameterene Amiloride

Amiloride is the open-ring version of triamterene

Both inhibits the luminal sodium channels in the distal tubule
This blocks the reabsorption of Na+ and excretion of K+
Aldosterone is not antagonized by both amiloride and triamterene
CARDIAC GLYCOSIDES
Cardiac glycosides increase the output force
of the heart and increase its rate of
contractions by acting on the cellular sodium-
potassium ATPase pump.

Treatments for congestive heart failure and

cardiac arrhythmias; however, their relative
toxicity prevents them from being widely used
Chemistry of Cardiac Glycosides
Contains two portion: sugar (glycone) and non-sugar (aglycone;
steroid) portions
Lactone group is
attached at C17

Glycone is
attached to C3
Plant-based

Animal-based
Aglycone portion of CG
• Rings A-B and C-D are fused in a cis
configuration
• Rings B-C is fused in a trans configuration
• Distinct from other more common steroid-
containing compounds – “U” shape
1 to 4 sugars can be present in cardiac
glycosides

Attached to the aglycone at the 3β-OH group.

These sugars predominantly exist in the cardiac

glycosides in the β –conformation

Numerous cardiac glycosides with differing

sugar skeleton but relatively few aglycone
structures.
Other sugar includes D-sarmentose, L-vallarose,
and D-fructose
 The sugar moiety appears to
The "backbone" U shape of
be important only for the
the steroid nucleus appears
partitioning and kinetics of
to be very important.
action.

SAR of A skeleton without 14β-OH

group but retaining the C/D
Lactones alone, when not

Cardiac
attached to the steroid
cis ring fusion was found to skeleton, are not active.
retain activity.

Glycosides
The lactone ring is not
The unsaturated 17-lactone
absolutely required. For
plays an important role in
example, using a,b-
receptor binding - Saturation
unsaturated nitrile (C=C-CN
of the lactone ring
group) the lactone could be
dramatically reduced the
replaced with little or no loss
biological activity.
in biological activity.
 Digoxin

Digitoxin
Acetyldigitoxin

Lanatoside C
Digoxin

• Extracted from the leaves of Digitalis lanata.

• It has positive inotropic and negative chronotropic activity
• Widely used medication for the treatment of congestive heart failure and
supraventricular arrhythmias, and is commonly used to slow ventricular
response in patients with atrial fibrillation.
• Has a narrow therapeutic index and highly variable kinetics
ORGANIC NITRATES
Organic nitrates
Esters of simple organic alcohols or polyols with nitric acid.

The organic nitrates are pharmacologic sources of nitric oxide (NO) for the body. In
the cardiovascular system, NO is naturally produced by vascular endothelial cells.

NO has several important functions:

• relaxation of vascular smooth muscle
• inhibition of platelet aggregation (antithrombotic)
• inhibition of leukocyte–endothelial interactions (antiinflammatory).
Chemistry of organic nitrates

The chemical nature of these molecules as esters constitutes

some problems in formulating these agents for clinical use.
• The small lipophilic ester = volatile àpotential loss of the active principle
• Moisture must be avoided – hydrolysis of the esters
• Possess explosive properties, especially in the pure concentrated form – dilution

The lipophilic nature of these esters, however, makes these

agents very efficient in emergency treatment of anginal episodes
CALCIUM CHANNEL BLOCKERS
• Blocks the influx of Calcium into vascular smooth
muscle, myocardium and cardiac conducting
system via L-type calcium channels.

1,4 – Dihydropyridine Benzothiazepine Phenylalkylamine

Mainly on Vascular Both VSM and cardiac Greater effect on cardiac
Smooth Muscle (VSM) muscle, but less on muscle than VSM
cardiac than Verapamil
(-DIPINE drugs) : Diltiazem Verapamil
Amlodipine,
Nimodipine, Felodipine
SAR of 1,4 - Dihydropyridine
1

6 2
1. C4 must contain a substituted
phenyl ring for optimum activity
5 3 • A non planar alkyl or
4 cycloalkyl decreases activity

2. 1,4 – DHP ring is essential

• Substitution at N1
• Oxidisation to piperidine
X • Reduction to pyridine
3. Phenyl substitution (X) important for
1
size and position

• Ortho or meta substitution

optimal 6 2
• Unsubstitution or para
substitution decreases activity
5 3
• ALL commercially available DHPs 4
have EWG at ortho/meta BUT
this is not required
• EDG at ortho/meta also works
• The substitution provides X
sufficient bulk to “lock” the
conformation
 1

4. Esters at C3 and C5 optimize activity

6 2
• Other EWG show decrease antagonistic
activity and some agonistic activity

5 3
5. If C3 and C5 are non-identical, C4 becomes
4
a chiral center

6. With the exception of amlodipine, C2 and

C6 are methyl
X
Benzothiazipine - Diltiazem

4'-aryl methyl ether is

* essential for activity

A basic substituent
appended to N1 with a
pKa in the physiological
range essential for
activity – 7.7
Phenylalkylamines - Verapamil

pKa = 8.9
 PERIPHERAL
SYMPATHOLYTICS
Peripheral sympatholytics
• Non-selective α-blockers
• Selective α-blockers
• β-blockers
• Mixed α/β –blocker
Non-selective α-blockers

• Block the effects of

catecholamine on α1 and α2
receptors
• An old but powerful drug in this
class is phenoxybenzamine
(dibenzyline), a β-
haloalkylamine that alkylates α-
receptors.
 nucleophile group X on the receptor can open the
aziridinium ion in a nucleophilic reaction to form a
covalent bond between the receptor and the drug

intramolecular Unfortunately, other biomolecules

nucleophilic substitution besides the target α-receptor are also
to form a highly reactive alkylated. Due to its receptor
aziridinium ion nonselectivity and toxicity, the use of
phenoxybenzamine largely is limited
Imidazoline nonselective α-antagonists that
also have antihypertensive activity, although
they have been replaced in general clinical use
by far better agents.
 Selective α-blockers
Prazosin, doxazosin, and terazosin contain a 4-amino-
6,7-dimethoxyquinazoline ring system attached to a
piperazine

Alfuzosin has a rotatable

propylenediamine group
Heterocyclic acyl groups attached to the second nitrogen
of the piperazine or the propyl chain - dramatic
differences in some of the pharmacokinetic properties of
these agents
β-blockers

β1 β2
Cardio myocytes
bronchioles

Cardiac muscle contraction Smooth muscle relaxation

HR and force Dilates and open airways

Isoproterenol
Dichloroisoproterenol

Replacement of catechol hydroxyls with Cl produces

a compound with β-antagonist activity, but of no
clinical use

replacement of the 3,4-dichloro substituents with a carbon bridge

to form a naphthylethanolamine derivative did afford a clinical
candidate, Pronethalol, only to be withdrawn in because of tumor
induction in animal tests.
Insertion of an oxymethylene bridge into the arylethanolamine structure
of pronethalol affords Propranolol, an aryloxypropanolamine and the first
clinically successful β-blocker

Side chain has been moved

from C2 of the naphthyl
group to the C1 position.

In general, the aryloxypropanolamines are more potent β-blockers

than the arylethanolamines, and most of the β-blockers currently
being used clinically are aryloxypropanolamines.
Selective β-blocker
• It was later discovered that 4-substituted
phenyloxypropanololamines produces compounds with
selective activity against β1 over β2 receptor
Lipophilicity and β-blocker

Adapted from Van de Waterbeemd et al., (2001) J. Med. Chem, 44, p1313
Mixed α/β-blockers
Ethanolamine group – β-blocking
properties

The α-methyl substituent attached to

the N-arylalkyl group appears to be
responsible for the a-adrenergic
blocking effect.