This document discusses various classes of antihypertensive drugs used to treat hypertension. It describes the mechanisms of action, structure-activity relationships, and synthesis of representative drugs from different classes. The main classes covered are ACE inhibitors, calcium channel blockers, diuretics, beta blockers, alpha blockers, and vasodilators. For each class, examples are given of commonly used drugs and their properties are discussed through consideration of molecular structure and synthesis routes.

1. ANTI-HYPERTENSIVE
DRUGS
Presented by
SANDEEP BINDRA

2. HYPERTENSION
Hypertension is the elevated blood pressure.
If no specific cause of hypertension are said to have essential or
primary hypertension
Patients with specific etiology are said to have secondary hypertension
Genetic factors, stress, environmental factors and dietary factors
contribute to development of hypertension.

3. CLASSIFICATION OF DRUGS
ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS
ANGIOTENSIN ANTAGONIST
CALCIUM CHANNEL BLOCKERS
DIURETICS
ΒETA-ADRENERGIC BLOCKERS
ALPHA ADRENERGIC BLOCKERS
VASODILATORS
CENTRALLY ACTING AGENT

4. CALCIUM CHANNEL BLOCKERS
 1,4-Dihydropyridine
oNifedipine, Amlodipine
 Phenyl alkyl amine
oVerapamil
 Benzothiazepine
oDiltiazem
 Diamino propanol ether
oBepridil
DIURETICS
oChlorthiazide, Furosemide,
Spironolactone
ACE INHIBITORS
 Sulfhydryl containing inhibitors
oCaptopril
 Dicarboxylate containing inhibitors
oEnalapril, Lisinopril
 Phosphate containing inhibitors
oFosinopril
ANGIOTENSIN ANTAGONIST
oLosartan
oTelmisartan
oValsartan

5. MOA ACE INHIBITORS AND ANGIOTENSIN ANTAGONIST

6. SAR OF ACE INHIBITORS
◦ N ring must contain a carboxylic acid group to mimic the C
terminal carboxylate of ACE substrate
◦ Larger hydrophilic heterocyclic in the N ring increases the
potency and alter pharmacokinetic properties
◦ X is usually a methyl group, which mimic the side chain
alanine of the ACE substrate
◦ When the stereochemistry of inhibitor is consistent optimum
activity occurs with L-amino acid.

7. SYNTHESIS OF CAPTOPRIL

8. MECHANISM OF CALCIUM CHANNEL BLOCKERS

9. SAR OF CALCIUM CHANNEL BLOCKERS
oSubstituted phenyl ring at C4 position optimise the
activity
oEWG at ortho or meta position, increases the activity
oEDG at para position, decreases the activity
o1,4-dihydro pyridine ring is essential for activity
2
3
N
H
1
4
6
5
10
11
9
12
14
13
CH3
7
R1
16
R2
15
R3
8
X
17

10. oN- substituted or oxidised (piperidine) or
reduced (pyridine) ring system, abolish the
activity
oEster group at C3 & C5 position optimise the
activity
oIn case of amlodipine, 1,4-DHP have C2 & C6
methyl group which enhances the activity.
2
3
N
H
1
4
6
5
10
11
9
12
14
13
CH3
7
R1
16
R2
15
R3
8
X
17

11. SYNTHESIS OF NIFEDIPINE
2-Nitrobenzaldehyde Methylacetoacetate Nifedipine

12. SAR OF THIAZIDE DIURETICS
oHydrogen atom at second position is more
acidic due to electron withdrawing sulfone
group
oA free sufamoyl group at 7th position is
essential for activity
oSubstitution at second position decreases the
polarity and increases the duration of action
8
5
7
6
NH
2
3
S
1
N
4
R2
R1
O O
H2NO2S

13. SYNTHESIS OF FURESIMIDE

14. BETA ADRENERGIC BLOCKER

15. ◦ Mechanism of Action: Competitively blocks both β1 and β2 adrenergic receptors. When
access to β-receptor sites is blocked by Propranolol HCl, the chronotropic, inotropic, and
vasodilator responses to beta-adrenergic stimulation are decreased proportionately
◦

16. SAR
•The aromatic ring and its substituent is the primary
determinant of β1 antagonistic activity. The aryl
group also affects the absorption, excretion, and
metabolism of the β blockers.
•β blockers are structurally similar to β agonists. The
catechol ring can be replaced by a variety of ring
systems without loss of antagonistic activity.
•Replacement of catechol hydroxyl group with
chlorine of phenyl ring system retains β blocking
activity. Example: pronethalol,
dichloroisoproterenol.
•N, N–disubstitution decreases the β blocking
activity, and the activity is maintained when the
phenyl ethyl, hydroxy phenyl ethyl, or methoxy
phenyl ethyl groups are added to amine as a part of
the molecule.

17. SYNTHESIS OF PROPRANOLOL
• The two carbon chains are essential for activity.
• The introduction of the –OCH2 group into the molecule between the aromatic ring and the ethyl amine side
chain provides β blocking agents, for example, propranolol.
• As in the sympathomimetics, bulky aliphatic groups, such as the tert-butyl and isopropyl groups are normally
found on the amino function of the aryloxypropanolamine β receptor antagonists. It must be a secondary amine
for optimal activity.
◦

19. ALPHA ADRENERGIC BLOCKER
CLASSIFICATION

20. MACHENISM OF ACTION

21. SAR OF PARAZOSIN
•Cyclohexanediamine derivatives are having no
potency and selectivity
•Dialkylpiperizine compounds are having high
affinity and selectivity for α1-adrenoceptors.
•Cis Derivatives are the most potent. [2]

22. SYNTHESIS OF PARAZOSIN
i. 2-amino-4,5-dimethoxybenzoic acid reacts
with sodium cyanate to give 6,7-
dimethoxyquinazoline-2,4-diol.
ii. Later compound undergoes chlorination to
give 2,4-dichloro-6,7-dimethoxyquinazoline.
iii. It then reacts with ammonia to produce 2-
chloro-6,7-dimethoxyquinazolin-4-amine.
iv. Latter compound reacts with (furan-3-
l)(piperazin-1-yl) methanone to give prazosin.

23. VASODILATOR
hydralazine, minoxidil, nitrates, nitroprusside
◦ Mechanism of Action
◦ In general, Vasodilators dilate or prevent constriction of the blood vessels, which allows greater blood
flow to various organs in the body. Many vasodilators bind to receptors on endothelial cells of the blood
vessel, which stimulate calcium release. Calcium activates the enzyme nitric oxide synthase (NO
synthase) and converts L-arginine into NO. It leaves the endothelial cell via diffusion and enters vascular
smooth muscle cells. NO activates GTP and converts it into cGMP. cGMP then stimulates myosin-light
chain phosphatase, which removes a single phosphate from myosin and actin filaments. The
dephosphorylation of myosin and actin filaments allows vascular smooth muscle relaxation.
◦

24. SYNTHESIS OF HYDRALAZINE

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