General introduction about hypertension and structure activity relationship of Different types of antihypertensive drugs, and related questions that were asked in exams. detailed SAR and mode of action of ACE inhibitors

1. Anti-hypertensive
Drugs
Subject - Medicinal Chemistry-II
Subject Code - BP-501T
Himanshu Joshi
Enrollment no. – 17PHM3PHM1030
B.R.Nahata College of Pharmacy,
Mandsaur University, Mandsaur, MadhyaPradesh
hjhimanshujoshi61@gmail.com

2. Overview
1. What’s Hypertension – Introduction, Causes, Types.
2. Antihypertensive drugs – Introduction,
Classification.
3. ACE Inhibitors – MOA, Classification, SAR.
• AT-II Antagonist – SAR, MOA.
4. Adrenoceptor Blocking Agents -
• α - Adrenergic Blockers
• β - adrenoceptor Blockers
• α + β – adrenoceptor Blockers
• Adrenergic Neuron Blockers
• Centrally Acting Agents
5. Vasodilators
6. Related Questions?????

3. What’s Hypertension (HTN or HT) ?
• It’s also known as High Blood pressure (HBP).
• It’s a condition in which the force of the blood against
the artery walls is too high or elevated.
• HBP doesn’t cause symptoms, but long term HBP
however, is found to be major risk factor for coronary
heart disease, stroke, heart failure, atrial fibrilation,
vision loss, chronic kidney diseases and dementia.
Environmental
Factors
Stress Na+ Intake Obesity Smoking
CAUSES OF HYPERTENSION

4. • The systolic reading of 130 mmHg refers to the pressure
as the heart pumps blood around the body.
• The diastolic reading of 80 mmHg refers to the pressure
as the heart relaxes and refills with blood.
• The AHA (American Heart Association) 2017 guidelines
define the following ranges of blood pressure:
Systolic (mmHg) Diastolic (mmHg)
Normal blood pressure Less than 120 Less than 80
Elevated Between 120 and 129 Less than 80
Stage 1 hypertension Between 130 and 139 Between 80 and 89
Stage 2 hypertension At least 140 At least 90
Hypertensive crisis Over 180 Over 120

5. Types of Hypertension
Essential/Primary HT (90-95% case)
Due to non-specific lifestyle and
genetic factors.
Secondary HT (5-10% case)
Due to an identifiable cause, such as
chronic kidney disease, endocrine disorder
or the use of birth control pills etc.

6. Antihypertensive Drugs
• These agents are used to treat hypertension (HBP).
• Antihypertensive medication seeks to prevent the
complications of HBP, such as stroke and myocardial
infarction.

7. Classification of Antihypertensive Drugs
Trick:-DAAV-5HT
A. Diuretics
1. Potassium Sparing Diuretics – Sprinolactone,
Triamterene
2. Thiazide – Chlorothiazide, Hydrochlorothiazide
3. Loop Diuretics – Furosemide
B. Agent Acting of Renin-Angiotensin System (RAS)
1. ACE inhibitor – Fossinopril, Captopril, Enalapril
2. Angiotensin Antagonist – Valsartan, Losartan

8. C. Adrenoceptor Blocking Agents
1. α – Adrenergic Blockers – Terazosin, Tolazoline,
Prazosin, Phenotolamine
2. β – Adrenergic Blockers – Propanolol, Atenolol,
Metoprolol
3. α + β Adrenergic Blockers – Labetalol, Carvedilol
4. Centrally Acting Agents – Methyldopa, Clonidine,
Guanfacine, Guanabenz
5. Ganglionic Blocking Agents – Pentolinium,
Trimethphan
6. Agents Acting on Adrenergic Neuron Blockers –
reserpine, Guanethidine

9. D. Vasodilator
a. Directly Acting Vasodilator
i) Potassium Channel agonist – Minoxidil, Diazoxide
ii) Arterial Dilators – Hydralazine, Dihydralazine
b. Calcium Channel Blockers – Diltiazem, Amlodipine,
Nifedipine, Verapamil
E. 5-HT (Serotonin) Antagonist - Ketanserine

10. ACE Inhibitors
• These drug primarily used for treatment of
hypertension & Congestive Heart Failure.
• These agents cause relaxation of blood vessels
and also decrease blood volume which leads to
low B.P.
• It also decrease the oxygen demand from the
heart.

11. Mode of Action
• AT-II (Angiotensin-II) is dominant hormone and
having essential role in regulation of fluid,
electrolyte balance, blood pressure and blood
volume.
AT-II
Stimulate synthesis
of Aldosterone
To raise B.P.
It constrict the
arterioles.

12. Mode of Action
• In body the RAS Renin-Angiotensin System get
activated by following factors :-
1. lowering in NA+ ion level concentration in
body.
2. Lower blood volume.
3. Lower renal pressure.
• ACE inhibitors directly blocks the formation of
AT-II by inhibiting the ACE (Angiotensin
Converting Enzyme).

13. Mode of Action
• At same time it increases the bradykinin level
which reduce the vasoconstriction, reduced NA+
and H2O reabsorption.
• Increases the vasodilation and low the B.P.
And Blood Volume.

14. Mode of ActionAngiotensinogen
(Plasma α2 – globulin)
From liver
Angiotensin I
Angiotensin II
VASCONSTRICTION Increased Aldosterone
secretion
Increased
Peripehral Vascular
Resistance
Increased Na+ &
H2O retention
Increased BLOOD
PRESSURE
Renin (From Kidney)
ACE
Kininogen
Bradykinin
Kallikerin
Inactive kinin VASODILATION
Decreased
Peripehral Vascular
Resistance
Decreased BLOOD
PRESSURE
ACE
INHIBITORs
Increase the
level of
Inhibits

15. Classification of ACE inhibitors on the
basis Chemical molecule
ACE
Inhibitors
Sulphydryl
E.g: Captopril
Dicarboxylate
E.g: Enalapril,
Lisinopril
Phosphate
E.g:
Fossinopril

16. Structure Activity Relationship (SAR)
1. Substitution on N-ring
• The N-ring must contain a carboxylic acid to mimic like the
C-terminal of ACE substrates.
• Large hydrophobic heterocyclic rings in the N-ring increase
the potency and alter the pharmacokinetics parameters.
2. Substitution on X
• If X is substituted by methyl group CH3 to mimic like the
side chain of alanine with decarboxylate series.
• If X is substituted by n-butyl amine it becomes orally active
drugs.

17. 3. Substitution on Zn2+ binding site
• Compound A, B and C serves as a Zn2+ binding
group.
A. Compound (A) Sulfhydryl group
 Shows superior binding to Zn2+ binding site.
 Sulfhydryl containing drugs produce skin rash and
taste disturbances in majority of cases.
 Sulfhydryl containing compounds can form
disulfides, which may shorten duration of action.

19. Dicarboxylate group containing drugs
H
N
COOR3H
R1
O
R2
Drug R1 R2 R3
ENALAPRIL CH3 C2H5
ENALAPRILATE --”-- CH3 H
LISINOPRIL --”-- (CH2)4NH2 H
RANIPRIL CH3 C2H5
Quinapril CH3 C2H5

20. Angiotensin II Antagonist
LOSARTAN VALSARTAN

21. = COOH
N
N
N
N
COOH
A B C
SAR
Acidic group
1) The "acidic group" is thought to mimic either Tyr
phenol or the Asp, carboxylate of angiotensin II.
Groups capable of such a role include the
carboxylic acid (A), a phenyl tetrazole (B), or a
phenyl carboxylate (C).
2) In the biphenyl series, the tetrazole and
carboxylate groups must be in the ortho position
for optimal activity.

22. SAR
3) The n-butyl group  provides hydrophobic
binding and mimics the side chain of Ile of
angiotensin II. E.g. candesartan and telmisartan,
this n-butyl group can be replaced with a
substituted benzimidazole ring.
4) The imidazole ring, or an isosteric equivalent, is
required to mimic the His,, side chain of
angiotensin II.

24. MOA
• AT 2 Blocker are competitive inhibitors of AT II,
devoid partial antagonistic activity and 10,000
time more selective for AT1 receptor than AT2.
• Block action of AT II such as vasoconstriction.

25. α - Adrenergic Blockers
Drug R
Prazosin
TerazosinN
NH3CO
H3CO
NH2
N
N
COR
SAR
1. All these drugs are similar in structure (quinazoline) .
2. Nature of acyl group has significant effect on
pharmacokinetic properties.
3. 4 – amino group is essential for α1 receptor affinity.
4. Piperazine is essential but it can be replaced with
piperdine moiety without loss of activity.
O
O

26. MOA
• They used in treatment of hypertension.
• They produce their effect by blocking post synaptic
α 1 – receptor in blood vessels and cause
vasodilation.
Tolazoline and Phentolamine both are non-
selective α- adrenergic antagonist. Both stimulate
gastrointestinal smooth muscle and also increase
gastric acid secretion.

27. β - adrenoceptor Blockers
Drug Ar R
Propanolol H
Pindolol H
Cardio Selective Beta Blockers
Atenolol H
Metoprolol H
Ar OCH2
H
C
H2
C
OH
H
N C CH3
R
H
N

28. SAR
1. The beta blocker have structural similarity with
epinephrine.
2. The aryloxy propanol amine are more potent than
aryl ethanolamine.
3. Replacement of ethereal oxygen with S, CH2, or
NCH3 is reduction of beta blocking activity.
4. The most effective amine substituent is isopropyl
and tertiary butyl.
5. Substitution of methylene carbon with alkyl group
generally causes reduction of β blocking potency.
Ar OCH2
H
C
H2
C
OH
H
N C CH3
R
H

29. MOA
• It has effect on: -
Decreases renin release
Resetting of baroreceptors
Reduced cardiac output
Decreased PVR

30. α + β – adrenoceptor Blockers
It combines with both non selective β and α
antagonistic activity.

31. Adrenergic Neuron Blockers
Guanethidine
MOA
 Acts presynaptically to inhibit release of neurotransmitter
from adrenergic neurons.
 The adrenergic blockade is due to: -
• Blockade of release & reuptake of NA.
• Depletion of NA stores at sympathetic nerves ending.
• Hypotensive effect is due to fall in cardiac output.

32. Reserpine
• Obtained from Raouwolfia serpentina
[Sarpdgandha].
• It blocks the transport of biogenic amine (NA,
adrenaline & 5-HT) in synaptic vesicle from
axoplasm in adrenergic nerve  this leads to
depletion of NA & produce fall in BP.

33. Centrally Acting Agents
• These drugs interfere with release of NA.
• Methyl DOPA is an inhibitor od aromatic D amino acid
decarboxylase and it is metabolised in CNS to
Methylnephrine  produces antihypertnsive effect 
by stimulating α - 2 adrenergic receptor in brain stem.
• Clonidine is an imidazoline derivative and stimualte α
- 2 adrenergic receptor in vasomotor centre of brain
 resulting in sympathetic outflow of peripheral
vessel and block release of NA.
HO
HO
H2
C C
CH3
H3N
COOC2H5
Methyl Dopa
Cl
H
N
N
H
N
Cl
clonidine

34. Vasodilators
• It cause vasodilation by stimulating guanylate
cyclase in arteriolar smooth muscle.
• Stimulant appears to be nitric oxide from local
oxidation of hydrazine moiety.

35. Minoxidil
• It dilates arterioles by opening potassium channels,
which causes hyperpolarisation and relaxation of
smooth muscles  this lowers PVR (Peripheral
vascular resistence)  fall BP

36. Sodium Nitroprusside
• Causes vasodilation in both arteries & venous.
• It form an active nitrathiol with glutathione
that increases cyclic GMP  Vasodilatation 
decrease PVR  Low BP

37. Related Questions
• Write structural classification of
antihypertensive drugs and explain MOA &
SAR of ACE inhibitors?
• Write a short note on hypertension?
• Classify antihypertensive drugs and explain
MOA & SAR of any one drug?
Reference of Structural classification
Textbook of Medicinal Chemistry by Malleshappa N Noolvi, Anurekha
Jain, Harun M Patel, CBS Publisher & Distributors, Page no. 376-379

38. Thanks Readers