UME - Antihypertensives.pdf

1. PCH 523
Medicinal Chemistry II
PART 2 - ANTIHYPERTENSIVE DRUGS

2. ❖ Hypertension:
➢ An increase in BP such that systolicis > 140 mm/Hg & diastolic > 90
mm/Hg on 2 or more occasions after initial screening
• Essential Hypertension= mostcommon.
✓ Exact Origin unknown.
✓ Contributing Factors - family history, hyperlipidemia,
diabetes, obesity, aging, stress, excessive alcohol & smoking.
• Secondary Hypertension is about 10% , related to endocrine or renal
disorders
Stages of Hypertension
Stage Systolic Range
(mm/Hg)
Diastolic Range
(mm/Hg)
High Normal 85 - 99 130 -139
Stage 1 90 - 99 140 - 159
Stage 2 100 -109 160 - 179
Stage 3 > 109 > 179

3. Classification of Antihypertensive Drugs
1) Angiotensin inhibitors and
antagonists.
- Angiotensin Converting
Enzyme (ACE) inhibitors.
- Angiotensin receptor
antagonists
2) Diuretics
- Thiazides
- Loop diuretics.
- Potassium-sparing diuretics
3) Vasodilators
- Nitric oxide releasers.
- Potassium channel openers.
- Calcium channel blockers.
4) Sympatholytic drugs
- Centrally acting antiadrenergic
agents.
- Adrenergic neuron blocking
agents.
- Alpha adrenergic blockers.
- Beta adrenergic blockers.
- Alpha-beta adrenergic
blockers.

4. Angiotensin converting enzyme (ACE) inhibitors

5. ACEIs
❖Angiotensin converting
enzyme (ACE) inhibitors
➢Sulfhydryl containing
inhibitors. eg. Captopril
➢Dicarboxylate containing
inhibitors: eg. Enalapril,
Lisinopril, Quinapril,
Ramipril
➢Phosphonate containing
inhibitor: eg. Fosinopril
❖Angiotensin antagonists
e.g. Besartan,
Candesartan,
Telmisartan,Valsartan.

6. ❖ SAR of ACEIs
➢ Among the three zinc binding group, sulfhydryl group is superior, but they form
disulfide which result in shorter duration of action and the side effect of skin
rashes.
➢ N - ring must contain a carboxylic acid group to mimic the C -terminal
carboxylate of ACE substrate.
➢ Larger hydrophilic heterocyclic in the N - ring increase 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. • Captopril
• Synthesis
• Use: It is used in condition such as post myocardial infarction,congestive heart failure and
preservation of kidney function in diabetic nephropathy

8. ❖Enalapril
✓prodrug of Enalaprilate.
✓devoid of side effects of rash and loss of taste
seen in Captopril.
✓hydrolyzed in the liver by esterase to active
dicarboxylic acid Enalaprilate

9. Angiotensin II receptor Antagonists (A-II blockers)
✓ Example: Losartan
✓ Newer drugs similar to ACE inhibitors
✓ Prevent release of aldosterone (Na+ retaining
hormone)
✓ Act on renin - angiotensin system
✓ Difference between ACE antagonists & A-II blockers is
A-II blockers block angiotensin from angiotensin I
receptors found in many tissues, blocks at receptor
site.
✓ A-II blockers cause vasodilation & decrease
peripheral resistance

10. ❖Losartan
➢ First non-peptide imidazole to be introduced as an
orally active angiotensin-II antagonist.
➢ Inhibits competitively angiotensin-II to produce
vasodilator effect.
➢ Use: antihypertensive agent and also in the
treatment of heart failure.
➢ Adverse effects: Headache, dizziness, back pain and
myalgia

11. Calcium Channel Blockers
➢Free calcium increases muscular contactility
and subsequently increases peripheral
resistance and BP
➢So, Calcium blockers,
✓Decrease calcium levels & promote vasodilation
➢Two sub-groups
✓1, 4 - Dihydro pyridine
✓Benzothiazepine derivatives

12. ❖1, 4 - Dihydropyridine
N
H
COOR 3
R2OOC
CH3
R6 1
2
3
5
6
4
X
Compounds R 1 R2 R3 X
Amlodipine - CH2 O (CH2)2 NH2 - C2H5 - CH3 2 -Cl
Felodipine - CH3 - C2H5 - CH3 2,3 - Cl2
Nifedipine - CH3 - CH3 - CH3 2 - NO2
Nitrendipine - CH3 - CH3 - C2H5 3 - NO2

13. ❖ 1, 4 - Dihydropyridine contd.
➢ Following structural features are important for activity;
➢ A phenyl ring substitution at 4th position optimizes activity.
Substitution at para or unsubstituted phenyl ring decreases the
activity.
➢ 1, 4 - Dihydropyridine ring is essential for activity. Substitution at
N, or oxidation or reduction of the ring decreases or abolishes the
activity.
➢ The 3rd and 5th position ester group optimizes activity. Any other
electron withdrawing substitution results in agonist activity.
➢ When the ester at C3 and C5 are non - identical the C4 become chiral
and stereoselectivity is observed. S- enantiomers have proved to be
more effective.
❑ Read up: the synthesis of Amlodipine and Nifedipine
N
H
COOR 3
R2OOC
CH3
C
H3
R1
1
2
3
5
6
4

14. ❖Benzothiazepine derivatives
➢Diltiazem
(+) - Cis -3- (acetyloxy) -5- [(2 -dimethylamino) ethyl] - 2,3-
dihydro-2- (4 -methoxy phenyl) 1,5 - benzothiazepin - 4 (5 H) one

15. Vasodilators
❖ Drugs: hydralazine, minoxidil, sodium nitroprusside, diazoxide,
❖ Site of Action- vascular smooth muscle
❖ Hydralazine
➢ Properties:
✓ white or almost white crystalline powder
✓ slightlysoluble in methylene chloride and alcohol
✓ soluble in water
➢ Uses: treatment of moderate to severe hypertension.
➢ Mechanism of action
✓ Alters intracellularCa2+
✓ Prevents oxidation ofnitricoxide
➢ Assay: Potentiometric titration, HPLC-UV
N
N
N
H
NH2
1-(Phthalazin-1-yl)hydrazine

16. Hydralazine Synthesis
❖ Minoxidil (piperidino pyrimidine derivative)
➢ indicated for patients with severe hypertension, who do not respond to
other drugs.
➢ Use: last line of therapy to treat moderate to severe essential hypertension.
➢ Side effect: excessive hair growth.
➢ Mechamism of Action: opens K+ channels on arteriolar membranes,
stabilizes membrane
COOH
CHO
+ N
H2 NH2
NH
N
O
N
N
OH
N
N
Cl
POCl3
NH2NH2.HCl
N
N
NHNH 2
2-Formyl
benzoic acid
Hydrazine
Hydralazine
N
N
+
N
OH
NH2
N
H2

17. Central Sympatholytics (α-2 Agonists)
❖Drugs: clonidine (Catapres), methyldopa
(Aldomet)
❖Site of Action: CNS medullary cardiovascular
centers
❖Mechanism of Action
✓Stimulate Alpha-2 receptors
✓decrease sympathetic activity
✓decrease epinephrine, norepinephrine &
✓Decrease renin release
✓Decrease peripheral vascular resistance

18. ❖Clonidine (Catapress)
➢A phenyl imino imidazoline derivative
➢selective α2 - adrenergic receptor agonist.
➢Use:
✓antihypertensive agent.
✓possess sedative property and used for
withdrawal syndrome of opioid analgesic.
➢Adverse effects: Dry mouth, drowsiness,
headache and constipation.
N
N
H
NH
Cl
Cl

19. ❖Methyldopa
✓Both an alpha-2-agonist and an aromatic amino
acid decarboxylase enzyme inhibitor
• Mechanism of action in the CNS is unknown
• Use: It is drug of choice for treating hypertension
during pregnancy.
CH3
NH2
COOH
O
H
O
H
L-α-Methyl-3,4-dihydroxy
phenylalanine

20. BETA-ADRENERGIC ANTAGONISTS
➢ They block the effects of endogenous and exogenous
catecholamine.
➢ These drugs slow the heart rate and decrease the force of
contraction.
➢ They competitively inhibit β – Adrenergic receptors.
➢ β-Blockers are classified into two main types:
✓ Aryl ethanol amines: eg. Isoproterenol, Dichloro
isoproterenol, Pronethalol.
✓ Aryloxy propanol amines: eg. Propranolol, Practolol,
Metaprolol, Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol
➢ Therapeutic uses of β-blockers: Used in the treatment
hypertension, coronary artery disease, arrhythmiasis
and open angle glaucoma.

21. Structure Activity Relationship
• The O-CH2 group between aromatic ring and the ethylamino side chain is
responsible for the antagonistic property.
• The catechol ring can be replaced by a variety of ring system without loss of
antagonisticactivity.
• The aromatic portion of the molecules could be varied with good activity.
Converting the aromatic portion to phenanthrene or anthracene decrease
the activity.
• Replacement of catechol hydroxyl group with chlorine or phenyl ring system
retains β-blocking activity. eg. Pronethalol, Dichloro isoproterenol.
• N, N - disubstitution decreases β-blocking activity.
• Activity is maintained when phenyl ethyl, hydroxy phenyl ethyl or methoxy
phenyl ethyl groups are added to amine as a part of the molecule.
• The most effective substituents at amino group is isopropyl and tertiary
butyl group.
O
CH2NH.R
OH

22. ❖ Atenolol
• Atenolol
➢ Use: It is a ß1 - selective drug
with low lipid solubility.
➢ Mainly used in the treatment
of essential hypertension
❖ Propranolol
➢ It is a nonselective β-adrenergic
antagonist and it has equal
affinity for β1 and β2 receptors.
➢ Effective antihypertensive agent.
➢ Used to treat arrhythmiasis,
angina pectoris, post myocardial
infarction, migraine prophylaxis
➢ Assay: UV-vis, HPLC
O NH CH(CH3)2
OH
1-(Isopropylamino)-3-(1-napthyloxy)
-2-propanol

24. Mixed α and β - adrenergic blockers
❖ Labetolol
✓ Phenyl ethanol amine derivative
✓ Competitive inhibitor of β1, β2 and α1 adrenergic receptor.
✓ more potent β antagonistthan α antagonist
✓ optically active because it has two optically active centers
✓ 1R, 1'R isomer possess β-antagonistic activity and 1S,1'R isomer possess α
-antagonisticactivity
✓ exists as a mixture of four isomers. It is the mixture that is used clinically in
treating hypertension.
✓ Properties: white or almost white powder, sparingly soluble in water and
alcohol, but insoluble in methylene chloride.
✓ Assay:Dissolve the sample in a mixture of anhydrous formic acid and
acetic anhydride. Titrate with 0.1 M perchloric acid and determine the end
point potentiometrically.

25. ❖Carvedilol
✓Both β and α- adrenergic blocking agent.
✓Only S isomer is β- blocking and both
enantiomers have α- blocking activity.

26. α- ADRENERGIC BLOCKING AGENTS
❖Drugs: Prazosin, Terazosin, Doxazosin
❖Mechanism of Action
✓Competitive antagonist at α−1 receptors
❖Site of Action- peripheral arterioles,
smooth muscle
❑Blocking α-receptors on vascular smooth
muscle allows muscle relaxation, dilation of
vessel, and reduced resistance

27. ➢ Quinazoline derivatives
➢ possesses quinazoline, piperazine and acyl moieties.
➢ The presence of 4th amino group and hetero moiety at 2nd position is
essential for α1 receptor antagonisticactivity

28. ❖Prazosin (Minipress)
➢Use: It lowers blood pressure by blocking a1 -
adrenoreceptors.
➢Adverse effects: Postural hypotension,
palpitations and lack of energy.
N
N N
N
O
O
NH2
CH3O
CH3O
1
2
3
4
5
6
7
8
1-(4-Amino-6, 7 - dimethoxy-2-quinazolinyl)-4-
(2-furanyl carbonyl) – piperazine

29. ➢Read up: antiarrythmic agents used as
cardiovascular drugs.
➢Quiz: Describe the mode and action of the
differentantiarrythmic agents used in the
treatment of hypertension.