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Medicinal Chemistry-III, Tutorial - 3
Medicinal Chemistry – III
Tutorial – 5 (Home Work)
Cardiovascular Drug Development
(Beta blockers, ACE inhibitors, Calcium channel blockers, Angiotensin II receptors Blockers)
1. The scheme below represents key stage in the optimisation of the inhibitors of Angiotensinconverting Enzyme (ACE). Write the name of each structure and briefly explain why each
modification was made in the lead optimisation process.
N
HOOC
HOOC
COOH
N
O
O
O
SH
(1)
HOOC
COOH
N
COOH
H
N
(2)
H
N
(3)
COOH
N
O
H3CH2CO
O
C
COOH
N
H
N
O
NH2
(5)
(4)
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
Answer:
N
HOOC
COOH
N
COOH
HOOC
H
N
COOH
N
O
O
O
SH
(1) Succinyl proline
(2) Captopril
HOOC
H
N
(3) Enalaprilate
COOH
N
O
H3CH2CO
O
C
H
N
COOH
N
O
NH2
(5) Lisinopril
(4) Enalapril
(1) Succinylproline is a weak but selective ACE inhibitor. The carboxyalkanoyl moiety and
(2)
(3)
(4)
(5)
the carboxyl group attached to the pyrrolidine moiety form important ionic interactions
with the zinc atom and arginine (Arg 145) respectively at the binding site of the enzyme.
As the interaction with the Zinc atom in the enzyme is very crucial, the carboxyl group of
carboxyalkanoyl moiety of succinylproline was replaced with a methylthiol group in
captopril. This increased the potency one thousand-fold due to the fact that sulphur has
greater affinity for Zinc than oxygen. Moreover, addition of methyl substituent forms
additional hydrophobic interactions with S’ pocket at the binding site of ACE and also
enhances the potency. But the thiol group (SH) was found to cause unwanted side effects
such as agranulocytosis, skin rashes and loss of taste. It has short half-life that necessitates
two or three times per day dosing reducing patient compliance.
Enalaprilate was developed to decrease side effects of captopril by replacement of thiol
group (SH) with carboxylate group (COOH). The phenethyl group forms extra hydrophobic
binding interactions with S1 pocket of the enzyme which compensates the drop in activity
as carboxylate group shows weaker interaction than a thiol group with zinc ion. But it
shows poor oral absorption and bioavailability due to the presence of 2 carboxylic acid
(COOH) groups which undergoes ionisation in the gut.
To improve the oral activity of enalaprilate a prodrug called enalapril was developed where
the carboxylic acid groups were masked by conversion to the ethylester. It has improved
oral activity and absorb well from the gut before undergoing hydrolysis back to the active
enalaprilate. But enalapril may not be a good choice of drug for patients with hepatic
insufficiency.
Lisinopril was developed similar to enalaprilate by extending the methyl substituent to an
aminobutyl substituent. Although it has 2 COOH groups, it is well absorbed in the gut
because the lysine residue in lisinopril permits peptide-mediated transport from the gut to
the portal circulation. So no enzymatic hydrolysis is required for activation as compared to
that of a prodrug (enalapril) and hence less likelihood of problems for patients with hepatic
insufficiency.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
2. What is the name and use of the following drugs? Write two (02) advantages and two (02)
disadvantages of compound-2 as compared to compound-1.
HOOC
COOH
N
COOH
N
O
O
SH
(1)
(2)
Answer:
 The compound (1) is known as succinyl proline and it can be used as an inhibitor of
angiotensin converting enzyme (ACE) for the treatment of cardiac hypertension.
 The compound (2) is known as captopril and it is also used as an inhibitor of
angiotensin converting enzyme (ACE) for the treatment of cardiac hypertension.
 Advantages: (a) Captopril has one thousand-fold more potency than succinyl proline
because sulphur has greater affinity for Zinc than oxygen. (b) Moreover, methyl
substituent forms an additional hydrophobic interaction with S1’ pocket at the binding
site of ACE which also enhances the potency.
 Disadvantages: (a) The thiol group (SH) of captopril causes unwanted side effects such
as agranulocytosis, skin rashes and loss of taste. (b) It also has short half-life that
necessitates two or three times per day dosing reducing patient compliance.
3. Write the name and clinical use of the following drugs. Briefly explain why the compound
(2) has better activity than compound (1). Write one disadvantage of the compound (2).
HOOC
H
N
(1)
COOH
N
O
H3CH2CO
O
C
H
N
COOH
N
O
(2)
Answer:
 The compound (1) is known as enalaprilate and it is used as an inhibitor of angiotensin
converting enzyme (ACE) for the treatment of cardiac hypertension.
 The compound (2) is known as enalapril and it is also used as an inhibitor of
angiotensin converting enzyme (ACE) for the treatment of cardiac hypertension.
 The compound (1) shows poor oral absorption due to the presence of 2 carboxylic acid
(COOH) groups which undergoes ionisation in the gut. Whereas the compound (2) is
the prodrug of enalaprilate (compound 1) where the carboxylic acid group is masked
by conversion to the ethylester. Hence the compound (2) has improved oral activity and
absorb well from the gut before undergoing hydrolysis back to the active enalaprilate.
 Disadvantage of compound 2: It may not be a good choice of drug for patients with
hepatic insufficiency.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
4. Which of the following angiotensin converting enzyme inhibitors (ACEIs) is considered
as the most suitable drug of choice for the oral treatment of hypertension of a patient
suffering from hepatic insufficiency? Give two (2) reasons.
HOOC
H
N
COOH
N
H3CH2CO
O
O
C
H
N
COOH
N
HOOC
O
COOH
N
H
N
O
NH2
(2)
(1)
(3)
Answer yourself
5. Which of the following beta (β) blockers can be used as a safer drug for the management
of cardiac hypertension for a patient suffering from asthma? Explain your answer from the
point of view of selectivity and improvement of CNS side effects.
Answer:
 Propranolol is a non-selective beta blocker. It blocks both β1 and β2 adrenoreceptors. It will
cause bronchoconstriction due to β2 antagonism and hence propranolol cannot be used for
the management of cardiac hypertension for a patient suffering from asthma. It also shows
CNS side effects due to high lipophilicity as it can cross BBB.
 Atenolol is cardioselective β1-blocker / antagonist. It will not cause any
bronchoconstriction as it does not antagonise β2 adrenoreceptors. Hence atenolol can be
used for the management of cardiac hypertension for a patient suffering from asthma. It is
more polar (hydrophilic) than propranolol and shows much fewer CNS effects as compared
to propranolol.
6. Which of the following beta (β) blockers CANNOT be used as a safe drug for the
management of cardiac hypertension for a patient suffering from asthma? Explain your
answer from the point of view of selectivity and CNS side effects.
CH3
CH3
O
O
H
N
H
N
OH H
CH3
H
N
OH H
CH3
NHCOCH3
Pindolol
Practolol
Answer yourself
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
1.
Which of the following statements are TRUE regarding Second-generation β-blockers?
I.
They are cardioselective β1-blocker.
II.
They can block bronchial β2-receptor and not safe for asthmatic patients.
III.
The amido group in the para position of the aromatic is capable of forming extra
H-bonding to provide selectivity for the cardiac β1-receptor.
IV.
The amido group in the ortho or meta positions of the aromatic is capable of
forming extra H-bonding to provide selectivity for the cardiac β1-receptor.
A.
B.
C.
D.
2.
Which of the following statements are TRUE regarding First-generation β-blockers?
I.
They are cardioselective β1-blocker.
II.
They can block bronchial β2-receptor and not safe for asthmatic patients.
III.
The can cause tiredness of limbs and cross the blood-brain barrier (shows CNS
effects).
IV.
They can increase the renin release at kidney.
A.
B.
C.
D.
3.
I and II only.
I and III only.
II and III only.
II and IV only.
I and II only.
I and III only.
II and III only.
II and IV only.
Which of the following statements are TRUE regarding Propranolol?
CH3
O
H
OH
N
H
CH3
Propranolol
I.
II.
III.
IV.
A.
B.
C.
D.
4.
They are cardioselective β1-blocker.
They can block bronchial β2-receptor and not safe for asthmatic patients.
R-enantiomer is the active enantiomer.
S-enantiomer is the active enantiomer.
I and II only.
I and III only.
II and III only.
II and IV only.
Which of the following binding interaction is shown by the methyl group of Enalaprilate at
the ACE binding site?
A.
B.
C.
D.
Ionic interaction with zinc atom.
Ionic interaction with Arg-145.
Hydrophobic interaction at S1 pocket.
Hydrophobic interaction at S1’ pocket.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 3
5.
Which of the following drug is a calcium channel blocker?
A.
B.
C.
D.
6.
Hydralazine
Losartan
Propranolol
Nefidipine
Which of the following ACE inhibitors is less suitable for a patient with hepatic insufficiency?
A.
B.
C.
D.
7.
Captopril
Enalapril
Enalaprilate
Lisinopril
Which of the following statements are TRUE regarding the following angiotensin converting
enzyme inhibitors (ACEIs) - A and B?
HOOC
H
N
COOH
N
O
CH3
(A)
I.
II.
III.
IV.
A.
B.
C.
D.
H3CH2CO
O
C
COOH
N
H
N
O
CH3
(B)
Drug A is a prodrug of drug B.
Drug B is a prodrug of drug A.
Drug A is more suitable for patients with hepatic insufficiently.
Drug B is more suitable for patients with hepatic insufficiently.
I and II only
I and III only
II and III only
II and IV only
Dr Pran Kishore Deb