Download Tutorial - 5: Cardiovascular Drug Development: ACE inhibitors, Beta

Medicinal Chemistry-III, Tutorial - 5
Medicinal Chemistry – III
Tutorial – 5 (Home Work)
Cardiovascular Drug Development
(ACE inhibitors, Beta blockers, 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.
HOOC
O
O
O
SH
(1)
HOOC
HOOC
COOH
N
COOH
N
COOH
N
H
N
(2)
COOH
N
H
N
(3)
O
H3CH2CO
O
C
COOH
N
H
N
O
NH2
(5)
(4)
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)
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)
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 5
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
COOH
N
H
N
H3CH2CO
O
O
C
H
N
COOH
N
HOOC
O
COOH
N
H
N
O
NH2
(2)
(1)
(3)
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.
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
7. Write the name, structures, use, side effect and mechanism of action of one (01)
PRODRUG acting as angiotensin converting enzyme (ACE) inhibitor.
8. Draw the hypothetical binding mode of interaction of enalapril inside the binding pocket
of angiotensin converting enzyme (ACE).
9. Write the name, structures, uses, side effects and mechanism of action of any two (02)
angiotensin converting enzyme (ACE) inhibitor.
10. Write the name, structures, uses and mechanism of action of any two (02) calcium channel
blockers.
11. Write the name, structures, uses and mechanism of action of any two (02) angiotensin-II
receptors blockers.
12. Write the structures, uses and mechanism of action of Hydralazine.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 5
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 - 5
5.
Which of the following drug is a calcium channel blocker?
A.
B.
C.
D.
6.
Which of the following ACE inhibitors is less suitable for a patient with hepatic insufficiency?
A.
B.
C.
D.
7.
Hydralazine
Losartan
Propranolol
Nefidipine
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
H3CH2CO
O
C
CH3
(A)
I.
II.
III.
IV.
A.
B.
C.
D.
8.
(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
Hydralazine
Losartan
Propranolol
Amlodipin
Which of the following drug is an example of ACE inhibitor?
A.
B.
C.
D.
10.
O
CH3
Which of the following drug is an example of AT1 receptor inhibitor?
A.
B.
C.
D.
9.
COOH
N
H
N
Enalapril
Losartan
Propranolol
Amlodipin
Which of the following drug can form stronger binding interaction with zinc atom at the
binding site of ACE?
A.
B.
C.
D.
Captopril
Enalapril
Enalaprilate
Lisinopril
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 5
11.
Which of the following type of interaction is shown by the thiol (SH) group of Captopril at
the ACE binding site?
A.
B.
C.
D.
12.
Which of the following AT-II receptor blockers has longest duration of action and largest
volume of distribution?
A.
B.
C.
D.
13.
Candesartan
Losartan
Telmisartan
Valsartan
Which of the following Angiotensin II receptors blockers metabolite is 10 times more active?
A.
B.
C.
D.
14.
Ionic interaction with zinc atom
Ionic interaction Arg-145
Hydrophobic interaction S1 pocket
Hydrophobic interaction S1’ pocket
Candesartan
Losartan
Telmisartan
Valsartan
Which of the following statements are TRUE regarding the given drug molecules?
O
O
O
O
A.
B.
C.
D.
15.
N N
N
N
N
N
O
O
(A)
I.
II.
III.
IV.
OH
N N
N
N
N
N
O
O
(B)
Compound (A) is a prodrug of compound (B).
Compound (B) is a prodrug of compound (A).
Compound (A) is not suitable for patient suffering from hepatic insufficiency.
Compound (B) is not suitable for patient suffering from hepatic insufficiency.
I and II only.
I and III only.
II and III only.
II and IV only.
Which of the following β-blockers is not suitable for the treatment of hypertension for a
patient suffering from asthma?
A.
B.
C.
D.
Atenolol
Practolol
Propranolol
Metoprolol
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 5
16.
Which of the following drug represents a direct acting vasodilator?
A.
B.
C.
D.
17.
Candesartan
Hydralazine
Lisinopril
Nefidipine
What is the effect of ACE inhibitors on Bradykinin?
A.
B.
C.
D.
18.
Inactivate Bradykinin and cause vasoconstriction.
Prevent inactivation of Bradykinin and cause vasodilation.
Activate Bradykinin and cause vasoconstriction.
Prevent activation of Bradykinin and cause vasodilation.
Which of the following β-blockers is most suitable for the treatment of hypertension for a
patient suffering from asthma?
A.
B.
C.
D.
19.
Atenolol
Pindolol
Propranolol
Timolol
Which of the following ACE inhibitor is NOT suitable for patient with hepatic insufficiency?
HOOC
COOH
N
H
N
H3CH2CO
O
O
C
H
N
COOH
N
HOOC
O
COOH
N
H
N
O
COOH
N
O
NH2
(2)
(1)
A.
B.
C.
D.
20.
SH
(4)
(3)
I only.
II only.
III only.
IV only.
Which of the following β-blockers are not suitable for the treatment of hypertension of a
patient suffering from asthma?
CH3
O
H
OH
N
H
CH3
CH3
CH3
O
H
N
OH H
CH3
O
O
N
NHCOCH3
(I)
A.
B.
C.
D.
H
N
N
H
H 3C
O
N
OH H
H
CH3
OH
N
H
CH3
CH3
N S
CH2CH2OCH3
(II)
(III)
(IV)
I and II only.
II and III only.
II and IV only.
III and IV only.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 5
21. Study the following drug molecules and answer the questions given below:
(A)
(B)
COOH
N
H
N
HOOC
(C)
N N
N
N
N
N
CH3
O
O
H
N
H
OH
CH3
HO
NHCOCH3
(D)
(E)
(F)
CH3
H
N
HOOC
COOH
N
O
H3CH2CO
O
C
H
N
COOH
N
O
O
H
OH
N
H
CH3
NH2
(G)
(H)
H2N
(I)
CH3
NH
COOH
N
N
N
O
H
OH
N
H
CH3
O
SH
CH2CONH2
(J)
(K)
(L)
HN
N
O
N
O
O
O
N
N
N
(M)
O
H
H3C
N N
N
N
COOH
N
H
CH3
O
(O)
O
H3CO2C
N
OH H
O
(N)
NO2
CO2CH3
H
N
O
O
H
Cl
CO2C2H5
H3CO2C
N
H
O
OH
N
H
H
N
O
N
O
NH2
OH
22. Compounds _____________ are 3rd generation β-blockers and compound ______ act as a selective
β1-partial agonist and its name is ______________________________________.
23. The name of compound (L) is _____________________________________ and it at as a
_____________________________ for the treatment of _________________________________.
24. Compounds _____________ are 2nd generation ___________________blockers.
Dr Pran Kishore Deb
Medicinal Chemistry-III, Tutorial - 5
25. Compounds ______________ are 2nd generation cardioselective β1-blocker used for the treatment
of angina and hypertension and much safer for asthmatic patients.
26. Compound/s ______________ nonselective β-blocker used for the treatment of hypertension BUT
not safer drug for patients suffering from _____________________________.
27. The name of the compound (F) is _______________________ and it ______ enantiomer is active
and it cause ____________________________, _____________________________________ and
______________ side effects.
28. Compound _______ act as a direct acting vasodilator and its name is _______________________.
29. Compound/s _____________________ is/are calcium channel blockers and its/their name is/are
_________________________________________________________.
30. The name of the compound (K) is ___________________________ and it’s a prodrug of
___________________________ which is used for the treatment of hypertension mainly in
combination with _____________________diuretics.
31. The carboxylic acid metabolite of compound ______ is 10 times more active and its name is
______________________________.
32. Compound _______ has longest duration of action (t1/2= 24 hr) and the largest volume of
distribution among all angiotensin II receptor blockers and its name is _____________________.
33. Compound ___________ act as a prodrug of ______________________ which shows
antihypertensive effect by blocking angiotensin II receptor (AT1).
34. Compounds _______ and ______ both contain two carboxylic acid groups and act as ACE
inhibitors but only compound ______ can undergo better oral absorption due to
__________________________________________ whereas compound ______ shows poor oral
absorption because ______________________________________________________________.
35. Compound _____ is a prodrug and its name is _______________________. It acts as a potent ACE
inhibitor but cannot be given to patient suffering from ___________________________________.
36. The compound ________ act as a ACE inhibitor and shows strong binding interaction with zinc as
compared to other ACE inhibitors ___________________.
Dr Pran Kishore Deb