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Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 22
ANTIULCER AGENTS
Part 1: Histamine antagonists
©1
Contents
Part 1: Histamine antagonists
1. Introduction
1.1. Ulcers
1.2. Therapy of ulcers
1.3. Parietal cells and gastric acid
release
2. Histamine
2.1. Properties
2.2. Actions
3. Classical Antihistamines
4. Histamine as a Lead Compound
5. SAR for H1 and H2 Agonists
6. Strategies for converting Agonists
to Antagonists (3 slides)
7. Na-Guanylhistamine
7.1. Biological properties
7.2. Structure and chemical
properties
continued…
8. Binding Theory for Agonists and
Antagonists
8.1. Binding regions
8.2. Binding of histamine
8.3. Binding of Naguanylhistamine
9. Chelation Binding Theory
9.1. The proposal
9.2. The evidence
9.3. Binding modes for
analogues
10. Chain Extension Strategy
10.1.
Aim
10.2.
Results
10.3.
Proposed binding for
3C extension
analogues (2 slides)
10.4.
Further evidence (2
slides)
©1
continued…
11. Distinguishing between the Polar
Binding Regions
11.1.Strategy
11.2.Rationale
11.3.Method
11.4.SK&F 91581
11.5.Comparison between the
thiourea and guanidine
groups
12. Chain Extension (2 slides)
13. The Imidazole Ring
13.1.
Structures
13.2.
Basicity
13.3.
Varying basicity
13.4.
Tautomer studies (2
slides)
14. Alternative Rationales (2 slides)
15. From Metiamide to Cimetidine (3
slides)
16. Cimetidine (Tagamet)
16.1.
Properties
16.2.
The cyanoguanidine
moiety
continued…
16.3.
16.4.
16.5.
The cyanoguanidine
moiety - tautomers
The cyanoguanidine
moiety - conformational
isomers
The cyanoguanidine
moiety - binding mode
17. Analogues
17.1.
17.2.
The urea analogue
Rigid nitropyrrole
analogue
18. Desolvation Theory
18.1.
The process
18.2.
Hydrophobic analogues
(3 slides)
19. Dipole Moment Theory
19.1.
Proposal
19.2.
Dipole-dipole
interactions
19.3.
QSAR study including
dipole-dipole interactions
20. Ranitidine (Zantac)
[53 slides]
©
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1. Introduction
1.1 Ulcers
• Localised erosions of the mucous membranes of the stomach
and duodenum
• Potentially fatal if untreated
• Caused by stress, infection (H. Pylori) and drugs (NSAIDS)
• Aggrevated by gastric acid (HCl) in the stomach
1.2 Therapy of ulcers
• Lower the levels of gastric acid
-histamine antagonists and proton pump inhibitors
• Antibacterial agents vs. H. Pylori
• Herbal remedies
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1. Introduction
1.3 Parietal cells and gastric acid release
Acetylcholine
oesophagus
Histamine
+
H2
cAMP
Parietal
Cells
Stomach
Gastrin
+
M3
+
+
+
Cck2
+
H+
Cl Stomach
HCl
Pyloric
Sphincter
Duodenum
•
Antrum
Receptors
Ion channel
Proton pump
Release of gastric acid is promoted by acetylcholine, gastrin and histamine
©1
2. Histamine
2.1 Properties
• A chemical messenger released by cells
• Acts as a local hormone
NH3

HN

Nš
NH3
N
NH
Imidazole ring
•
•
•
•
•
Two possible tautomers
pKa for the -NH2 group = 9.80.
% ionisation at pH 7.4 = 99.6
pKa for the imidazole ring = 5.74
Imidazole ring is not ionised at blood pH
©1
2. Histamine
2.2 Actions
Histamine is released by cell damage
Stimulates dilation of blood vessels with increased
permeability
White blood cells escape blood vessels and access
area of tissue damage
White blood cells combat infection
BUT
Also released by allergies, asthma, hay fever and insect bites
©1
3. Classical Antihistamines
Commonly used to treat symptoms such as inflammation & itching
MeO
NMe2
O
NMe2
N
N
Mepyramine
•
•
•
•
•
•
•
•
Diphenhydramine
Benadryl
But no effect on gastric acid release
Casts doubt on histamine receptors being present on parietal cells
Histamine may promote gastric acid release indirectly
SK&F propose two types of histamine receptor (H1 and H2)
H1 - responsible for classical actions of histamine
H2 - proposed as the receptor on the parietal cells
Claim that H2 receptors are unaffected by classical antihistamines
Implies classical antihistamines are H1 specific
©1
4. Histamine as a Lead Compound
•
No known H2 antagonist at the time - no lead compound
•
SK&F decide to use histamine itself as the lead compound
•
Aim is to alter an agonist into an antagonist
•
Compare development
adrenaline
•
Need to know SAR requirements for H2 agonists
•
Analogues tested by their ability to promote gastric acid release
•
Does not prove existence of H2 receptor
of
propranolol
(b-blocker)
©1
from
5. SAR for H1 and H2 Agonists
•
•
Two nitrogen atoms are required for H1 agonist activity
All three nitrogen atoms are required for H2 agonist activity
NH3
NH3
HN
HN
N
H1 Receptor
N
H2 Receptor
©1
6. Strategies for converting Agonists to Antagonists
•
Add extra functional groups to find extra binding interactions
with the binding site
•
Extra binding interactions may result in a different mode of
binding resulting in a different induced fit for the receptor
•
Different induced fit may fail to activate the receptor
•
A a result, analogue binds but fails to activate the receptor
•
Analogue likely to bind more strongly than an agonist
©1
6. Strategies for converting Agonists to Antagonists
Histamine
HN
N
HN
NH3
N
Receptor (Inactive)
NH3
Induced Fit - Receptor 'Switched on'
Extra
Functionality
HN
N
NH2
HN
N
NH2
Receptor (Inactive)
Different induced fit
©1
6. Strategies for converting Agonists to Antagonists
Examples - extra hydrophobic groups
NHR1R2
NHR1R2
N
N
HN
R
3
N
Results
•
•
•
No antagonist activity observed with extra hydrophobic groups
Try adding extra hydrophilic groups instead
Aim is to search for extra polar binding regions
©1
7. Na-Guanylhistamine
H
N
HN
N
NH2
Guanidine moiety
H2N
7.1 Biological properties
• Partial agonist - promotes HCl release but less strongly than
histamine
•
Prevents histamine from fully promoting the release of HCl
•
SK&F suggest that N-guanylhistamine is binding to the
proposed H2 receptor, resulting in weak activation
•
Whilst present, N-guanylhistamine blocks histamine from
binding
©1
7. Na-Guanylhistamine
7.2 Structure and chemical properties
•
•
•
The guanidine group is basic and ionised
Different tautomers are possible
The positive charge can be delocalised
H
N
HN
N
NH2
H
N
HN
HN
N
H2N
H2N
H
N
HN
N
H
N
NH2
N
H2N
NH2
H2N
The positive charge is more diffuse and can be further away
from the imidazole ring
©1
NH2
8. Binding Theory for Agonists and Antagonists
8.1 Binding regions
Antagonist
binding region
Imidazole ring
binding region
Agonist
binding region
•
•
•
•
•
Three binding regions are proposed for the H2 receptor - an
imidazole binding region and two polar binding regions
Two binding modes are proposed - one for agonists and one for
antagonists
The imidazole binding region is common to both binding modes
One of the polar binding regions is accessed by agonists and the
other by antagonists
The antagonist polar region is further from the imidazole
binding region
©1
8. Binding Theory for Agonists and Antagonists
8.2 Binding of histamine
Antagonist
binding region
Imidazole ring
binding region
NH3
HN
N
HN
N
Agonist
binding region
No interaction as an antagonist
•
•
•
•
•
Antagonist
binding region
NH3
Strong interaction as an agonist
Histamine has a short chain
Charged -nitrogen can only reach the polar agonist region
The antagonist binding region is out of range
Histamine can only bind as an agonist
Histamine acts as a pure agonist
©1
8. Binding Theory for Agonists and Antagonists
8.3 Binding of N-guanylhistamine
Antagonist
binding region
H2N
NH2
Imidazole ring
binding region
NH
HN
N
N
Agonist
binding region
Binding as an antagonist
Receptor not activated
•
•
•
HN
NH
NH2
H2N
Binding as an agonist
Receptor activated
Positive charge on the structure is more diffuse and further out
Allows N-guanylhistamine to bind in two different modes
Structure binds as an agonist in one mode and as an antagonist
in the other mode, making it a partial agonist
©1
9. Chelation Binding Theory
9.1 The proposal
H
H
N
N
HN
N
N
H
H
Strong interaction
O
H
O
Receptor
X=NH,S
SK&F propose that the guanidine moiety interacts with a carboxylate ion in the
antagonist binding region by means of two H-bonds and an ionic interaction
9.2 The evidence
S
H
N
NH2
NH2
HN
HN
N
A
NH2
N
B
X
X= SMe, Me
Structures A and B are both partial agonists, but structure A has greater
antagonist properties
©1
9. Chelation Binding Theory
9.3 Binding modes for analogues
H
S
N
HN
N
H
N
Strong interaction
H
N
N
HN
H
N
O
H
O
H
Weak interaction
O
X
O
Receptor
Positive charge is localised further out
leading to better interactions with the
antagonist binding region
•
H
Receptor
X=Me, SMe
Only one H-bond is possible with the
antagonist binding region. Charge is also
directed away from the carboxylate ion weaker antagonist property.
The chelation binding theory was eventually disproved but it
served a purpose in explaining results and pushing the
project forward on rational grounds
©1
10. Chain Extension Strategy
10.1 Aim: To push the polar guanidine group further out and to
increase the interaction with the antagonist binding region
10.2 Results:
NH2
3C Bridge
HN
N
N
H
NH2
Guanidine
Partial agonist
Antagonist activity increases
•
•
NH2
3C Bridge
S
HN
N
NH2
Isothiourea
Partial agonist
Antagonist activity decreases!
Antagonist activity of the extended guanidine analogue
increases as expected
Isothiourea analogue might have been expected to have
increased antagonist activity since the charge is further out
©1
10. Chain Extension Strategy
10.3 Proposed binding for 3C extension analogues
NH2
HN
N
NH2
N
NH
H
H
S
HN
N
NH
H
Strong interaction
O
Weak interaction
O
O
Receptor
•
O
Receptor
Different form of hydrogen bonding taking place
Compare 2C bridged analogues
H
X
N
HN
N
H
N
Strong interaction
H
O
H
O
Receptor
X=NH,S
©1
10. Chain Extension Strategy
10.3 Proposed binding for 3C extension analogues
Antagonist
binding region
NH2
HN
NH2
HN
Imidazole ring
binding region
N
HN
N
Agonist
binding region
Good binding as an antagonist
NH2
HN
NH2
Binding as an agonist
©1
10. Chain Extension Strategy
10.4 Further evidence
X
HN
N
N
NH
H
H
Partial agonists with good antagonist
activity (X= Me or SMe)
Binding mode
X
HN
N
N
NH
H
H
Strong interaction
O
O
Receptor
X=NH2, SMe, Me
©1
10. Chain Extension Strategy
10.4 Further evidence
NH2
NH2
S
HN
NH2
HN
N
N
Agonist
binding region
Poor binding as an antagonist
•
X
HN
Agonist
binding region
Good binding as an antagonist
Emphasis now switches to the types of binding interactions at
the polar binding regions
©1
11. Distinguishing between the Polar Binding
Regions
11.1 Strategy:
• Replace the ionic guanidine group with a neutral H-bonding
group
11.2 Rationale:
• May allow a distinction to be made between the two polar
binding regions.
• Ionic bonding is known to be crucial for the agonist binding
region
• It may not be crucial for the antagonist binding region
11.3 Method:
• Replace the basic guanidine moiety with a neutral thiourea
group
©1
11. Distinguishing between the Polar Binding
Regions
11.4 SK&F 91581
HN
N
Thiourea
H
N
NH2
S
No agonist activity, very weak antagonist
©1
11. Distinguishing between the Polar Binding
Regions
11.5 Comparison between the thiourea and guanidine groups
Similarities - Planarity, geometry, size, polarity, H-bonding ability
Differences - Thiourea is neutral while guanidine is basic and ionised
Thiourea
H
N
NH2
S e-withdrawing
Neutral
Guanidine
H
N
NH2
NH2
Basic
Conclusions • Agonist polar region involves ionic and H-bonding interactions
• Antagonist polar region may not require ionic interactions. H-bonding may
be sufficient
©1
12. Chain Extension
Strategy
•
Extend the carbon bridge to 4 carbons
•
Pushes thiourea group further out
•
May increase the interaction with the antagonist binding region
Results
Discovery of burimamide
HN
N
Chain extension
N
H
S
NHMe
©1
12. Chain Extension
Properties of burimamide
•
•
•
100 times more active as an antagonist compared to Nguanylhistamine
No antagonist activity at H1 receptors
Activity too low for oral use
Conclusions –
•
•
•
Chain extension leads to a pure antagonist with good activity
Chain extension allows a better overlap of the thiourea group
with the antagonist binding region
Establishes the existence of H2 receptors
©1
13. The Imidazole Ring
13.1 Structures
H
N
I

š
N
H
H
N
N
R
N
N
R
H
H
H
•
•
-H
R
N
š
N

R
II
H
III
Imidazole ring can exist as two tautomers (I) and (II) as well as
two ionised forms (III)
Which of these is preferred?
©1
13. The Imidazole Ring
13.2 Basicity
e-withdrawing
HN
CH2CH2NH3
N
Histamine
pKa = 5.74
Ionisation = 3%
HN
H
N
Imidazole
pKa = 6.80
e-donating
HN
CH2CH2CH2CH2NHCSNHMe
N
Burimamide
pKa = 7.25
Ionisation = 40%
Conclusions
• The imidazole ring of histamine is not ionised when it interacts
with the imidazole binding region
• The ionised form of burimamide is unlikely to bind well
• Decreasing the basicity and ionisation of the imidazole ring in
burimamide closer to that of histamine may increase the
binding interactions to the imidazole binding region
©1
13. The Imidazole Ring
13.3 Varying basicity
Strategy
Convert the side chain of burimamide to an e-withdrawing group
Thiaburimamide
HN
N
Electron withdrawing
S
S
N
H
NHMe
pKa = 6.25
Increase in antagonist activity
Non-ionised imidazole is favoured
©1
13. The Imidazole Ring
13.4 Tautomer studies
Tautomer I vs tautomer II
H 
Inductive effect
N
R
• Favoured tautomer for histamine is I
š
N
• Side chain is electron withdrawing
• Inductive effect decreases with distance
• Np is less basic than N
• N is more likely to be protonated
• Favoured tautomer for thiaburimamide is also tautomer I
Strategy
• Increase the basicity of N relative to Np to further increase the
percentage population of tautomer I vs tautomer II
• Add an electron donating group to the imidazole ring closer to
N than to Np
©1
13. The Imidazole Ring
13.4 Tautomer studies
Metiamide
Electron donating
HN
N
Me
S
S
Electron withdrawing
•
•
•
•
•
•
•
•
N
H
NHMe
10 fold increase in antagonist activity w.r.t burimamide
Electron-donating effect of methyl group is more significant at
N
Increases basicity of N
Favours tautomer I over tautomer II
Increase in pKa to 6.80
Increase in ionisation to 20%
Increase in the population of tautomer (I) outweighs the
increase in population of the ionised structures (III)
©1
Unacceptable side effects - kidney damage
14. Alternative Rationales
•
The increases in activity for thiaburimamide and metiamide
may be due to a conformational effect
•
The thioether link increases the length and flexibility of the side
chain
•
This may lead to increased binding
•
The methyl substituent may orientate the side chain into the
active conformation - i.e. the methyl group acts as a
conformational blocker
©1
14. Alternative Rationales
Oxaburimamide
HN
N
•
S
O
N
H
NHMe
Less potent than burimamide despite the side chain being
electron withdrawing
Possible explanations
• The ether link is smaller and less flexible
• The ether may be involved in a ‘bad’ hydrogen bond
• There may be an energy penalty involved in desolvating the
oxygen prior to binding
©1
15. From Metiamide to Cimetidine
•
•
•
The side effects of metiamide may be due to the thiourea group
The thiourea group is not a natural functional group
Replacing thiourea with a natural functional group may remove
the side effects
O
S
N
H
NHMe
Thiourea
Toxic side effects
N
H
NH
NHMe
Urea
Drop in activity
N
H
NHMe
Guanidine
Drop in activity but
no agonist activity!
Conclusions
• First guanidine analogue to be a pure antagonist
• The longer 4C chain pushes the guanidine unit beyond the
agonist binding region, but not beyond the antagonist binding
region
©1
15. From Metiamide to Cimetidine
Binding interactions for the 4C extended guanidine
H2N
NH2
NH
S
HN
N
HN
N
Agonist
binding region
S
NH
NH2
H2N
Binding as an antagonist
No binding as an agonist
©1
15. From Metiamide to Cimetidine
Strategy:
•
Retain the guanidine group
•
Guanidine is a natural group present in the amino acid arginine
•
Increase activity by making the guanidine group neutral
•
Add a strong electron withdrawing group to decrease basicity
(e.g. NO2 or CN)
Cimetidine
Me
S
HN
N
H
N
NHMe
N
CN
Electron withdrawing
cyanide group
©1
16. Cimetidine (Tagamet)
16.1 Properties
•
Comparable activity to metiamide
•
Less side effects
•
Inhibits H2-receptors and lowers levels of gastric acid released
•
Marketed in 1976
•
Biggest selling prescription drug until ranitidine
•
Metabolically stable
•
Inhibits cytochrome p450 enzymes
•
Drug-drug interactions with diazepam, lidocaine and warfarin
©1
16. Cimetidine (Tagamet)
16.2 The cyanoguanidine moiety
•
H
N
NHMe
N
CN
Acts as a bio-isostere for the thiourea group
H
N
NHMe
S
•
Both groups are planar and of similar geometry
•
Both groups are polar but essentially neutral
•
Both groups have high dipole moments
•
Both groups have low partition coefficients
•
The cyanoguanidine group is weakly acidic and weakly basic amphoteric
•
The cyanogaunidine group is not ionised at pH 7.4
©1
16. Cimetidine (Tagamet)
16.3 The cyanoguanidine moiety - tautomers
•
The favoured tautomer is the imino tautomer
H
RN
N
CN
NHMe
I
Amino Tautomer
•
•
•
N
RHN
CN
NHMe
II
Imino Tautomer
H
N
RHN
CN
NMe
III
Amino Tautomer
The electron withdrawing effect of the CN group is an
inductive effect
The inductive effect is felt most at the neighbouring nitrogen
The neighbouring nitrogen is least likely to form a bond to
hydrogen
©1
16. Cimetidine (Tagamet)
16.4 The cyanoguanidine moiety - conformational isomers
Steric
interaction
N
R
N
N
H
Me
Z,E
•
•
•
CN
N
H
H
H
N
N
R
Me
E,E
NC
CN
Steric
interaction
H
N
N
N
N
R
H
Me
R
CN
N
N
H
H
Z,Z
E,Z
Me
The E, E and Z,Z conformations are not favoured - X-ray and
nmr evidence
Bad news for the chelation bonding theory
Chelation to the one carboxylate group requires the E,E or the
Z,Z conformation
©1
16. Cimetidine (Tagamet)
16.5 The cyanoguanidine moiety - binding mode
NC
H
E,Z
NC
N
N
N
R
H
O
O
Me
Receptor
Two H-bonds are not possible
for the favoured conformations
X
H
N
N
N
R
H
Me
X
Receptor
Two separate H-bonds to 2 different
H-bond acceptors are more likely
©1
17. Analogues
17.1 The urea analogue
Me
S
HN
N
H
H
N
NMe
O
•
The preferred conformation for the urea analogue is E,E or Z,Z
•
Weak antagonist
•
Unable to bind to two different binding groups in the antagonist
binding region
©1
17. Analogues
17.2 Rigid nitropyrrole analogue
H
Me
S
HN
NO2
N
N
N
H
•
•
•
•
Unable to adopt the E,E or Z,Z conformation
Strongest analogue of cimetidine
Locked into the active conformation
Can only interact with two separate H-bond acceptors in the
antagonist binding region
©1
18. Desolvation Theory
18.1 The process
H
O
H
H
R
G
O
H
H
•
•
•
•
•
•
O
Desolvation
Energy penalty
R
G
R
Binding
Energy released
G
H
A guanidine unit is highly polar and highly solvated
Solvated water must be removed prior to binding
An energy penalty is involved
The ease of desolvation may affect strength of binding and
activity
A urea group is more hydrophilic than a cyanoguanidine group
May explain lower activity of the urea analogue
©1
18. Desolvation Theory
18.2 Hydrophobic analogues
HN
N
Me
X
S
N
H
NHMe
Aminal system (Z)
Strategy
• Increase the hydrophobic character of the planar aminal system
• Implies less solvation
• Implies less of an energy penalty associated with desolvation
• Implies easier binding and a stronger activity
Result
• Antagonist activity of analogues increases as hydrophobic
character increases
©1
18. Desolvation Theory
18.2 Hydrophobic analogues
log (Act)
‘Outrider’
.
HN
6.0
NCN
CHNO2
NHMe
NHMe
NHMe
HN
HN
.
S
..
HN
NCN
HN
NH2
NH2
5.0
N
HN
4.0
.
O
N
H
.
.
HN
-1.8
HN
. .
.
HN
NNO2
.
HN
S
NHMe
NNO2
NH2
O
N
HN
O
N
H
NHMe
O
NH2
-1.4
-0.6
-1.0
log P of HZ
Log (activity) = 2.0 log P + 7.4
©1
18. Desolvation Theory
18.2 Hydrophobic analogues
HN
N
Me
CHNO2
S
N
H
NHMe
Greater activity than expected
Hydrophilic group should
lower activity
HN
N
O
Me
N
S
N
H
N
H
Lower activity than expected
based on the hydrophobicity of the
group present
©1
19. Dipole Moment Theory
19.1 Proposal •
A dipole-dipole interaction takes places between the drug and
the binding site on approach of the drug
•
The dipoles line up and orientate the drug
•
Good interaction with the binding site occurs if the binding
groups are positioned correctly w.r.t the binding regions results in good activity
•
Poor interaction occurs if the binding groups are not
positioned correctly with respect to the binding regions - leads
to poor activity
©1
19. Dipole Moment Theory
19.2 Dipole-dipole interactions
Approach and orientation
Strong hydrogen bonding
O 2N
H
N
NMe
R
H
O 2N
H
N
NMe
R
H
Receptor
surface
Receptor
surface
Dipole
Moments
H-Bonding regions
Approach and orientation
Weak hydrogen bonding
O
N
N
H N
R
H
O
N
N
H N
H
R
Receptor
surface
Receptor
surface
©1
19. Dipole Moment Theory
19.3 QSAR study including dipole-dipole interactions
• The orientation of the dipole is more important than its strength
• Log (activity) = 9.12 cos q + 0.6 log P -2.71
q
30o
Ideal dipole
orientation
X
H
•
•
•
•
•
Observed dipole
orientation
N
N
R
H
Activity increases as hydrophobicity increases (log P)
The ideal angle of the dipole moment = 30o
At 30o, q= 0o and cos q = 1
At 30o, Log (activity) = 9.12 + 0.6 log P - 2.71
When dipole moment does not equal 30o, cos q < 1
and activity falls
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20. Ranitidine (Zantac)
Me2N
4
5
3
CHNO2
2
O
S
N
H
NHMe
•
Contains a nitroketeneaminal group
•
Different heterocyclic ring
•
Took over from cimetidine as the most widely sold prescription
drug in the world
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