Medicinal Chemistry (DT409)

fourth year of Drug Technology

AntihistAmines

Nesrin Attiah Alhussadi

2020
 ?What is an antihistamine
• A drug that reduces or eliminates the effects mediated by the chemical
histamine.

• Histamine is released by your body during an allergic reaction and acts on

a specific histamine receptor.

• True antihistamines are only the agents that produce a therapeutic effect
that is mediated by negative modulation of histamine receptors (other
agents may have anti-histaminergic action but are not true antihistamines).

• The term antihistamine only refers to H1 receptor antagonists actually

inverse agonists

• Antihistamines compete with histamine for binding sites at the receptors.

Antihistamine cannot remove the histamine if it is already bound.
 ?What are allergies
• Allergies are caused by a hypersensitivity reaction of the antibody class
IgE (which are located on mast cells in the tissues and basophils in the
blood)

• When an allergen is encountered, it binds to IgE, which excessively

activates the mast cells or basophils, leading them to release massive
amounts of histamines.

• These histamines lead to inflammatory responses ranging from runny

nose to anaphylactic shock

• If both parents have allergies, you have a 70% of having them, if only
one parent does, you have a 48% chance (American Academy of
Asthma, Allergies and Immunology, Spring 2003).
 Allergies

Structure of Histamine

• When it is released, histamine causes

Mast Cells
inflammation by increasing

•Histamine is distributed in Mast Cells , vasodilation capillary

in all peripheral tissues of the body and musclesmoothcausing ,permeability

basophils, which circulate in the blood mucus secretion, and parasympathetic ,

nerve stimulation
 Synthesis of Histamine
■ Formed from the amino acid Histadine in a decarboxylation reaction
with the enzyme histadine decarboxylase

■ Occurs primarily in mast cells and basophils

Histamine Receptors
 Clinical Uses of Antihistamines
■ Allergic rhinitis (common cold(
■ Allergic conjunctivitis (pink eye)
■ Allergic dermatological conditions
■ Urticaria (hives(
■ Angioedema (swelling of the skin(
■ Puritus (atopic dermatitis, insect bites(
■ Anaphylactic reactions (severe allergies(

■ Nausea and vomiting (first generation H -

1

antihistamines(
■ Sedation (first generation H -antihistamines(
1
 Adverse effects
■ Associated with the first generation H1-antihistamines and due to their lack of
selectivity for the H1 receptor and anti-cholinergic activity. Side effects are
due to CNS depression:
■ Sedation
■ Dizziness
■ Tinnitus (ringing in the ear(
■ Blurred vision
■ Euphoria
■ Uncoordination
■ Anxiety
■ Insomnia
■ Tremor
■ Nausea/vomitting
■ Dry mouth/dry cough
■ Newer second generation H1-antihistamines are more selective for the
peripheral histamine receptors and have far less side effects (drowsiness,
fatigue, headache, nausea and dry mouth)
 H1-Antagonists- Classification
1stGeneration Antihistamines (Classical
antihistamines)
•Competitive inhibitors of histamine action at tissue
level.
•Binding is reversible and displaced by higher levels of
histamine.
•Additional anticholinergic activity, some possess anti-
serotoninergic activity and many of them also inhibit
neuronal uptake of norepinephrine.
•Also have local anesthetic effect, but carry risk of
irritation and sensitization.
 1st Generation Antihistamines (Classical
antihistamines(

1.Ethylene diamines

2.Ethanolamines (Aminoalkylethers)

3.Alkylamines (Propylamines)

4.Piperazines (Cyclizines)

5.Tricyclics (Piperidines)

6.Phenothiazine
 Common Structural Features of classical first
generation antihistamines
■ 2 aromatic rings, connected to a central carbon, nitrogen, or
oxygen
■ Spacer between central atom and the amine, usually 2-3
carbons in length. (Can be linear, ring, branched, saturated or
unsaturated)
■ The amine is substituted with small alkyl groups
■ Chirality at X and having the rings in different planes increases
potency of the drug
 Ethylene diamines. 1
Pyrilamine
Tripelenamine

IUPAC: N,N-dimethyl-N-(phenylmethyl)- IUPAC: N-(4-methoxybenzyl)- N-

N-pyridin-2-ylethane-1,2-diamine N',N'dimethyl- pyridin-2-ylethane-1,2-
diamine

IUPAC:N-(4,5-Dihydro-1H-imidazol-2-
ylmethyl) -N-(phenylmethyl)aniline

Antazoline
 2. Ethanolamines (Aminoalkylethers(
Doxylamine
Diphenhydramine

IUPAC: 2-(diphenylmethoxy)- IUPAC: (RS)-N,N-dimethyl-2-(1-phenyl-1-

N,N-dimethylethanamine pyridin-2-yl-ethoxy)-ethanamine

Clemastine
Orphenadrine

IUPAC: N,N-dimethyl-2-[(2-methylphenyl) IUPAC: (2R)-2-{2-[(1R)-1-(4-chlorophenyl)

- phenyl-methoxy]-ethanamine -1-phenylethoxy]ethyl}-1-methylpyrrolidine
 3. Alkylamines (Propylamines(
Pheniramine Chlorpheniramine

IUPAC: N,N-dimethyl-3-phenyl-3- IUPAC: 3-(4-chlorophenyl)-N,N-dimethyl-

pyridin-2-yl-propan-1-amine 3-pyridin-2-yl-propan-1-amine

Phenindamine
Triprolidine

IUPAC: 2-[(E)-1-(4-methylphenyl)-3- IUPAC: 2-methyl-9-phenyl-2,3,4,9-

pyrrolidin-1-yl-prop-1-enyl]pyridine tetrahydro-1H-indeno[2,1-c]pyridine
 4. Piperazines (Cyclizines)
Chlorcyclizine
Cyclizine

IUPAC: 1-benzhydryl-4-methyl-piperazine IUPAC:1-[(4-Chlorophenyl)(phenyl)

methyl]-4-methylpiperazine

IUPAC: (RS)-1-[(4-chlorophenyl)(phenyl)methyl]-
4-(3-methylbenzyl)piperazine

Meclizine
 Hydroxyzine

IUPAC: (±)-2-(2-{4-[(4-chlorophenyl)-phenylmethyl]
piperazin-1-yl}ethoxy)ethanol

Buclizine
IUPAC: (RS)-1-[(4-chlorophenyl)- phenyl-methyl]
-4- [(4-tert-butylphenyl) methyl] piperazine
 5. Tricyclics (Piperidines(
Cyproheptadine Azatadine

Ketotifen
 Phenothiazine .6
Trimeprazine
 2nd Generation Antihistamines
 Antagonists at H1 receptors
 Competitive antagonists though some are
noncompetitive at higher doses
 High therapeutic index
 Poorly lipophilic - do not readily traverse blood
brain barrier
 Highly selective with little or no anticholinergic activity
 Additional anti-allergic mechanisms of some, like
inhibition of late phase allergic reaction by acting on
leukotrienes or anti platelet factor activating effect
Ethylenediamines
Acrivastine

IUPAC: (E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidin-
1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoic acid

Piperazines
IUPAC: (±)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-
piperazinyl]ethoxy]acetic acid

Cetrizine
Piperidines
Terfenadine

IUPAC: (RS)-1-(4-tert-butylphenyl)-4-{4-[hydroxyl
(diphenyl)methyl]piperidin-1-yl}-butan-1-ol

Astemizole

IUPAC: 1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl)
ethyl]-4-piperidyl]benzoimidazol-2-amine
 IUPAC: Ethyl4-(8-chloro-5,6-dihydro-11H- benzo
[5,6]Cyclohepta[1,2-b]pyridin-11-ylidene)
-1- piperidinecarboxylate

Loratadine
 3rd Generation Antihistamines
Levocetrizine

Desloatadine

IUPAC: 2-(2-{4-[(R)-(4-chlorophenyl)(phenyl) IUPAC: 8-chloro-6,11-dihydro-11-

methyl]piperazin-1-yl}ethoxy)acetic acid (4-piperdinylidene)- 5H-benzo[5,6]
Cyclohepta [1,2-b]pyridine

Fexofenadine

IUPAC: (±)-4-[1 hydroxy-4-[4-(hydroxyl diphenylmethyl)-1-

piperidinyl]-butyl]-a, a-dimethyl benzene acetic acid hydrochloride
 SAR
Ar1 R1
X C C N
Ar2 R2

 A protonable amine

 A connecting atom X which can be O, C or N

 A carbon chain, usually ethyl

 Variations in the diaryl groups, connecting moiety, substituents on

the connecting moiety, and substituents on the terminal nitrogen
account for the differences observed in potency as well as
pharmacologic, metabolic, and adverse reaction profiles.
■ Ar1 and Ar2 substituents

 These provide bulk producing antagonistic activity

 Generally two aromatic rings - phenyl, benzyl, or an isostere such

as pyridyl; Pyridyl generally results in more potent compounds
than phenyl

 If fused must be non–coplanar as in the three ringed structures

related to TCA’s and phenothiazines

 Para substitution with small lipophilic groups increases potency

and decreases metabolism due to decreased ring hydroxylation.

 Ortho or meta substitution reduces antihistaminic activity

 This diaryl pattern is present in both first- and second-generation
antihistamines.

 Atom X can be an oxygen, nitrogen, or carbon, which links the side

chain to an “aromatic tail.” The nature of atom X is the basis for
the structural classification of H1 antagonists. The classical H1

antagonists are divided into six classes based on what X equals:

 X =C–O: (Aminoalkyl Ethers(

1. Ethanolamines

2. Propanolamines (clemastine, diphenylpyraline(

 X = C:

3. Propylamines (Saturated and Unsaturated(

■ X = N:

4. Ethylenediamines

5. Piperazines (Cyclizines) and Tricyclics

6. Miscellaneous: This forms the sixth class of traditional antihistamines

and would include many of the newer antihistamines since they do
not fall into one of the older, traditional, classes

Connecting Chain

■ Its function is to separate the nitrogen from the rings by 5–6 Å

■ May be saturated, unsaturated, branched or part of a ring

■ Branching decreases antihistaminic potency except for the phenothiazines

where β carbon branching increases antihistaminic potency.
Basic aliphatic amine

 Must be able to accept a proton (basic) at physiological pH

■ R1 and R2 : Potency order is 3° > 2° > 1°

 Quaternization does not antihistaminic but

does
increase increase anti-cholinergic

 activity
May be incorporated into a heterocycle which is although larger,
the heterocycle constrains

 Dimethyl is the optimum configuration

 Larger substituents decrease antihistaminic potency due to steric

hindrance unless they are part of a heterocycle structure when
the ring constrains the two ethyls so they are still active
 Receptor Interaction
■ The H1 antagonists do not occupy the same area or space as the natural

receptor substrate

 Only the protonated nitrogen binds the same anionic site as Histamine

 The aromatic tail binds adjacent to the Histamine binding site thus
produces the nonspecific conformational perturbation of the receptor.
This changes the shape of the receptor decreasing the affinity for
Histamine

 It seems that sites outside may be chiral because steroselectivity is

observed with some H1 antagonists

 As previously discussed the optical isomers of α-Methyl histamine are

equipotent as agonists
 Histamine H2-Antagonists
H
■ Guanylhistamine provided the lead. CH2CH2 N C NH2
NH
■ Extension of the side chain increased anti H2 potency but a HN N
Guanylhistamine
some agonist activity remained. Replacing the basic H
CH2CH2CH2 N C NH2
guanidino group with the neutral thiourea yielded
S
effective H2 antagonists. b HN N SK&F 91581
H
 Burimamide lacked agonist action but was not orally CH2CH2CH2CH2 N C NH2
S
absorbed c HN N SK&F 91863
 In Metiamide (1) reduce the pKa of the ring N, reduced CH2CH2CH2CH2 N C NHCH3
ionization, increased membrane permeability and S
H
d HN N Burimamide
absorption and 10X more potent than Burimamide, (2)
H
cause the t tautomer to predominate which interact with H3 C CH2–S–CH2CH2 N C NHCH3
H2 e HN N
S
Metiamide
 But caused kidney damage and granulocytopenia, H
H3 C CH2–S–CH2CH2 N C NHCH3
possibly due to the thiourea so was replaced by the NH
f HN N
isosteric guanidine. This compound being highly basic
H
was 20 times less potent H3 C CH2–S–CH2CH2 N C NHCH3

 HN N Cimetidine ™
N
CN
Replacement of this group with strong electron
g withdrawer but more lipophilic cyano derivative yielded I
Cimetidine.
 SAR
H H
H3C
S N N CH3
NH N
Cimetidine C
N N
 Need an aromatic ring with n electrons next to the side chain. The imidazole
ring is not required (the other H2 antagonist don’t have it) but if it is present the
t tautomer should predominate. The t tautomer is promoted by electron donors
at position 5 and electron withdrawers at position 4.
 The terminal nitrogen group should be polar but not basic for maximal potency
 Separation of the ring from the nitrogen group by 4 atoms gives maximal
potency.
 Cimetidine is an extremely successful drug in the treatment of ulcers.
 Note the electron donor methyl at C5 and electron withdrawing side chain at C4
Also the non basic cyano guanidine terminal nitrogen group.
 However, cimetidine has several disadvantages. It is an inhibitor of CYP, which
leads to many drug–drug interactions. It exhibits anti-androgenic action and can
cause gynecomastia. Further it has 60 to 70% oral bioavailability.
Ranitidine is a furan derivative, an isostere of the H H
S N N CH3
imidazole with n electrons on the oxygen, with 50%
O H
C NO2
bioavailability. It is 4 - 10 X potent than Cimetidine with a
CH3
N
longer DoA. Further, it is a weaker CYP inhibitor. The
CH3 Ranitidine
tertiary amine side chain allows the formation of salts.
SO2NH2
Famotidine, a thiazole derivative, is 9–15 X potent than N
H
S N
Ranitidine or 40–60 X than Cimetidine. No cases of H
S N
gynecomastia have been reported. It is a weak inhibitor of
N NH2
CYP. Like Ranitidine salts can easily be prepared for this
NH2
compound. but its absorption is incomplete with only 40 Famotidine

to 50% bioavailability. H H
S N N CH3
Nizatidine is also a thiazole derivative similar to
S N HC
NO2
Ranitidine (5–18 X Cimetidine), but more bioavailable,
CH3
N
90%, with no antiandrogenic or enzyme inhibition.
CH3 Nizatidine
 Histamine H2 Receptor Interaction
 Cationic Histamine binds to the receptor via the formation of three hydrogen bonds

 The cationic nitrogen and t–nitrogen of the imidazole ring are hydrogen donors and
the p–nitrogen acts as a proton acceptor

 Participation of the ammonium group in the hydrogen bonding inevitably leads to a

decrease of the positive charge on the ammonium group

 This decrease in positive charge induces a tautomeric change in the imidazole ring
resulting in a stronger binding of the p–nitrogen and proton release by the t–
nitrogen

 The net result is a proton shift at the receptor surface which is believed to trigger

the H2 stimulating effect

 This mechanism calls for the presence of a hydrogen atom in position 3

of histamine, and recall that 3–methylhistamine is unable to stimulate the receptor.
 H3-Receptor Antagonists
 Potential for treating asthma, migraine, hypertension, septic shock, and
in learning and memory degenerative disorders like AD

 Thioperamide and its congeners (4(5)-substituted imidazole derivatives) are

examples of the potent and selective H3 receptor antagonist

■ Some of the more prominent new H3 receptor antagonists are GT-2016, and GR-

175737, which show receptor affinities in the low nanomolar range.

 None of this class of compounds is in clinical use; however, few are undergoing
further pharmacologic evaluation as potential therapeutic agents.
Cl
S O

N NH N N
O

N
HN N HN N HN N
GT-2016
Thioperamide GR-175737