Antihistamines

PHR215: Medicinal Chemistry-I

 Histamine H1 Antagonists

The term antihistamine historically refers to drugs that

antagonize the actions of histamine at H1 receptors.
Antihistamines competitively block histamine receptor

Histamine is an important
chemical mediator of
hypersensitivity

Histamine
 Chemistry & biosynthesis of Histamine

CH 2CH 2NH2
H N N
Ethylamine
Imidazole

Histidine decarboxylase

4 –aminoethyl imidazole
Histidine
 Properties and Action of Histamine
+NH3

HN N

At pH 7.4, histamine exists almost exclusively (96.6%) in

a monocationic form.
Most histamine is synthesized and stored in mast cells and
basophilic granulocytes
Histamine is mediated by specific cell surface receptors (H1, H2, and
H3)
 Storage and release of histamine

 Most histamine is synthesized and stored in mast cells

and basophil granulocytes.
 Histamine is released by exocytosis in response to a
variety of immune (antigen and antibody) and non-
immune (bacterial products, xenobiotics, physical effects
and cholinergic effects) stimuli.
 Histamine is released from mast cells in the gastric
mucosa by gastrin and acetylcholine.
Storage and endogenous release
of histamine
 Histamine receptors

 Once released, the physiological effects of

histamine are mediated by specific cell-surface
receptors.

 Extensive pharmacological analysis suggests the

existence of four different histamine receptor
subtypes H1, H2, H3 and H4.
 Histamine receptors
Type Location Function
H1 Found on smooth muscles, Causes vasodilation, bronchoconstriction
endothelium, and central bronchial smooth muscle contraction, separation
nervous system tissue of endothelial cells (responsible for hives),
and pain and itching due to insect stings; the
primary receptors involved in allergic rhinitis
symptoms and motion sickness; sleep regulation.
H2 Located on parietal cells Primarily stimulate gastric acid secretion
And we use antiacidic drugs for this receptor

H3 Found on central nervous Decreased neurotransmitter release:

system and to a lesser histamine, acetylcholine, norepinephrine,
extent peripheral nervous serotonin
system tissue
H4 Found primarily in Plays a role in chemotaxis.
the basophils and in
the bone marrow. It is also
found onthymus, small
intestine, spleen, andcolon.
 H1-Blocker/Antihistamine
1. Antihistamines are drugs that competitively blocks the H1
receptors.

2. Antihistamines antagonize the stimulant action of

histamine on the smooth muscles of gastro intestinal
tract (GIT), uterus, and blood vessels, and inhibit
histamine augmented salivary secretion.

3. H1-receptor antagonists have been used clinically to

treat various allergic disorders, such as seasonal or
perennial allergic rhinitis and chronic urticaria.
 M/A of H1 Antihistamine
 After the release of histamine by the mast cells, it binds with histaminergic
receptors (H1, H2, and H3) to elicit a series of events that mediates the
characteristic responses through second messenger systems.

 The histaminergic receptors are G-protein coupled type. H1 receptors are

coupled to phospholipase-C and their activation leads to the formation of
inositol phosphate (Ip3) and diacylglycerol (DAG), respectively, from
phospholipids in cell membrane.

 Ip3 causes rapid release of Ca2+ from endoplasmic reticulum. DAG

activates the protein kinase C. Altogether the turnover of Ca2+ and protein
kinase-C activates Ca2+/calmodulin dependent protein kinase and
phospholipase A2.

 The antihistaminergic (H1-antagonist) binds to the H1 receptors and decreases

the production of phospholipase-C and their activation to form IP3 and DAG

 thereby blocks the characteristic response of histamine.

M/A of H1 Antihistamine
 Clinical Uses of H1-Blockeres
• 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 H1-antihistamines)
• Sedation (first generation H1-antihistamines)
 Toxic Reaction and Side Effects of
H1 Antagonists:

1. Side effects are frequent but mild.

2. Sedation, diminished alertness and concentration, light headedness,
motor incordination, fatigue and tendency fall asleep.
3. Anticholinergic properties- dryness of mouth, alteration of bowel
movement, urinary hesitancy and blurring of vision.
4. Epigastric distress and headache.
5. Acute overdose causes excitation, tremors, hallucinations, macular
incardination, convulsions, flushing, hypotension, death.
 General Structure of antihistamines

A protonatable amine Ar1 R1

A connecting atom X which can X C C N
Ar2 R2
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.
 SAR of H1 blocker Ar1 R1
X C C N
Ar2 R2
 Ar1 and Ar2 substituents
 Ar & Ar may be phenyl, benzyl, or an isostere such as pyridyl;
Pyridyl generally results in more potent compounds than phenyl
 Para-substitution with small lipophilic groups increases potency
and decreases metabolism due to decreased ring hydroxylation
 Ortho or meta substitution reduces antihistaminic activity
substitutes aromatic group
 If fused must be non–coplanar as in the three ringed structures
related to TCA’s and phenothiazines

 This diaryl pattern is present in both first- and

second-generation antihistamines.
 Ar1 R1
X X C C N
Ar2 R2
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.
 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
SAR of H1 blocker

Ar1 R1
X C C N
Ar2 R2
Connecting Chain
 Its function is to separate the nitrogen from the rings.
 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.
 Ar1 R1
X C C N
Basic aliphatic amine Ar2 R2

 For better activity the terminal nitrogen should be tertiary amine.

i.e. must be able to accept a proton (basic) at physiological pH
 R1 and R2 : Potency order is 3° > 2° > 1°
 Quaternization does not increase antihistaminic activity but does
increase anticholinergic activity
 May be incorporated into a heterocycle which is although larger,
the heterocycle constrains
 Dimethyl is the optimum configuration
 Larger substiuents decrease antihistaminic potency due to steric
hindrance unless they are part of a heterocyclic 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 a-
Methylhistamine are equipotent as agonists
 Classification of H1 blockers
The classical H1 antagonists are divided into six classes based on
what X equals:
a. Aminoalkyl ether
Ethanolamine
Diphenhydramine
Dimenhydramine
Bromodiphenhydramine
Doxylamine
Propanolamine
Diphenylpyraline,
Clemastine

b. Ethylene diamine
- Triplennamine
- Pyrilamine maleate
- Methapyrilene
- Autazoline
c. Propylamine derivatives
- Pheniramine maleate
- Chlorpheniramine maleate
- Triprolidine HCl
- Autazoline

d. Piperazine derivatives
- Cyclizine HCl
- Meclizine HCl
- BuclizineHCl

e. Phenothiazine derivatives
- Promethazine HCl
- Trimeperazine tartate
. Second generation
o Loratidine
o Terfenadine
o Cetirizine
o Fexofenadine

Third generation
o Desloratidine
o Levocetirizine
 a. Aminoalkyl
Aminoalkyl Ethers ethers
Ar' R'
Ethanolamines and the Propanolamines
N
Ar O R
Br O
H
O CH3 O CH3 N CH3
N O CH3 N
N N
Cl
CH3 CH3
CH3 N N O

CH3

Diphenhydramine Bromodiphenhydramine Dimenhydrinate

Diphenhydramine is the first important member of this class

introduced in the year 1943 which has sedative properties
As in the previous class, para substitution with Br in
Bromodiphenhydramine yields twice as potent as the parent
compound.
Dimenhydrinate is a salt of 8–chloro theophylline (theoclate) (a
purine acid) with diphenhydramine (motion sickness)
 a. Aminoalkyl ethers

Cl

O CH3 O CH3
N N
CH3 CH3 CH3
N

Orphenadrine Carbinoxamine

Ortho methyl produces Orphenadrine an anticholinergic used as

a skeletal muscle relaxant in muscle strains and sprains, has
lower antihistaminic potency because of the orientation of the
rings.
Isosteric replacement of phenyl by a 2–pyridyl results in a slight
increase in potency but when combined with a para chloro
substituent to produce Carbinoxamine a 39 fold increase in
potency is seen.
Cl
CH3
O CH3 O CH3 O O N
N N
CH3 H3C H3C
N CH3 N
N CH3

Carbinoxamine Cl
Doxylamine Diphenylpyraline
Clemastine
 SAR 3 Several of these compounds have chiral centers where one
isomer is more potent. Thus levo (S) Carbinoxamine is 24 times as
potent than the dextro (R). This implies that the receptor must
possess a degree of asymmetry in the area where the rings bind in
order to account for this large difference in potency. Replacement
of central hydrogen by a methyl generally results in a slight
increase in potency, e.g., Doxylamine.
 SAR 4 Diphenylpyraline and Clemastine have three carbons
separating the oxygen and the nitrogen atoms thus they are
propanolamines. Lengthening the chain increases potency and
longer DoA.
 CH3
O N
O
H3C
N
CH3

Cl
Diphenylpyraline Clemastine

Clemastine is a long lasting agent with duration of action up to 12

hours. The dextrorotatory isomer is R,R at its two chiral centers. A
comparison of all four diastereoisomers indicates that the
configuration of the center close to the nitrogen is not as
important as the configuration of the center close to the rings.
Thus the order is R,R > R,S > S,R > S,S. Although a modern agent
it has sedating side effects.
Chemical Synthesis of Diphenhydramine
 Chemical Synthesis of Doxylamine

Reaction of 2-acetylpyridine with phenylmagnesium bromide gives the

tertiary alcohol. Alkylation of these as their sodium salt with dimethylamino
ethyl chloride affords doxylamine.
 Chemical Synthesis of Carbinoxamine

Synthesis is similar to doxylamine, with pyridine-2-aldehyde and 4-

chlorophenylmagnesium bromide.
 b. Ethylenediamines
 Work on H1 antagonists began in France in 1933 and in 1942 the
first clinically useful H1 antagonist was reported,
Phenbenzamine.
 It possesses two nitrogens
CH3 CH3

N N
N CH3 N N CH3

Phenbenzamine Tripelennamine

SAR 1 Isosteric replacement. 2–pyridyl produced the more potent

Tripelennamine. However, the 3– or 4–pyridyl can not be
considered isosteres and produced less potent compounds
SAR 2 Substitution.
Para substitution (Cl, Br, CH3) can increase potency.
Ortho substitution is highly undesirable
Meta substitution is either ineffective or unfavorable,

Thus introduction of a para methoxy on Tripelennamine produces

Pyrilamine, a more potent but less toxic drug

CH3 CH3

N N
N N CH3 N N CH3

H3C
O
Tripelennamine Pyrilamine

As a class the Ethylenediamines have low to moderate potency

with low anticholinergic side effects, low antiemetic effects and
moderate to high sedation.
 Chemical Synthesis of Triplennamine

Pyrilamine is synthesised by bis-alkylating 2-aminopyridine with 2

dimethylaminoethylchloride in the presence of sodium amide, followed by 4-methoxybenzyl
chloride.
 c. Propylamines
 When ArCH2(Ar)N- in ethyldiamines is replaced by Ar(Ar)CH-
moiety ， or omitted -O- in aminoether, then propylamine is there.

R'
Ar N
R
Ar'

 Compared to traditional antihistamines like ethyldiamines,

aminoethers, tricyclics ， propylamines have stronger
antihistamine action but weaker central analgesic activity.
 c. Propylamines
CH3
CH3
CH3 N
N N CH3
N N CH3
N CH3

Cl Br

Pheniramine Chlorpheniramine Brompheniramine

Prepared during 1948 to 1952, contains the most potent

classical H1 antagonists with low anticholinergic side
effects and thus are the most widely used.
 CH3

c. Propylamines
CH3
CH3 N
N CH3 N
N N CH3
N CH3

Cl
Br
Pheniramine Chlorpheniramine
Brompheniramine

Pheniramine is the prototype and is the weakest member;

Halogenation at the para position increases potency significantly,
e.g., Chlorpheniramine is 10 to 20 times more potent.
Brompheniramine is slightly more potent but long half-life (25 h).
All three drugs are chiral; the S isomers have 200 to 1000 times
greater binding to the receptor.
Pheniramine is marketed as a racemate, but Chlorpheniramine and
Brompheniramine have been resolved and are marketed both as the
racemate and in the more active S–dextrorotatory form.
 N N N
Triprolidine and Pyrrobutamine
N
have unsaturation in the
propylamine side chain and
H3 C E–Triprolidine H3 C Z–Triprolidine therefore exist as geometric
isomers.

N
N
In both cases the E isomer is more potent.
E-Triprolidne is 1000 times more potent than the
Cl Z.
Pyrrobutamine
E–Pyrrobutamine is 165 times more potent than Z.
The N–substituent is a pyrrolidino ring. It fits the structural
requirements.
Para substituents on phenyl cis to nitrogen increase potency but
decrease potency if on phenyl trans to nitrogen. Concluded that
the two aromatic groups have a different function in the interaction
with receptor
 N
N N N N
HO
N

O
H3 C E–Triprolidine H3 C Z–Triprolidine
CH3

Acrivastine

Acrivastine is a modern non–sedating agent.

It is related to Triprolidine and is slightly more potent.
The unsaturated carboxylic acid substituent is responsible for the
lack of sedation.
Non–sedating agents have difficulty in crossing the BBB
 Synthesis of Pheniramine/chlorpheniramine

Pheniramine is synthesised by reacting pyridine-2-aldehyde and phenylmagnesium

bromide to give the tertiary alcohol. Reduction of this alcohol followed by alkylation
with dimethylamino ethyl chloride in presence of sodamide affords pheniramine.
 Tricyclic H1 receptor antagonists

 If fused together the adjacent position of two aromatic ring,

tricyclic H1 receptor antagonist is there.
Y

X
N R
R'

 If X = N ， Y = S ， then phenothiazine
 If X= C, Y is replaced with bioisostere, -CH=CH- ， then
cyproheptadine .
 Further modification of cyproheptadine produce loratadine
 Loratadine
Cl

N
• Strong selective H1 receptor antagonist,
but no anticholinergic activity and central N

nerve system inhibition, belong to second O O

generation non-sedative antihistamines.

The main difference compared to other tricyclics

antihistamines, is the replacement of neutral aminoformate for
basic tertiary amine. It is believed this is the reason of its
decrease of central analgesic .
Chemical Synthesis of Azatadine

cyanoketone decarboxylation

2-chloropyridine derivative

1-methyl-4-magnesiumchloropiperidine
 Chemical Synthesis of Azatadine
 Azatadine is synthesised by reacting 1-methyl-4-
magnesiumchloropiperidine with 6,11-dihydro-5H-
benzo[5,6]cyclohepta[b]pyridin-11-one, which forms carbinol, the
dehydration of which in an acidic medium leads to the formation of
cyproheptadine.
 Cyclic ketone is prepared by acylation of the anion from
phenylacetonitrile with nicotinoyl chloride to give cyanoketone.
 Hydrolysis of the nitrile followed by decarboxylation gives ketone, and
reduction then leads to diaryl ethane. Functionality is introduced into
pyridine ring by treatment with peracid/peroxyacid followed by treatment
with phosphorous oxy chloride, and leads to the corresponding 2-
chloropyridine.
 Displacement of halogen with cyanide followed by hydrolysis gives
carboxylic acid. Cyclization by means of poly phosphoric acid yields the
ketone.
 Chemical Synthesis of Loratadine

Azatadine derivative is demethylated at N-position by reaction with

cyanogens bromide; this, followed by reaction with ethylchloro
formate, affords loratadine.
 Piperazines
 When Ar （ Ar ） CHN- replaces Ar'

ArCH2 （ Ar ） N- moiety in Ar N

N
ethylenediamine, and make two nitrogen R
atom in piperazine ring, then the
piperazines antihistamines are constructed

 Other than stronger H1 receptor antagonism effect ， they

display other characteristic ， like relieving asthma effect.
 They have moderate potency with a slow onset and prolong
duration of action, moderate sedation and low anticholinergic
effects.
 They also possess peripheral and central antinausea activity, thus
they are used as antiemetic, antivertigo and antinausea products
OH
OH

O O
O

N N
N
N N
N

CH3

Cl Cl Cl

Meclizine Hydroxyzine Cetirizine

 Cetirizine Hydrochloride
O
Cl O
N OH .2HCl
N

 Because of the easy ionization of Cetirizine, the drug is not easy

to permeate blood brain barrier (BBB) , little amount of the drug
is able to arrive central nerve system.
 It belongs to non-sedative antihistamine,
 One of the representative of second generation antihistamines.
 Synthesis of Cetirizine

Alkylation of N-protected piperazine with 4-chlorobenzhydrylchloride

followed by deprotection gives mono substituted piperazine. The second
nitrogen is alkylated with 2-chloroethoxyacetamide, followed by hydrolysis
of amide with acid to give acid cetrizine.
 Piperidines
 Limitation of the entrance to central and increase the selectivity
to H1 receptor, is the guiding ideology for design of new
antihistamine drugs. This resulted in the development of non-
sedative H1 receptor antagonists.
 Clemastine (aminoethers), Acrivastine (propylamines),
Loratadine (tricyclics), and Cetirizine (piperazines) all belong
to non-sedative H1-receptor antihistamines.
 Via the introduction of hydrophilic group, the drug is difficult
to enter CNS because of BBB, therefore the sedative effect is
overcome (weakened).
 Whilst Clemastine and Loratadine have higher selectivity to
peripheral H1 receptor, therefore avoid side effect to Centrum.
Other non-sedative antihistamine drugs belong to piperidines
selective peripheral H1-receptor antagonists.
 Mizolastine
Country of Origin : France
Originator : Synthelabo First
Introduction : Germany,
Switzerland Introduced by :
Galderma Trade Name : Mizollen

 Mizolastine was marketed in Germany and Switzerland as Mizollen for the

symptomatic relief of seasonal and perennial allergic rhinoconjunctivitis and
urticaria.
 Mizolastine is a new long-acting, orally active antihistaminic agent with a rapid
onset of action.
ANTIULCER AGENTS
 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)
 Aggravated by gastric acid (HCl) in the stomach

Therapy of ulcers
 Lower the levels of gastric acid
 -histamine antagonists and proton pump
inhibitors
 Antibacterial agents vs. H. Pylori
 H2 blockers

Physiology of acid secretion

 Gastric acid is secreted from parietal cells located
mainly in the upper portion of the stomach and is
stimulated by three endogenous substances-
– Gastrin
– Acetylcholine and
– Histamine
 The parietal cell contains receptor for-
– gastrin G , gastrin-cholecystokinin B
– acetyl choline (muscarinic, M3) and
– histamine (H2)
 H2 Receptor Antagonists
H2 receptor antagonists are commonly referred to as
H2 blockers.

Chemistry
 The H2 receptor antagonists in clinical use are histamine
congeners that contain a bulky side chain in place of the
ethylamine moiety.
 Early representatives of the group, such as burimamide and
cimetidine (prototype) retain the imidazole ring of
histamine.
 This ring is replaced in more recently developed
compounds by a furan (ranitidine) or a thiazole
(famotidine, nizatidine).
 SAR & structural requirements:
General formula for H2 antagonists:
Basic heterocycle Flexible chain/
Polar group
Group Aromatic ring

These are the result of modification of histamine structure.

The imidazole ring of histamine is not required for competitive
antagonism of histamine at H2
Separation of ring & nitrogen group with the equivalent of 4
carbon chain is necessary for optimum antagonist activity.
The terminal nitrogen group should be polar, non-basic
substituents for maximal activity.
 Cimetidine
 It is a classical drug used in the treatment of acid related
disorders.
 It acts by blocking H2 receptors, thereby inhibiting
gastric acid release.
 It also inhibits the release of pentagastrin, responsible for
the stimulation of acid release.
 The parent compound of cimetidine is histamine.
 SAR of Cimetidine
 Guanidine analogue of histamine possess weak antagonist
activity to the acid secretory activity of histamine.
 Increasing the length of side chain from 2 to 4 carbons
coupled with replacement of strongly basic guanidine group
by neutral methyl thiourea function leads to burimamide.

Burimamide

Histamine
Guanidine
 Insertion of electronegative thioether in the side chain of
methylene group increase activity

 Introduction of 5-methyl group favors H2 receptor selectivity

 Because of increased toxicity

replacing thiourea sulphur
with cyano-imino function
to give cimetidine. Metiamide

Cyano-imino function cimetidine.

 SAR STRUCTURE
NH2
HISTAMINE
H1=H2 Agonism HN N

NH2
CH3
5-Methylhistamine
H2>H1 Agonism
HN N

N-Guanylhistamine: NH C NH2
Partial H2 agonist
NH
(weak – antagonist) HN N
 CH2CH2 NH C N HCH 3
Burimamide:
Full H2 Antagonist
low potency S
HN N

CH3 CH2CH2 NH C N HCH 3

Metiamide
S
Full H2 antagonist
Higher potency S
HN N

CH3 CH2CH2 NH C N HCH 3

Cimetidine: S
Full H2 antagonist N
HN N
Higher potency CN
 CH2CH2NH2

HN
Histamine
N

H
HN C N CH3
H2
C
H3C H2 C
C H2 N C N
S

HN
N Cimetidine

H3C
O H2
H2 C H2
N C C H
S N H
H3C C N
H2 C
CH3
HC
NO2

Ranitidine
H2N
N H2
C H2 NH2
C N C
S C
H2N C
S H2
N SO2NH2

Famotidine
H3C
N H2
H2 C H2
N C C H
S N H
H3C C N
S H2 C
CH3
HC
NO2

Nizatidine
 Ranitidine
H3C
O H2
H2 C H2
N C C H
S N H
H3C C N
H2 C
CH3
HC
NO2

 Nitroketeneaminal group is essential for optimum activity

 Substitution at 2,5 position of furan ring is essential
 Replacement of sulfur by methylene decrease activity
 Replacement of S next to ring decrease activity
 Replacement of furan ring with more hydrophobic ring such
as phenyl or thiophene decrease activity
 Methyl substitution at C-4 in ring increase activity
 Methyl substitution at C-3 eliminates activity
 Famotidine
H2N
N H2
C H2 NH2
C N C
S C
H2N C
S H2
N SO2NH2

Sulfonylamidine group is not essential

4 or 5 unit chain length is required
Replacement of S by -CH2- increase activity
 Replacement of sulfur by methylene increase
activity
 Indications of H2 receptor antagonists
 Benign gastric and duodenal ulceration
 Stomach ulcer
 Reflux esophagitis
 Other conditions where reduction of gastric acidity is
beneficial
Typical Dosage
 Cimetidine 200-400 mg 2-4 x/day
 Ranitidine 150 mg 1-2x/day
 Famotidine 20 mg 1-2x/day
 Nizatidine 150 mg 1-2x/day
Synthesis of ranitidine

5-dimethylaminomethyl-2-(2′-
aminoethyl)thiomethylfuran
Synthesis of Cimetidine
Proton Pump Inhibitors
(PPIs)
 Proton Pump Inhibitors
methylsulfinyl
benzamidazole
'linker'
pyridine H
O N OCHF2 H
O N OMe
N S
N S
N
Me N

MeO OMe MeO Me Omeprazole

Pantoprazole

H Na
O N O N
N S N S
N N

O Me O Me
F3C Lansoprazole Rabeprazole
MeO

Act as prodrugs
Activated by the strongly acidic conditions found in the canaliculae
of parietal cells
 N

N N
N N
H H H

1H-Pyrrole 1H-Imidazole 1H-Pyrazole

NH
N N
N
H H
H

Pyrrolidine Pyrroline
(2-shown) Imidazolidine

H
N N
NH NH
N N
H H N N
H

Pyrazolidine Pyrazoline
(3-shown) Piperazine Pyrazine

N N N
H N N

Piperidine Pyridine Pyrimidine Pyridazine