hon, thomas - COSMOS - UC Davis

Thomas Hon
COSMOS UC Davis
Cluster 8: The Chemistry of Life
August 5, 2011
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Astemizole:
Reducing
its Potency and Serious
Cardiac Side Effects

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Abstract
Two new drugs were designed based off the framework of the original to improve
its functionality in the human body. The original drug is an antihistamine called
astemizole that relieves allergies. The main concern with astemizole is that it can
potentially induce serious cardiac effects to the body that may lead to death. The drug
was altered two different ways to provide probable solutions to lower its potency and
prevent cardiac problems from occurring. Astemizole and its two analogs were drawn out
on ChemDraw Ultra and Chem3D Pro to show their unique spatial and structural
arrangements. Lipinski’s rules were used to see how well the analogs could be absorbed
by or permeate through the body. Both analogs only met three out of the four rules. The
analogs did not meet the requirement of having partition coefficients no greater than 5.
Nevertheless, the analogs are appropriate because they both have a lower partition
coefficient than astemizole, which also had a partition coefficient above 5. Computersimulated
programs will be needed to confirm the binding abilities of the analogs to
receptors before the analogs can be synthesized and tested on living organisms.
Introduction
Astemizole is a second-generation antihistamine that relieves seasonal or yearround
allergies. The label “second-generation” is attributed to astemizole because it does
not cross into the central nervous system (CNS) like most first-generation antihistamines
do. Instead, astemizole only binds to the peripheral nervous system (PNS), targeting

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many of the body’s organs, including the stomach, intestines and uterus (“Astemizole
Hismanal”). The absence of astemizole from CNS leads to fewer adverse side effects
(Simons and Simons). Second-generation antihistamines also selectively bind better than
those from the first-generation. First-generation antihistamines often activate many
receptors in the body that produced unfavorable effects, such as epistaxis, anorexia, and
dysuria. Second-generation antihistamines cure this problem by latching onto fewer
receptors. Ultimately, most antihistamines target the histamine H1 receptor, the protein
receptor that is responsible for allergies (“Antihistamines, H1 Receptor”).
Astemizole functions by binding to the H1 receptor in place of histamine through
competitive inhibition (Simons and Simons). As a result, histamine is blocked from
binding to its own receptor. This process results in the inability of bodily cells to accept
histamines. Since histamine is the firebrand of allergies, fewer allergies occur when
antihistamines bind to receptors in the body. Therefore, less irritation occurs in the
respiratory tract of the human body and allergies are alleviated (“Antihistamines, H1
Receptor”).
Janssen Pharmaceutica discovered astemizole in 1977. Branded under the name
Hismanal, it was first introduced to North American markets in the mid-1980s
(“Astemizole Hismanal”). Early studies showed that astemizole was similar in efficacy to
other similar antihistamines at that time, but also had the added benefit of not causing
drowsiness in patients (Richards). Troubling signs with the use of this product, though,
arose as time wore on. The main concern with this drug was that it triggered Torsades de

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Pointes (TdP) in multiple patients, a potentially fatal form of ventricular tachycardia.
(Simons et al.). Ventricular tachycardia is a type of heartbeat irregularity called
ventricular arrhythmia that occurs when the ventricles of the heart start beating faster
than usual but at a normal pace. However, as time passes, the heart changes in the QT
interval, or the time it would take for the ventricles to contract (ventricular
depolarization) and recover (ventricular repolarization). This prolongation of the QT
interval leads to an extended period of ventricular repolarization, meaning that the flow
and timing of ions that cross the myocardial (the heart's muscular tissue) cell membranes
are disrupted. (“Ventricular Tachycardia”). During repolarization, these myocardial cells
are usually resistant to electrical current, but when the ventricular repolarization is
extended, these myocardial cells are more susceptible to electrical current. When
myocardial cells are hit by an electrical current during repolarization and premature
ventricular depolarization occurs, TdP is triggered (Dulak). Since there are varying
degrees of TdP, it may be fatal or non-fatal and can sometimes be treated effectively with
medication.
Written reports of TdP activated by astemizole in the human body started
appearing in medical journals a few years after the drug was introduced on the market. In
1988, a 15 year-old girl in England had two episodes of TdP after collapsing outdoors.
She had taken one tablet of astemizole 10 mg daily, the recommended dose, for ten
weeks. She and her family had no history of cardiac problems or sudden death. After
being admitted to intensive care, she continued to have a prolonged QT interval until TdP
struck her five hours later. She was treated with appropriate anti-arrhythmic drugs

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immediately after TdP hit her and did not exhibit a reoccurrence of TdP after treatment.
Her QT interval returned to normal in six days (Simons et al.).
Another incidence, though non-TdP, appeared five years later. A 19 year-old
woman suffered cardiac arrest while swimming. She had taken 20 mg of astemizole,
twice the recommended dose, for several weeks because of hay fever. Her QT interval
was prolonged, and stayed prolonged even after two months with a slightly high QT
interval of 0.463 seconds. Although she had no family history of sudden death, her father
and sister had long QT syndrome. Therefore, the 19-year old was postulated to have
suffered from congenital long QT syndrome. However, astemizole likely aggravated her
QT interval to dangerous levels near the point of possible TdP. Luckily, TdP did not
strike her (Broadhurst). Both cases showed that astemizole was a primary factor in
inducing extreme cardiac problems.
Multiple cases of TdP and/or prolonged QT interval after ingestion of astemizole
prompted government agencies to issue warnings about the intake of the drug. The
Committee on Safety of Medicines, a British regulatory agency, issued a warning about
astemizole in 1992 because of its potential to cause ventricular arrhythmias, or
irregularities in heartbeat (Simons et al.). In February 1998, the US Food and Drug
Administration (FDA) issued a warning stating that Hismanal (astemizole) could pose a
fatal risk to patients with irregular heart rhythms. The FDA also ordered some changes to
Hismanal's label to reflect concerns about the antihistamine's reaction with other drugs.
The FDA's warning and the accumulation of adverse reports and warnings on astemizole
may in part have led Janssen Pharmaceutica to voluntarily withdraw it from the market

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permanently in 1999 (“US Janssen”). Hismanal has not been remarketed since in the
United States.
Astemizole has the chemical formula C 28 H 31 FN 4 O and is created synthetically.
This drug is readily absorbed from the gastrointestinal tract, metabolized by
hemoproteins in the liver called Cytochrome P450, and excreted in the feces
(“Hismanal”). Its Chemical Abstracts Service name is 1-[(4-Fluorophenyl)methyl]-N-[1-
[2-(4-methoxyphenyl)ethyl]-4 piperidinyl]-1H-benzimidazol-2-amine. It exists in the
solid form of a white crystalline powder. It is insoluble in water and soluble in most
organic solvents such as chloroform or methanol. The molar mass of astemizole is
458.57 g.
F
N
H
N
N
O CH 3
N
Fig. 1. Structure of Astemizole in 2D
Hypotheses
The replacement of the element fluorine with chlorine or the methyl group with
carboxylic acid on astemizole will decrease the potency of the drug and prevent
ventricular arrhythmias, specifically QT interval prolongation or TdP, from occurring in
patients.

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Methods
The ends of astemizole looked the most promising for improvement. Background
information on elements and their binding properties was collected, and the hypotheses
listed above were put into drawings via computer software. ChemDraw Ultra 10.0 was
used to develop two-dimensional representations of astemizole and its analogs. Chem3D
Pro 10.0 was used to create the previously mentioned figures in three dimensions. On
Chem3D Pro, the structure was drawn first. Then, MM2 was run to optimize the structure
and minimize its energy. The “calculate properties” feature was executed by using
ChemPro inside Chem3D Pro software. This allowed the Log P values of the analogs to
be calculated. Finally, CCDC Conquest 1.13 provided a standardized three-dimensional
version of astemizole from the Cambridge Structural Database (CSD). Comparisons of
the CSD structure to the one created in Chem3D Pro were done to find differences in
conformations, bond length, and bond angles between the different models of astemizole.
The first analog of astemizole consisted of a chlorine instead of a fluorine (Fig. 2).
Although the addition of fluorine onto the original drug allowed for an effective drug in
relieving allergies, the potent property of fluorine probably contributed to the drug’s
possible fatal side effect of TdP. One study on an inhibitor found that the inhibitor
without the fluorine was six times less potent than the one with fluorine (Bohm et al.)
Another study showed that the introduction of fluorine substituents increased the potency
of drugs ten-fold on average compared to the same drugs without fluorine (Purser et al.)
Fluorine also forms a strong binding affinity with its target protein, the H1 receptor, but
the attachment may be too strong. The binding of most H1 antagonists is readily

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reversible. However, astemizole does not readily dissociate from H1 receptors (Simons
and Simons). The glue-like binding of astemizole with its receptor is usually a favorable
condition because a tighter adhesion means that the drug can exert a greater amount of
potency. Astemizole, with its ability to stick firmly onto the H1 receptor protein, can
effectively block histamine from binding to the H1 receptor. Therefore, the consumer can
be administered a lower dosage of astemizole for allergy relief. However, too much
potency may contribute to adverse side effects. As with the case of astemizole, QT
interval prolongation may lead to TdP, a deadly case of cardiac arrest.
Cl
N
H
N
N
O CH 3
N
Fig. 2. First Analog: Structure of Astemizole with Chlorine instead of Fluorine in 2D
Chlorine is a viable alternative to fluorine because it has a lower electronegativity
than fluorine, meaning that it will not bind as strongly to the H1 receptor protein. A
slightly looser bond between astemizole and receptor will lower the potency of
astemizole. Chlorine also has a lower bond dissociation energy (BDE), a measure of bond
strength, than fluorine with carbon. Carbon bonded to fluorine has a BDE of 536 kJ/mol
while carbon bonded to chlorine has a BDE of 397 kJ/mol. A lower BDE corresponds to
a weaker bond. Comparing the two BDEs, the carbon-chlorine (C-Cl) bond will

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dissociate quicker. The faster dissociation of the C-Cl bond will allow Cl to react quicker
in the body to fight off histamines and lower astemizole’s toxicity by getting out of the
body faster. Although chlorine may exhibit stronger inhibitory activity than that of
fluorine in antihistamines, this hypothesis is countered by two currently marketed
antihistamine drugs in the United States that contain chlorine (Netter and Bodenschatz).
Cetirizine (Zyrtec) and Azelastine (Astelin) both have chlorines attached to benzenes
attached to carbon chains similar to that of the first analog. However, neither Zyrtec
(“Cetirizine”) nor Astelin (“Azelastine”) show side effects of QT interval prolongation or
TdP. The chlorine in both of these drugs do not justify the above findings and shows that
it poses little to no harm to the cardiovascular system. Replacing the fluorine with a
chlorine will also not change the molecular structure much; the other parts of the
molecule will likely have the same interactions with the H1 receptor as before. All these
aspects of the analog will reduce it from causing TdP or QT interval prolongation.
An aspect that is not often considered is the net economic benefit of chlorine
chemistry, or drugs that contain chlorine. Consumers save about $450 billion per year by
buying drugs produced by chlorine chemistry, with the estimate based on the increased
cost of maintaining health without the benefit of chlorine-containing drugs (“Chlorine
Chemistry”). The replacement of fluorine with chlorine in astemizole can potentially
erase its deadly side effects as well as allow astemizole to be more affordable for
consumers.

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Fig. 3. First Analog: Structure of Astemizole with Chlorine instead of Fluorine in 3D
The second analog of astemizole contained a carboxylic acid instead of the methyl
group (Fig. 4). A new area of research is developing where nanoparticles are used in drug
delivery systems. These nanoparticles help the drug target specific areas it is intended for.
Precise targeting can lead to less toxicity within the bodily system. In a recent study,
magnetic nanoparticles containing modified carboxyl groups were successfully produced
and hypothesized to be practical for use in drug delivery systems (Hiroki et al.). Since
carboxyl groups are potentially effective components for drug delivery, and drug delivery
is used to lower drug toxicity, carboxyl groups like carboxylic acids can potentially
reduce astemizole’s toxicity within the human body.

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F
N
H
N
N
O
COOH
N
Fig. 4. Second analog: Structure of Astemizole with Carboxylic Group instead of Methyl
Group in 2D
Astemizole not only binds to H1 receptors, but also inadvertently binds to H3
receptors. H3 receptors that are stimulated significantly reduce the incidence and duration
of ventricular fibrillation, a possible fatal result of TdP or QT interval prolongation (Levi
and Smith). However, astemizole increases the risk of lethal cardiac side effects (“Second
Generation”). Astemizole may need improved binding conditions surrounding the H3
receptor to stimulate it. The carboxylic acid in my second analog allows it to act as a
buffer when deprotonation occurs (Fig. 5), regulating the pH of the binding site of the
protein. The buffer may control the drug from inflicting its large potency on the H3
receptor. The controlled pH environment will allow a greater chance for the H3 receptor
to be stimulated and astemizole to properly bind. Deprotonation of carboxylic acid will
also allow charges to be balanced in the body and H+ ions to counteract or lower the
potency of the highly electronegative fluorine molecule on the second analog. The
regulatory effects of this analog will likely hamper its ability to induce cardiac
irregularities.

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Fig. 5. Deprotonation of Carboxylic Acid
Fig. 6. Second analog: Structure of Astemizole with Carboxylic Group instead of Methyl
Group in 3D
Results
The modified versions of astemizole may be viable drug candidates. For a drug to
likely function effectively in the body, Lipinski’s Rules of Five are used as a guide. They
measure how well the body can absorb the drug or allow it to permeate. The rules state
that in each drug, the number of hydrogen bond donors cannot exceed 5, the number of
hydrogen bond acceptors cannot exceed 10, the octanol to water partition coefficient log
P cannot exceed 5, and the molecular weight cannot exceed 500 g/mol. After evaluating
astemizole and two other analogs, all three drugs have much fewer than five H bond

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donors and fewer than ten H bond acceptors (Table 1). The three drugs have molecular
weights over 450 g/mol, but they all fit within the 500 g/mol limit set by Lipinski. One
area of astemizole that contradicts Lipinski’s Rules is its partition coefficient. Astemizole
has a Log P of 5.74, which is over the Log P of 5 set by Lipinski. The other two analogs
also have a Log P over 5 (Table 2). However, the Log Ps of these analogs are lower than
astemizole’s. All these factors evaluated about the analogs of astemizole signify that they
are likely to work well in the body. Since experiments have not been performed on these
analogs, they will have to be thoroughly tested to see if they are effective in performing
the same function as astemizole but with less serious side effects.
# of H Bond
Modification
Donors
# of H Bond Acceptors
Astemizole 1 5
Astemizole with Cl instead of F 1 5
Astemizole with COOH instead of
CH3 2 7
Table 1. Number of hydrogen bond donors and acceptors listed for astemizole and two
novel analogs.
Modification Log P Molecular Weight
Astemizole 5.74 (from internet) 458.57 g/mol
5.648
Astemizole with Cl instead of F (from Chem3D Pro) 475.08 g/mol
Astemizole with COOH instead of
CH3
5.283
(from Chem3D Pro) 488.61 g/mol
Table 2. Partition coefficients Log P and molecular weights shown for astemizole and
two novel analogs.

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The structure of astemizole from the Cambridge Structural Database (CSD) in
CCDC Conquest (Fig. 7) was also compared to the 3D figure of astemizole created using
Chem3D Pro (Fig. 8). Astemizole created with Chem3D looks much more planar than
and not as angular as the one from CSD. The bond lengths in CSD are shorter than the
ones in Chem3D, and bond angles in CSD appear to be wider than those on Chem3D.
The minimizing energy program in Chem3D allowed astemizole’s conformations to be
positioned in the most desirable away. However, this may cause astemizole to act
differently in the body. More thorough research will have to be done to see which models
of astemizole (ex. from Chem3D and CSD) bind better to the histamine H1 receptor.
Fig. 7. Structure of Astemizole from Cambridge Structural Database (CSD) in CCDC
Conquest 1.13

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Fig. 8. Structure of Astemizole in 3D
Discussion
The two analogs created provide alternatives to the potentially deadly drug of
astemizole. Many benefits may be associated with the alterations made to the analogs, but
setbacks may arise during experimentation. The new element or group substituted in for
the original may react or bind differently in the body, or exhibit other adverse side effects
that are more powerful than those of astemizole. Advanced computer simulation software
can be used to see how well the analogs bind to the H1 receptor or other histamine (H2-
H4) receptors. If the analogs bind well enough, the drugs will have to be synthesized and
tested through the three main phases of clinical trials. Repeated testing of the analogs
inside living organisms will be necessary to make sure that the analogs are effective in
blocking histamine and safe to use. The tests will provide helpful feedback on the
absorption, distribution, metabolism, excretion, and toxicity of the analogs.
Antihistamines have a large influence on many people's daily lives. Pharmacies as
well as many websites are making them available to consumers in large quantities. The
estimated worth early in 2011 of the world antihistamine market was about 4.2 billion
euros, or 5.45 billion in U.S. dollars (“Orexo”). The significant market value of this

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product around the world illustrated the mass amount of people purchasing these drugs to
alleviate their allergy symptoms. In the first decade of the 21 st century, the FDA approved
of many histamines to be sold over-the-counter, such as Claritin (“FDA Sends”) or Zyrtec
(“FDA Approves”). The switch from prescription to over-the-counter has made
antihistamines more accessible to the American public and allowed these medications to
drop in prices to attract consumers to purchase them. Currently marketed antihistamines
in the U.S. approved by the FDA are generally safer to take than those marketed in the
past. However, older ones like astemizole were stepping stones to the development and
creation of improved ones that exhibit fewer side effects and greater effectiveness.
Recent developments on the molecular level have allowed scientists to discover
more detailed information receptor proteins in the body. In late June 2011, scientists
solved the three dimensional crystal structure of the human Histamine H1 receptor
protein by growing crystals. The discovery will provide scientists a better understanding
of how the receptor works and interacts with its environment (“Human Histamine”).
More research and development into antihistamines, specifically how they adapt and bind
to receptors, will provide a deeper understanding into how their side effects can be
minimized.

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Acknowledgments
I would like to thank Professors Allen, Guo, and Mascal for giving lectures that
advanced my scientific knowledge and answering my questions, teacher assistants
Asuman, Slava, and Zane for answering my questions and helping me in labs and on how
to use chemistry computer software, Professor Tantillo for explaining the considerations
that go into making drugs, teacher fellow David for giving me feedback on my research
project, and my parents for their constant encouragement and support.

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