LEUKOTRIENES

The leukotrienes are a family of biologically active molecules,

formed by leukocytes, mastocytoma cells, macrophages, and
other tissues and cells in response to immunological and
nonimmunological stimuli. They exhibit a number of biological
effects such as contraction of bronchial smooth muscles,
stimulation of vascular permeability, and attraction and
activation of leukocytes. Compared to histamine, which causes
constriction of airways and edema formation, the leukotrienes
are three to four orders of magnitude more potent and the
effects have longer duration. The leukotrienes were discovered
in 1938 as a smooth muscle-contracting factor in lung
perfusates. It was referred to as "slow reacting substance"
(SRS) or "slow reacting substance of anaphylaxis" (SRS-A) until
1979 when its structure was reported. The term "leukotriene"
was introduced at that time as a trivial name for the new type
of compound.
Leukotriene modifiers (leukotriene antagonists) are medicines
used to manage allergic rhinitis or allergies, as well as
prevent asthma. These novel drugs work by blocking the action
of leukotrienes. They are not used as the first mode of
treatment.
Allergies occur when the immune system overreacts and treats
an essentially harmless foreign protein as a dangerous invader
capable of causing infection. The immune system mounts a fullscale response to the triggering protein. This response involves
a cascade of inflammatory chemicals, which recruit the
involvement of other cells, and promote still more
inflammation. Symptoms of allergic rhinitis may include
swelling in the nasal passages, increased mucus production,
stuffy (or runny) nose, itching, and more.
Leukotrienes are fatty immune system chemicals derived from
dietary omega-3 and omega-6 fatty acids. They play a key role
in some of the more troubling symptoms of allergic rhinitis and
allergy-induced asthma. By binding with certain receptors on
muscle cells, they can cause the smooth muscles of the

windpipe to contract, which accounts for their role in allergyinduced asthma. Asthma patients suffer from shortness of
breath and wheezing caused by constriction of the airways.
Drugs that modify the production or activity of leukotriene are
known as leukotriene inhibitors (they are also called leukotriene
receptor antagonists or leukotriene modifiers). Some of these
drugs work by limiting the production of leukotrienes by cells
such as leukocytes (a type of white blood cell), while others
block leukotrienes from binding with their receptors on smooth
muscle cells. If the fatty signaling molecules cannot bind with
their cellular targets, they cannot trigger muscle contraction.

MONTELUKAST (SINGULAIR)

Drugs such as montelukast (Singulair) and zafirlukast (Accolate)

are widely prescribed for the treatment of exercise and allergyinduced asthma. A third drug, zileuton (Zyflo), indirectly inhibits
leukotriene synthesis, and thus is also in the leukotrienemodifier class of drugs. Singulair is also prescribed for the
treatment of perennial (year-round) and seasonal (recurring,
yet temporary) allergic rhinitis. Of course, allergic rhinitis is
characterized by stuffy, runny, or itchy nose, among other

symptoms. These drugs are usually taken by mouth, once a

day.
Leukotriene inhibitors are yet another class of drugs to be used
in the fight against allergies and allergy-related illnesses, but
they are still considered second-line treatment. Inhaled
corticosteroids are the most effective treatment, offering
comprehensive relief from the various symptoms of allergic
rhinitis, so they are considered first-line treatment. However, in
cases where patients suffer from both allergy-induced asthma
and allergic rhinitis, leukotriene modifiers may be considered
first-line treatment.
With their introduction in the 1990s, leukotriene inhibitors
became the first new class of drugs for the treatment of asthma
and some symptoms of allergic rhinitis in about 30 years.
Although inhaled corticosteroids remain the international
standard for first-line treatment of mild asthma, some studies
have shown that leukotriene modifiers provide effective
singular, first-line therapy for the control of mild asthma in
children.

Side Effects of Leukotriene inhibitors

Although they are widely prescribed, and considered relatively
safe, leukotriene inhibitors have been associated with side
effects among some users. Possible side effects listed for the
drug, Singulair, for instance, include alterations in mood and
increased suicidal thoughts.
The Food and Drug Administration (FDA) initiated an inquiry
into these and other neuropsychiatric effects in 2008. In 2009,
they concluded that existing clinical trials reveal an increased
risk of developing insomnia among users of this class of drugs,
compared to placebo.

According to the FDA, information gathered from patients after

the public release of the drugs indicates an increased risk of:
agitation
aggression
anxiety
dream abnormalities and hallucinations
depression
insomnia
irritability
restlessness
suicidal thinking and behavior (including suicide)
tremor
The FDA concluded its review by noting, neuropsychiatric
events were not commonly observed, at least not in clinical
trials, although the FDA also noted that these trials were not
specifically designed to detect such reactions. Singulair does
not interact significantly with other drugs, such as the asthma
drug theophylline.

LEUKOTRIENE ANALOGS AND

STRUCTURE ACTIVITY RELATIONSHIPS
At Zeneca Pharmaceuticals, for example, early analysis of the
structures of LTD4 and FPL 55712 led to two hypotheses: (1)
the hydroxyacetophenone region of FPL 55712 was mimicking
the olefinic region of LTD4; and (2) the chromone carboxylic
acid segment of FPL 55712 was mimicking one of the other two
regions of LTD4, either the backbone C1-C5 carboxylic acid
region or the peptidic component (Figure 1). In order to test
these hypotheses, four hybrid molecules were synthesized that
combined each region of FPL 55712 with surrogates for either
the peptidic or C1-C5 region of LTD4. An aliphatic acid structure
was one of the first compounds identified that exhibited modest
cysLT antagonist activity. In order to reduce its conformational
flexibility, an aryl group was incorporated into the structure
with a resulting increase in potency. An exhaustive structure
activity relationship (SAR) analysis concluded that addition of a

methoxy group to the aryl moiety was associated with a

modest increase in potencythe best compound was
approximately fourfold more potent and 2.5-fold more selective
than FPL 55712.
Efforts to design LT receptor antagonists based solely on
leukotriene structure faced two major hurdles: replacing the
inherently unstable triene-containing chain and converting
cysLT agonist activity into antagonist activity. Based on nuclear
magnetic resonance (NMR) (13) and molecular modeling
results, initial efforts explored replacing the unstable triene with
a set of aryl-containing groups. This led to the examination of
homo-cinnamylcontaining LT mimics (14). These compounds
acted as agonists, but subsequent variation of the peptidyl
chain led to compounds that were partial agonists or weak
antagonists (15). One of the acid moieties was then deleted to
simplify the structure and remove the potential for agonist
activity. The resulting compound was a pure antagonist,
although less potent than FPL 55712.
A number of other cysLT receptor antagonists based on the
leukotriene structure were identified and advanced into clinical
trials. The Bayer group incorporated two aspects from other
chemical series into its compoundthe homo-cinnamyl triene
replacement pioneered at Zeneca, and shortened links to the
carboxylic acids, a modification pioneered at SmithKline in the
development of pobilukast. CGP 45715A is especially
interesting, because it incorporates both the
hydroxyacetophenone and chromone carboxylic acid motifs
from FPL 55712 into a leukotriene-based lipid backbone. Of
these cysLT analog antagonists, montelukast sodium is the
most clinically advanced.
The starting point in the development of montelukast appears
to be a quinoline-containing structure, likely identified as a
weak random screening lead. The Merck group hypothesized
that this molecule was mimicking the olefin backbone of cysLTs,
and that the addition of mimics for the acid and peptide regions
of LTD4, might improve its potency. As a first step, the
dithioacetal linkage first seen in some SmithKline compounds
was incorporated; this led to a compound with greatly
increased in vitro potency but poor oral bioavailability. When
one of the carboxylic acids was replaced by an amide, forming

MK-571, the new antagonist had even greater potency and

good efficacy following oral administration. The enantiomers
were resolved to yield MK-679 (verlukast), a compound with
better clinical effects than MK-571,but whose clinical
development was stopped for safety reasons. Further structure
activity relationship studies led to the development of
montelukast, an antagonist that appears free of the safety
concerns plaguing earlier members of this series.

REFERENCES
http://www.webmd.com/
http://www.healthline.com/health/allergies/leukotriene
http://www.sciencemag.org/
http://www.atsjournals.org/