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MOLECULES AND MEDICINE

ACETYLSALICYLIC ACID (ASPIRIN™)

Structural Formula Ball-and-Stick Model Space-filling Model

Year of discovery: 1897; Year of introduction: 1899 (Bayer); Drug category: Non-steroidal anti-
inflammatory drug (NSAID); Main uses: Treatment of pain, inflammation and fever; also as an
anticlotting agent for the prevention of heart attack. Approximate number of people using the drug
regularly: Over 100 million; Related drugs: \buprofen (Advil), Naproxen (Aleve), Celecoxib
(Celebrex), Clopidogrel (Plavix).

The acetyl (CH3;CO) derivative of salicylic
acid has been widely used as a general
purpose pain reliever for over a hundred
years. It is potent, relatively safe and
inexpensive. Annual production of aspirin is in
excess of 40,000 tons worldwide.
Written records from 500 B.C. indicate
that the Greek doctor Hippocrates used the
bark of the willow tree as a pain reliever for
individuals suffering from rheumatism and
various forms of inflammation.’
showed later that the active ingredient was
Salicylic acid (see formula below).
OH
hydrochloric acid (HCI) and enhances the
formation of a protective layer of mucus. [For
more detail regarding the function of COX,
sée page 40.]
Aspirin was widely used during the flu
epidemic in Europe in 1917-1918 because it
effectively lowers dangerously high fevers.
Such fevers are caused by elevated levels of
PGE, in the brain which are decreased by
aspirin. By the 1950s aspirin became by far
Research the most widely used painkiller globally. That
massive usage allowed the detection of
aspirin's anticlotting properties and the
realization that it could be used to lower the
risk of heart attack due to the clotting of blood

S¢ OH
in disease-narrowed arteries. Taken soon
after a heart attack, aspirin may also limit the
Salicylic acid size of the infarcted area.”
Subsequent research indicated that
By the end of the 19th century, doctors
aspirin inhibits blood clotting at low dosages
regularly prescribed salicylic acid for the
(80-90 mg per day). During the late 1980s
treatment of arthritic pain. However, salicylic
studies also showed that aspirin can limit
acid is no longer used as an oral medicine, brain damage due to occlusive stroke caused
since it is very irritating to the stomach and
by a blood clot, if taken early. The use of
can Cause serious gastrointestinal bleeding.
aspinn is contraindicated in hemorrhagic
lts main use is in topical medications to
remove warts and callouses.,
stroke, because it may increase bleeding.°
The anticlotting action of aspirin at low
Acetylsalicylic acid was discovered by the
doses is due to the irreversible inhibition of
German chemist Felix Hoffmann, who tried to
cyclooxygenase in blood platelets by transfer
make a less irritating medicine for his arthritic
of the acetyl group from aspirin to a critical
father. In 1897 he prepared aspirin, a more
serine hydroxyl group at the catalytic site of
potent and less irritating anti-inflammatory
the enzyme (see page 40). Since mature
agent, and just two years later Bayer & Co.
platelets have a lifetime of only about 2 weeks
began marketing it as Aspirin. Aspirin acts by
and are not able to synthesize new protein,
inhibiting the enzyme cyclooxygenase (COX)
the clotting ability of aspirin-treated platelets is
that directs the synthesis of a family of cell
permanently blocked.
regulators called prostaglandins (PGs). In the
stomach, a particular PG (PGE-) is beneficial 1. Curr. Opin. Invest. Drugs (ThomsonCurr. Drugs) 2003, 4,
517-518; 2. Drugs of Today 2006, 42, 467-479: 3. Mini-Rev.
because it inhibits the excessive production of Med. Chem. 2006, 6, 1351-1355; Refs. p. 80

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 PART II. ANTI-INFLAMMATORY AGENTS

NAPROXEN (ALEVE™)
Structural Formula Ball-and-Stick Model Space-filling Model

ith
me O ww "Yen .
es = Carbon = Hydrogen eS) = Oxygen

Year of discovery: Early 1970s; Year of introduction: 1976 (as Naprosyn by Syntex); Drug category:
Non-steroidal antiinflammatory drug (NSAID); Main uses: For many different types of pain, mild
fever or minor inflammation; Other brand names: Anaprox, Naprelan and Naprogesic; Related drugs:
Aspirin, Ibuprofen (Advil) and Celecoxib (Celebrex).

The remarkable success of aspirin as a emerged. lbufenac (isobutylphenylacetic acid)

medicine for the relief of inflammation, pain
and fever stimulated the search for even more
effective agents starting in the mid-twentieth
century. The overall objective was the
discovery of safer and more potent anti
inflammatory compounds, and especially of
compounds that are devoid of the erosive
gastric side effects of aspirin. Thousands of
compounds were synthesized and tested in
mice over more than two decades, Many
active compounds were discovered, including
phenylbutazolidin, indomethacin and piroxi-
cam, but all exhibited side effects, especially
is comprised of three subunits: (1) acetic acid
(blue), (2) a benzene ring (red) and (3) a
branched chain attached to the benzene ring
(green, see structures below). Although this
drug was several times more potent than
aspirin, it showed occasional hepatotoxicity in
humans. When a methyl group (orange) was
added to the acetic acid subunit (forming a
propionic acid subunit), a much safer drug
(ibuprofen) resulted with diminished gastro-
intestinal irritation and no hepatotoxicity, even
when administered in large doses (over 1
gram/day).’ Although ibuprofen was a great

yor
gastric irritation. success, continuing research led to more
potent molecules. During the early 1970s, the

OE
Syntex Co. prepared naproxen, a propionic
acid derivative with a naphthalene nucleus
(two benzene rings fused together, shown in
CHyCOOH
red).? It had twice the potency of ibuprofen
and, in addition, a longer half-life (ca. ~12
Indomethacin hours), allowing a once-daily dosing. Not long
(Indiocin™) (Feidene™) after its introduction as Naprosyn in 1976 (and
In one approach, the structure of later as Aleve), the sales of maproxen
acetylsalicylic acid (aspirin) was methodically exceeded $1 billion annually. Because of their
modified in the hope that these changes significantly better potency and safety profile,
would result in better properties. The ibuprofen and naproxen are today the most
replacement of the hydroxyl group of salicylic widely used non-steroidal anti-inflammatory
acid by nitrogen-containing groups led to a agents.
HO ae
class of compounds known as anthranilic acid eee

derivatives that retained most of the desirable o 0

CH,
properties of aspirin (see below). Acetic acid Ibufenac

c= Of
CH, CH, aga cuter
HO HO
ma Lh,

a = pe 0

Propionic acid
6

Ibuprofen (Advil™)
CH,

Acetaminophen (Tylenol, see page 210),

1. Int. J. Clin, Pract,, Suppl. 2003, 135, 3-8; 2. J. Am. Pharm.
ibufenac and ibuprofen (Motrin or Advil) also Assoc. (Wash). 1996, NS36, 663-667; Refs. p. 80
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CELECOXIB (CELEBREX™)
Structural Formula Ball-and-Stick Model
H
HwWOo
©
as
= Carbon . = Hydrogen © = Oxygen
Year of discovery: 1993; Year of introduction; 1999 (Pfizer); Drug category: Non-steroidal anti-
inflammatory drug (NSAID); Main uses: Treatment of osteoarthritis, rheumatoid arthritis and acute
pain (e.g., painful menstruation); Approximate number of people taking the drug annually: Over 23
million; Older drugs: Aspirin, Ibuprofen (Advil) and Naproxen (Aleve).
Non-steroidal anti-inflammatory agents
such as aspirin, ibuprofen and naproxen (see
page 39) act by inhibiting the biosynthesis of
prostaglandins (PGs) from arachidonic acid
(AA). There are two human enzymes that
catalyze the first step in the biosynthesis of
PGs, cyclooxygenase 1- and 2 (COX-1 and
COX-2; see page 40). Although COX-1 and
COX-2 catalyze the same _ biochemical
reaction, they are distinctly different in terms
of amino acid content (about 60% identity),
tissue distribution, and physiological function.
COX-1 has been described as a “constitutive”
enzyme because it appears to have a steady
presence in tissues and organs, for example
in the stomach where it affects gastric acidity
and mucous secretion. In contrast, COX-2
levels are normally low, but become elevated
at sites of inflammation, in certain tumor cells
or in response to stimuli such as growth or
wound-response factors. Glucocorticoid stero-
ids and anti-inflammatory cytokines (see page
45) downregulate the expression of COX-2.
COX-1 and COX-2 are both membrane-
associated proteins to which the membrane-
bound substrate AA is transferred directly.
The two enzymes have roughly similar
substrate binding sites, but that of COX-2 is
slightly larger and differently shaped. Since
COX-2 is not expressed in stomach and since
gastric ulcers and serious gastric bleeding
develop in about 1% of chronic users of COX-
1 inhibitors, research to find inhibitors that are
selective for COX-2 over COX-1 was initiated,
The selective COX-2 inhibitor celecoxib (Ce-
lebrex) emerged from this effort in 1999, and
became an important medicine for treatment
of osteoarthritis in people who cannot tolerate
aspirin or non-selective alternative COX-
1/COX-2 inhibitors.
PART II. ANTI-INFLAMMATORY AGENTS
Space-filling Model
o = Fluorine © = Nitrogen o = Sulfur
A competing drug, rofecoxib (Vioxx), was
developed at Merck and Co. and was
marketed about the same time as celecoxib.
However, it subsequently had to be withdrawn
when it was linked to a 1% increase in risk of
heart attack. Celecoxib appears to be consi-
derably safer than rofecoxib.'
ta
Q..
‘ gt
wer%, "
Rofecoxib (Vioxx) SC-558
Although COX-1 and COX-2 bind AA in
the same three-dimensional geometry, the
ligand-binding pockets are different for
inhibitors of COX-1 and COX-2. The picture
below shows a close structural relative of
celecoxib, SC-558, bound in the active site of
COX-2.* The selectivity results because the
phenylsulfonyl group (shown in green above)
binds in a pocket (formed from His90, Arg513
and Val523) that is not available in COX-'
since it is occupied by a bulky isoleucine side
chain rather than the smaller isopropyl group
of valine (Val523). The carboxyl group of
rofecoxib interacts not with Arg513 but with a
different residue, Arg120.
1, Future Cardiology 2005, 1, 709-722; 2, Nature (London)
1906, 384, 644-646. (1CX2); Refs, p, 80
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 MOLECULES AND MEDICINE

PREDNISONE (DELTASONE™)
Structural Formula Ball-and-Stick Model Space-filling Model

© = Carbon = Hydrogen So = Oxygen

Year of discovery: Early 1950s; Year of introduction: 1955 (as Meticorten by Schering and as
Deltasone by Pharmacia and Upjohn); Drug cafegory: Anti-inflammatory agentimmuno-
suppressanUVadrenocortical steroid; Main uses: For treatment of inflammatory diseases (e.g.,
asthma, Crohn's disease) and prevention of organ transplant rejection; Related drugs: Cortisol
(Hydrocortisone), Fluticasone (Flonase), (and others shown on next page).

Human adrenal glands, though weighing
only a few grams, are essential for life;
adrenalectomized animals survive only for a
matter of days. Research in the 1930s by
Oskar Wintersteiner at Columbia, Edward C.
Kendall at the Mayo Foundation, and
Thaddeus Reichstein at the Federal Technical
Institute (ETH) in Zurich resulted in the
identification of more than 25 members of the
adrenocortical family of steroids including
cortisol and the corresponding 11-ketone,
cortisone.
Kendall and Philip S. Hench's demonstration
in the 1940s that cortisol and cortisone
exerted profound anti-inflammatory effects in
humans, had a major impact on the medical
sciences.’ Reichstein, Kendall and
shared the Nobel Prize in Medicine in 1950 for
their discoveries.
Cortisol has a wide range of activities in
the body and its levels are tightly controlled.
Its biosynthesis (from the early precursor
cholesterol) in the adrenals is stimulated by
corticotrophin, a 39 amino acid peptide
produced in the brain and carried to the
adrenals by blood. Cortisol levels are partly
regulated by two enzymes, one that oxidizes
the 11-CHOH unit to C=O and the other that
catalyzes the reverse reaction. The intrinsic
bioactivity of cortisol is much greater than of
44
cortisone, which essentially serves mainly as
a storage depot. Cortisone is inactive at
corticosteroid receptors.
The receptors that mediate the many
biological activities of corticosteroid hormones
are of two general types: (1) glucocorticoid
(GR) and (2) mineralocorticoid receptors
(MR).
Cortisol has both GR and MR activity, but
the former dominates. Another adrenal
steroid, aldosterone shows much more potent
MR activity than GR activity. MR activation
causes sodium retention in the body, and was
of great importance during evolution because
NaCl was frequently in short supply. Since an
excess of NaCl in the body causes
hypertension, an antagonist of aldosterone
(Eplerenone, Inspra™) is used medically
when the cause of elevated blood pressure is
excessive body production of aldosterone.
Hench
Aldosterone Eplerenone (inspra™)
Cortisol is associated with a remarkable
variety of biological activities and plays many
functional roles throughout the body, for
example in the brain, peripheral muscle and
the various organs. It is a principal effector in
the hypothalamic-pituitary-adrenal (HPA) axis
of physiological control (see next page). In the
brain cortisol plays a crucial role in cognition,
maintenance of neurons and the regulation of
stress and mood.

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 PART Ii. ANTI-INFLAMMATORY AGENTS

a - Other members of the prednisone class

racronen
RELEASING
\ runTht&
PELEASE
OF CAF
The Hypothalamic-Pituitary-Adrenal Axis.
The discovery of the anti-inflammatory
properties of cortisol/cortisone in the 1940s
spurred the development of several synthetic
analogs of cortisone during the 1950s. Many
of these compounds are several times more
potent than cortisol, longer lasting and cause
less sodium retention. One of the most widely
used synthetic analogs, prednisone, was
introduced by Schering in 1955 as Meticorten.
Prednisone and other steroids of this class
have many therapeutic applications. They are
useful in rheumatic/inflammatory disorders,
allergies, malignancies such as leukemia and
with longer half-lives and enhanced potency
than prednisone are in common use; the most
widely used of which is dexamethasone (see
stereostructure at bottom left).
The anti-inflammatory activities of
glucocorticoids are not fully understood
because they affect the expression of
numerous genes.” However, one way in which
they exert anti-inflammatory effects is by
promoting the synthesis of lipocortin-1, a
calcium-binding protein that binds to cell
membranes.” In the membrane, lipocortin-1
inhibits the enzyme phospholipase A2 (PLA9)
that is responsible for the selective removal of
acyl groups from the C-2 position of
phospholipids to release free arachidonic acid
(AA). The net result is a diminished production
of AA and its biooxidation products including
proinflammatory eicosanoids, prostaglandins
and leukotrienes. In addition, the expression
of the cyclooxygenase enzyme (COX) is
downregulated.
OCO-nC pHa,

multiple myeloma, and skin diseases, Predni-

sone can be used orally or intramuscularly to
treat cases of acute inflammation. It is a
powerful immunosuppressant because it
reduces B- and T-cell-mediated immunity. For
this reason it is administered to patients after Phospholipid
organ transplant to prevent rejection. Fortuna- (Arachidonic Acid bound at C-2)
tely, prednisone and other members of this PLA,
class do not cross the blood brain barrier, and 0
thus have minimal effects on mental function.
Unfortunately, long term use of these a nC

corticosteroid hormones in systemic therapy is = =

contraindicated because of inevitable and Arachidonic Acid
serious side effects (e.g., osteoporosis).
5-Lipoxyge- Cyclooxyge-
nase (LOX) nase (COX)

nnn
(Proinflammatory agents)

Another way in which prednisone and

other corticosteroids reduce inflammation is
through their effect on the body's production
of TNF-c and other cytokines. For certain
inflammatory diseases, e.g., Crohn's disease
(inflammatory bowel disease), combination
therapy with prednisone and an anti-TNF
monocional antibody allows the use of lower
doses of each.
1. N. Engl J. Med. 2005, 353, 1711-1723; 2. Br. J.
Pharmacol. 2006, 148, 245-254: 3. Ann. N. Y¥. Acad. Sol.
2006, 1088, 306-409, Rets. p. 81

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 MOLECULES AND MEDICINE

METHOTREXATE (TREXALL™)
Structural Formula Ball-and-Stick Model Space-filling Model

fy Seti sey
@ = Carbon = Hydrogen @ = Oxygen
@ = Nitrogen

Year of discovery: 1948 (Lederle); Year of introduction: 1953; Drug category: Antimeta-
bolite/disease-modifying anti-inflammatory agenVimmunosuppressant; Main uses: For treatment of
inflammation associated with autoimmunity (rheumatoid arthritis, Crohn's disease and psoriasis):
Other brand names: Rheumatrex; Related drugs: Trimetrexate (Neutrexin), Pemetrexed (Alimta).

Methotrexate is an inhibitor of folic acid
biosynthesis which slows the proliferation of
cells. It has been known since the 1930s that
folic acid is essential for the development of
new cells. Adequate dietary intake of folic acid
is absolutely necessary for human health. A
deficiency of folic acid is especially serious in
pregnant women, since it leads to maldeve-
lopment of the fetus and results in defects of
the spine, brain and skull.
Folic acid undergoes reduction in the body
by the enzyme dihydrofolate reductase
(OHFR) in two stages, giving first dihydro-
folate and then the essential metabolite
tetrahydrofolate. Parts of the tetrahydrofolate
molecule are required as building blocks for
the synthesis of the nucleoside thymidine, an
ingredient for DNA formation. The figure
below shows in red the segment of the six-
membered ring of thymidine that originates
the immune system). Since cancer cells divide
even more rapidly, blockade of the synthesis
of tetrahydrofolate by inhibition of the enzyme
DHFR appeared to be promising for effective
cancer therapy. Methotrexate (MTX) was
successfully developed in 1948 by the Lederle
Company and marketed under the trade name
Trexall. Although MTX was originally used in
cancer chemotherapy, its main use is now in
the treatment of autoimmune — and
inflammatory diseases, {especially psoriasis
and rheumatoid arthritis.’ The combination of
the anti-TNF-c monoclonal antibody Enbrel
and MTX is currently a standard treatment of
rheumatoid arthritis.
Methotrexate is a disease-modifying anti-
rheumatic agent that not only reduces the
symptoms, such as pain and swelling, but also
slows the progression of the disease by
preventing further damage to joints. The

fOr Gr
from tetrahydrofolate. Methotrexate blocks effective dose of MTX is several orders of
DHFR and interferes with DNA synthesis. magnitude lower for inflammation than for
cancer.* Even at low doses, MTX appears to
decrease T-cell proliferation and the levels of
proinflammatory factors such as TNF-a and
interleukin-10. The figure below shows an X-
ray picture of MTX bound to the enzyme
DHFR from E. Coli.”
Foto Acid (Folate)

Ro
Because tetrahydrofolate is essential for
normal cell division, it is especially critical in
1. Pharm. Rep. 2006, 58, 473-492: 2. Biomed &
tissues that divide rapidly (e.g., bone marrow, Pharma 2006, 60,cot
678-687; 3.her
Biochemistry 1997,
.
blood cells, skin, gastrointestinal tissues and 36, 586-603, (1F.GT), Refs. p. 81

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 PART Il. ANTIINFLAMMATORY AGENTS

ALLOPURINOL (ZYLOPRIM™)
Structural Formula Ball-and-Stick Model Space-filling Model

OH

N= \
N i
LS | N

© = Carbon = Hydrogen © = Oxygen © = Nitrogen

Year of discovery: Early 1950s; Year of introduction: 1964 (Burroughs Wellcome, now
GlaxoSmithKline); Drug category: Xanthine oxidase inhibitor for treatment of inflammatory gout;
Main uses: For the prevention and treatment of gout attacks and certain types of kidney stones;
Related drugs: Colchicine, Probenecid (Benemic).

Allopurinol is used for the treatment of stones. Uric acid is formed in the last step in
arthritic gout. Arthritis encompasses of over the metabolic pathway of purines.
one hundred different rheumatic diseases and The conversion of hypoxanthine to
conditions affecting joints, muscle and bone. xanthine and of xanthine to uric acid is
These diseases include osteoarthritis, catalyzed by the enzyme xanthine oxidase
rheumatoid arthritis and gout. There are many (see scheme below).
symptoms associated with arthritis, but the
most common are pain, aching, stiffness, and
Lt Xanthine

swelling of the joints. Currently over 50 million

people in the US have arthritis and about 3 od
million of them suffer from gout, a very painful Hypoxanthine
form. Unlike other forms of arthritis, the cause
of gout has been pinpointed as being the
deposition of needle-like crystals of uric acid
in the connective tissue, joint spaces or both
(see below). Such uric acid deposits cause
inflammation of the affected joint and result in
swelling, stiffness and intense pain. The first
sign of gout is usually pain in the joints of the
big toes."* Treatment of gout can be achieved with a
combination of therapies. The pain can be
(e.g., naproxen),
* Sly

with NSAIDs
a

reduced
N colchicine and, in acute cases, injection of
re | BONE | | BONE corticosteroids into the affected joints. These
medicines are not safe for long-term use and
Uric acid do not prevent fulure gout attacks.
Allopurinol, a purine derivative, was first
prepared in the 1950s and shown to inhibit the
Deposit of uric Joint with gout enzyme xanthase oxidase (XO) and inhibit the
acid crystals biosynthesis of uric acid. Allopurinol is an
effective inhibitor of XO because it binds to
In healthy humans uric acid is produced the enzyme effectively competing with
by the breakdown of purines. Normally it ts xanthine. Since allopurinol has a_ nitrogen
excreted in the urine. In individuals with gout, atom at the 2-position (shown in blue) instead
uric acid is overproduced and accumulates of the C-H group of xanthine, it can not be
because the kidneys do not efficiently converted to uric acid.*
eliminate it. As a result, blood levels of uric
1. J. Clin. invest. 2006, 116, 2073-2075; 2. Crystal-induced
acid increase and uric acid crystallizes in the Arthropethies 2006, 189-212; 3. Pharmacol, Rev. 2006, 56,
joints and even in the kidneys, causing kidney 87-114; Refs. p. 81

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