NSAIDs
Books: 1. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical
Chemistry 11th ed. Lippincott, Williams & Wilkins ed.

Structurally diverse agents with anti-inflammatory activity

Activity is attributed to their ability to inhibit cyclooxygenase (COX)

Cyclooxygenase involved in the biosynthesis of prostaglandins

Prostaglandins are a class of eicosanoids

Eicosanoids are any product derived from arachidonic acid, a
twenty carbon fatty acid

Eicosanoids also include, thromboxanes, lipoxins, and leukotrienes.
Natural Eicosanoids
PGA2
O
O
9
11
HO
13
O
CH3
20
15
OH
O
COOH
COOH
CH3
CH3
OH
PGE2
HO
COOH
COOH
CH3
CH3
CH3
HO
PGG2
HO
OH
PGH2
COOH
CH3
O
O
COOH
COOH
CH3
CH3
O
OH
PGI2 Prostacycline
TXA2 Thromboxane A2
O
O
OH
CH3
O
OH
CH3
OH
TXB2
COOH
COOH
OH
PGJ2
O
OOH
OH
PGF2
COOH
OH
O
OH
PGC2
OH
PGD2
O
PGB2
1
COOH
5
HO
COOH
CH3
O
OH
Commercial Prostanoids
A. Ocular Hypertension & Glaucoma
BIMATOPROST
HO Lumigan
LATANOPROST
HO Xalatan
N
H
O
CH3
O
O
HO
HO
HO
OH
TRAVOPOST
Travatan
O
O
OH
CH3
OH
UNOPROSTONE isopropyl
Rescula
HO
O
HO
CH3
CF3
CH3
O
O
CH3
HO
O
CH3
CH3
CH3
Commercial Prostanoids -II
B. Pulonary Hypertension
EPOPROSTENOL
PGI
Flolan
ILOPROST
Ventavis
ONa
COOH
COOH
TREPROSTINIL sodium
Remodulin
O
OH
H
O
CH3
CH3 O
CH3
H
HO
HO
OH
OH
C. Other Uses
CARBOPROST
Hemabate
O
HO
COOH
MISOPROSTOL
Cytotec,(Arthortec)
OH
CH3
HO
H3 C
O
CH3
CH3
HO
OH
DINOPROSTONE
Prostglandin E2
Prostin E2, Prepidil, Cervidil
ALPROSTADIL
Prostglandin E1
Prostin VR, Caverject, Edex, Muse
O
O
COOH
COOH
CH3
CH3
HO
CH3
O
OH
HO
OH
OH
Prostaglandins - Nomenclature
Prostanoic acid
9
1
COOH
O
PGE1
O
PGE2
O
COOH
PGE3
COOH
COOH
20
11
15
HO
OH
HO
OH
HO
OH

The nomenclature is derived from the hypothetical compound prostanoic
acid

The different prostaglandins are divided into several main classes (A, B, C,
D, E, F, G, H) depending on the type and spatial relationship of the oxygen
functions on C-9 and C-11 of the cyclopentane ring (all have a hydroxyl on
C-15)

The  designation refers to the steroeochemistry of the OH at C-9, below
and on the same side (cis) of the ring as the ––OH on C-11.
Prostaglandins - Function

A class of highly active endogenous mediators

Depending on the individual Prostaglandin and the tissue they exert
many varied actions

Prostaglandins are also implicated in the inflammatory response and in
sensitizing pain receptors to the action of other mediators

Occurring during acute and chronic inflammatory illness,
prostaglandins are produced at the site of inflammation where they
mediate many of the symptoms of inflammation such as edema and
pain

Play critical roles in tissue homeostasis and function

They have a cytoprotective role in the kidney and gastric mucosa.
Prostaglandins - Biosynthesis
P ho s ph o lip ase A
1
P ho s ph o lip ase A
2
O
O
O C
(CH2 )nCH3
C O
O O
CH3
P
N
O
O
CH3
P ho s ph o lip ase C
CH3
P ho s ph o lip ase D

Prostaglandins are biosynthesized
from Arachidonic acid

Archidonic acid is found esterified as
a cell membrane phospholipid

The concentration of free arachidonic
acid is low
The biosynthesis of the eicosanoids depends primarily on its release from
cellular stores by acyl hydrolases or phospolipases.


Biosynthesis is enhanced by many physical, chemical and hormonal stimuli
and involves activation of enzymes by an increased concentration of calcium

Membrane bound Phospholipase A2 is involved in the release of arachidonic
acid.

Action of cyclooxygenase on arachidonic acid results oxygenated products
containing ring structures: prostaglandins, thromboxanes, and prostacyclin

action of various lipoxygenases result the hydroxylated products: HPETEs,
HETEs, lipoxins and leukotrienes
THE EICOSANOIDS
The Arachidonic Acid Cascade
O
O
C
O
C
(CH2)nCH3
O
O
O
CH3
P
O
Lipoxins
N
O
H 3C
CH3
Phospholipase A2 [3.1.1.14]
Arachinate
15–lipoxygenase
[EC 1.13.11.33]
15–HPETE
COOH
Cytochrome P450
Arachinate
12–lipoxygenase
[EC 1.13.11.31]
Arachidonic acid
Arachinate
5–lipoxygenase
[EC 1.13.11.34]
Epoxyeicosatriene acids
Dihydroxy acids
Cyclooxygenase
5–HPETE
COOH
12–HPETE
O
O
Leukotrienes
LTA4
LTC4
LTB4
COOH
O
LTD4
O
LTF4
COOH
O
O
LTE4
OOH
Prostaglandin G2
LT = Leukotriene
PG = Prostaglandin
TX = Thromboxane
HETE = Hydroxyeicosatetraenoic acid
HPETE = Hydroperoxyeicosatetraenoic acid
Peroxidase
COOH
O
O
Prostaglandins
OH
PGA2
PGB2
PGE2
PGC2
PGF2
PGD2
PGI2
Prostaglandin H2
Thromboxanes
TXB2
TXA2
O
C H
COOH
H2C
C H
O
OH
Malondialdehyde Hydroxyhepta
decatrienoic aacid
HHT
HO
OH
COOH
COOH
HO
Arachidonic acid
OH
Thromboxane B2
1
O
O
COOH
COOH
COOH
O
O
OOH
Prostaglandin G2
HO
OH
OH
19–Hydroxy Prostaglandin F2a
OH
Thromboxane A2
7
2
HO
HO
COOH
HO
O
3
O
O
COOH
OH
Prostaglandin H2
OH
Prostaglandin F2a
O
O
6
COOH
O
5
OH
Prostaglandin D2
PGH2 is also
converted into two
unstable yet highly
active
thromboxanes (so
named because
they were first
isolated from
thrombocytes)
4
COOH
COOH
COOH
O
HO
OH
OH
19–Hydroxy Prostaglandin E2
O
HO
OH
Prostaglandin E2
O
HO
COOH
COOH
OH
OH
19–Hydroxy Prostaglandin A2
OH
Prostaglandin I2
Prostacyclin
COOH
O
O
COOH
COOH
HO
OH
6–Keto– Prostaglandin F1a
OH
Prostaglandin C2
OH
OH
19–Hydroxy Prostaglandin C2
O
COOH
OH
Prostaglandin B2
Prostaglandin
endoperoxide synthase
2. Peroxidase
[EC 1.14.99.1]
Prostaglandin endoperoxide synthase
(cylcooxyenase domain)
Prostaglandin endoperoxide synthase
(hydroperoxidase domain)
1. Cyclooxygenase
OH
Prostaglandin A2
3.
4.
5.
6.
7.
Prostaglandin F2a synthase [EC 1.1.1.188]
Prostaglandin E2 synthase [EC 5.3.99.3]
Prostaglandin I2 synthase [EC 5.3.99.4]
Prostaglandin D2 synthase [EC 5.3.99.2]
Thromboxane A2 synthase [EC 5.3.99.5]
Products of 5–Lipoxygenases
Leukotriene Biosynthesis
COOH
Arachidonic acid
1
OOH
OH
COOH
CH3 inhibited by
O
Zileuton
N
HO NH2
S
COOH
2
5–HPETE
5–HETE
1
O
COOH
C5H11
Leukotriene A4
4
3
1.
2.
3.
4.
5.
6.
5–Lipoxygenase + FLAP [EC 1.13.11.34]
Peroxidase
Leukotriene A4 epoxide hyrolase (LTA4 hydrolase) [EC 3.3.2.6]
LTC4 synthetase (a glutathione–S–transferase) [EC 2.5.1.37]
g–Glutamyl transferase [EC 2.3.2.2]
Cysteinyl glycinase (an amino dipeptidase)
HO H
COOH
C5H11
C5H11
OH
Leukotriene B4
5
HO H
COOH
C5H11 H S
CHCOOH
NH2
Leukotriene E4
6
HO H
COOH
S
CHCONHCH2COOH
NHCOCH2CH2CHCOOH
Leukotriene C4
NH
2
COOH
C5H11 H S
CHCONHCH2COOH
NH2
Leukotriene D4
HO H
COOH
C5H11 H S
CHCOOH
NCOCH2CH2CHCOOH
Leukotriene F4
NH
2
Products of 15–Lipooxygenases
Lipoxin Biosynthesis
COOH
Arachidonic acid
1
COOH
COOH
2
OH
OOH
15–HPETE
15–HETE
3
OOH
OH
COOH
COOH
2
HPETE – Hydroperoxyeicosatetraenoic acid
HETE – Hydroxyeicosatetraenoic acid
OOH
OH
5,15–HETE
5,15–HPETE
COOH
O
1 Arachinate 15–lipoxygenase [EC 1.13.11.33]
2 Peroxidase
3 Arachinate 5–Lipoxygenase [EC 1.13.11.34]
OH
HO
OH
HO
OH
COOH
COOH
OH
6S–Lipoxin A
OH
OH
COOH
OH
Lipoxin B
OH
Lipoxin C
Protaglandin Endoperoxide Synthase

In 1971, John Vane and his colleagues showed that aspirin and other
nonsteroidal antiinflammatory drugs inhibited the enzyme, cyclooxygenase
and that this inhibition was responsible for their anti-inflammatory properties

The biosynthetic reactions are catalyzed by a enzyme complex commonly
named Prostaglandin endoperoxide synthase which is located in the
endoplasmic reticulum

It is a bifunctional enzyme with two catalytic sites adjacent but spatially distinct

On one side, it has the cyclooxygenase active site and on the opposite side,
it has an entirely separate peroxidase site, which is needed to activate the
heme groups that participate in the cyclooxygenase reaction
1.
First COX oxidizes and cyclizes arachidonic acid, forming PGG2, which has an
endoperoxide as well as an exoperoxide (that gives the name cyclooxygenase)
2.
PGG2 then diffuse to the peroxidase catalytic site where the exoperoxide at
C15 is reduced to PGH2
3.
PGG2 and PGH2 are chemically unstable (t1/2 of 5 min) and are converted
enzymatically by enzymes called synthetases into the other prostaglandins
3D Structure of the Enzyme Complex
The enzyme complex is a
dimer of identical subunits, so
altogether, there are two
cyclooxygenase active sites
and two peroxidase active
sites in close proximity
Each subunit has a small
carbon-rich knob that anchor
the complex to the membrane
of the endoplasmic reticulum,
shown in light blue at the
bottom of the picture
The cyclooxygenase active site is buried deep within the protein, and is reachable
by a tunnel that opens out in the middle of the knob. This acts like a funnel, guiding
arachidonic acid out of the membrane and into the enzyme for processing
COX-1 & COX-2
Side pocket

In COX1 residues Arg120 &Tyr355 stabilize the anionic group present in most
NSAIDs. NSAID aromatic rings are accommodated in the hydrophobic channel.
Ser530 is the residue acetylated by aspirin. Note the presence of the relatively
bulky Ile523

In COX2 residues Arg120, Tyr355 & Ser530 are present. However, residue 6 is
Val523 which allows copening of a side pocket. This pocket accommodates the
sulfonamide or isoster of COX2 inhibitors. They are stabilized by hydrogen
bonding with Arg513.
from Nature Reviews Drug Discovery, 2, 2003
COX-1 & COX-2 - II

Overall structure and catalytic activity of both are similar

Vivid distinctions in their regulation and expression

COX-1 is constitutive and its expression is regulated by hormonal signals
involved in maintaining physiologic homeostasis

COX-1 is expressed in all tissues

Importantly, COX-1 but not COX-2 is constitutively expressed in the
stomach, where it is involved in mucosal defense and repair

COX-2 expression and activity is largely responsive to adverse stimuli, such
as inflammation and physiologic imbalances

Control of COX-2 transcription and translation is thought to be the primary
mechanism by which steroids such as hydrocortisone and dexamethasone
modulate this enzyme. COX-2 has a binding site for steroids whereas COX1 does not

COX-2 is constitutively expressed notably in the brain and kidney
Mechanism of Action
Inhibitors of cyclooxygenase reduce the amount of Prostaglandins and thereby
reduce the inflammation process
primary insult: Unionized at stomach pH that allows passage into gastric
mucosal cells. The inside higher pH ionize them which can not pass through lipid
barriers and is trapped inside the cell. This alters the permeability of the cell
membranes and allows accumulation of hydrogen ions which cause cell damage
Microenvironment
low pH
AR—COO– + H +
AR—COOH
Unionized fract ion
predom inates
Int racellular
higher pH
AR—COOH
AR—COO– + H +
Ionized fract ion
predom inates
The secondary insult is the result of the mechanism of action. The inhibition of
PG synthesis prevents the cytoprotective action of the PG
Most of the gastric effects of NSAIDS are attributed to their acidic character which
participates in 1) decreasing surface hydrophobicity of the mucus gel layer with
subsequent loss of barrier properties; 2) uncoupling of oxidative phosphorylation with
subsequent increase in mucosal permeability and back diffusion of hydronium ion; 3)
ion trapping into the mucosal epithelium
Classes of COX Inhibitors
The COX inhibitors can be grouped into four classes based on their
mechanism of action.
1.
Irreversible inhibitors. Aspirin is the only known member of this group
2.
Reversible competitive inhibitors of both COX which is freely reversible
3.
Slow time dependent inhibition of both COX—they bind and induce a
conformational change in the enzyme thus binding very tightly and
dissociated very slowly. It can take several seconds to minutes to reach
equilibrium between the reversible and pseudo irreversible complex.
However, in vivo both mechanism 2 and 3 are essentially the same.
4.
Selective reversible competitive inhibitors COX–2. These agents
induce a slow conformational change in COX-2 but not in COX-1. The
change increases the inhibitor affinity by >10 fold by binding very tightly
and dissociating very slowly. Thus the isozyme selective induction of a
conformation change in the enzyme leads to potent inhibition of COX-2
that is not seen for COX-1

With the exception of Aspirin, all the NSAIDS are reversible competitive
inhibitors

Aspirin is a nonreversible inhibitor, for it acetylates the active site which is the
basis for its prophylactic use to prevent heart attacks

Research suggests a role for PG in CNS transmission and raises the
possibility that selective COX–2 inhibitors may modulate CNS function. This
is relevant for those COX–2 inhibitors that lack an acidic group and thus can
easily pass the BBB.

COX–1 provides a cytoprotective role in the stomach and kidneys. It helps
maintain the integrity of the mucosal epithelium and inhibition leads to gastric
damage, hemorrhage, and ulceration

The cytoprotective role in the stomach and kidney is largely due to the
vasodilating properties of PGs which enhance mucosal blood flow

Thus COX–1 produces prostaglandins that exert cytoprotective roles
whereas COX–2 produces prostaglandins involved in inflammation, fever and
pain; and COX–2 activation leads to inflammation

Thus COX–2 inhibition produces therapeutic effects and COX–1 inhibition
produces unwanted side effects. Unfortunately, most NSAIDS are more
effective at inhibiting COX–1 than COX– 2
NSAIDs & COX

The "classical" nonselective NSAIDs bind to both COX-1 and COX-2,
interacting with the hydrophobic channel of the COX isoenzymes

Aspirin, unlike other NSAIDs, irreversibly acetylates a serine residue in both
COX-1 and COX-2 preventing arachidonic acid from reaching the catalytic
site

Other nonselective NSAIDs compete directly with arachidonic acid, inhibiting
cyclooxygenase activity in a reversible manner

Coxibs, the COX-2-selective inhibitors, preferentially bind to and inhibit
COX-2. Coxibs are selective agents because they bind COX-1 poorly and in
a rapidly reversible manner, whereas they bind COX-2 more tightly

Preferential inhibition of COX-2 is thought to be due to the additional space
in the COX-2 hydrophobic channel, as well as to the presence of a side
pocket in the channel. This side pocket can discriminate the coxibs from
nonselective agents based on the different overall structures of these
agents, in particular, by the presence in coxibs of specific side chains

NSAIDs do not affect the peroxidase site
The COX Binding Site
1.
A cationic center and two hydrophobic areas
2.
The cationic site is attributed to a guanidinium group on Arginine
3.
The first hydrophobic area is located adjacent to the cationic center
4.
The second region lies under and out of the plane with the first hydrophobic
area and is commonly referred to as a trough

Some agents can bind only the cationic center and the first hydrophobic
area

Others can bind all three, resulting in better binding

The only way to bind both hydrophobic regions simultaneously is if the drug
contains two aromatic ring systems that are perpendicular and not coplanar

Binding to the trough can enhance potency. If the ring cannot fit into the
trough then it bangs into the walls of the enzyme, sterically inhibiting binding

If the two rings are separated by one or more sigma bonds, the two rings
may assume a large number of possible conformations due to free rotation
around a sigma bond, only a few compliment the receptor. Making rigid
molecule with correct conformation gives potent drugs
SAR Summary for COX Inhibitors
1.
Molecule must have an ionizable acid group and an aromatic ring system
2.
A second non coplanar aromatic ring increases potency by increasing
bonding interactions
3.
Limiting the number of possible conformers increase potency
4.
A two atom separation between the anionic charge and the aromatic ring
is the optimal
5.
Increasing the distance to 3 or 4 carbons generally decreases potency
6.
Introduction of a methyl at the first carbon increases potency and
introduces a chiral center
7.
The S–isomers are the more potent isomers
8.
Increasing the size of the alkyl decreases potency but incorporation of the
alkyl into a heterocycle retains activity
The Salicylates



Salicylic acid is a natural product, present in the
bark of willow and poplar trees
The active ingredient, isolated by a French
pharmacist in 1827, was Salicin, oxidized to
Salicylic acid
OH
OH
O
HO
HO
O
OH
Sal ici n
In 1875 a Swizz pharmacist, Lowig, distilled
meadowsweet flowers and got salicylaldehyde
Salicylate SARs

The simplest active compound is the salicylic acid anion,

The carboxylic group is necessary for activity and the hydroxyl group
must be ortho to it.

Introduction of electronegative groups and lipophilic groups increases
anti–inflammatory activity and toxicity.
ASPIRIN
SODIUM SALICYLATE
(Bisalate) O
O
OH
SODIUM THIOSALICYLATE CHOLINE SALICYLATE
Rexolate
Anthropan O
H3 C
O
H3C
ONa
O
O
ONa
OH
N
CH3
OH
SH
OH
H3C
O
MAGNESIUM SALICYLATE
Magan, Mobidin, (Trisalate)
O
SALSALATE
Salf lex, Disalcid
O
O
O
Benorylate
OH
C
O
N
H
O
O
CH3
O
O
Mg
O
O
H
H
OH

O
O
H3C
O
Salicylic acid and Sodium salicylate were the original products used
but required doses which had much gastric irritation and ulceration.
Salicylic acid in the unionized form has a bad taste, thus the sodium salt
is used more frequently

Salsalate and Benorylate are prodrug esters. The sodium salt is freely
soluble in water and helps in its dissolution and faster absorption. Salsalate
is only half as potent as an analgesic/antipyretic as Aspirin but produces
less GI irritation.

Salsalate is a diester of salicylic acid and benorylate is esterified with
Acetaminophen

Salsalate is insoluble in gastric pH but soluble in the small intestines, thus
causing less gastric problems.

Further, it is useful in hypersensitivity to Aspirin. Hypersensitivity to ASA is a
result of acetylated plasma proteins. Since it produces Salicylic acid it can
be used in Aspirin sensitive patients

Sodium thiosalicylate is used in rheumatic fever and acute gout and an
injectable form is available

Magnesium salicylate form stable aqueous solution and show some
success in overcoming the GI problems

Choline salicylate is absorbed faster than Aspirin producing higher
salicylate blood levels and an aqueous formulation is available
Aspirin
Searching for a less toxic better tolerated derivative of salicylic acid produced
aspirin. The knowledge that acetylation of the very toxic aniline produced the less
toxic acetanilide, acetylation of salicylic acid with acetic anhydride produced
Aspirin The name. Aspirin was coined by adding an a for acetyl to spirin from the
name of the plant from which salicylic acid was first isolated

It is slightly soluble in water, absorbed as such, but is hydrolyzed rapidly to
salicylate and acetate by esterases

Pharmacological actions are attributed to both the ASA and salicylic acid

ASA irreversibly inhibits the enzyme acetylating a serine residue thus
preventing access to the cyclooxygenase site

Salicylic acid forms a reversible ionic bond with the cationic site on
cyclooxygenase
NHCOCH2NCO
NHCOCH2NCO
CH2
O
COOH
O
H
CH3
O
NHCOCH2NCO
CH2
O + H+
COOH
O
CH3
O-
CH2
COOH
O
OH
+
O
CH3
Salicylamide and Diflunisal
SALICYLAMIDE
(Bisalate)
DIFLUNISAL
Dolobid
F
O
O
NH2
OH
OH
F
OH

Salicylamide is an isostere of salicylic acid, OH replaced by NH2 to
produce a non acidic amide which is stable in aqueous preparations and
does not cause GI tract ulceration and is absorbed only in intestine. It has
greater CNS penetration. It is reported to be as effective as Aspirin as an
analgesic/antipyretic and is effective in relieving arthritis pain but does not
appear to have antiinflammaatory actions. It does not satisfy SAR 1 possibly
works through a different mechanism. It can be used by those allergic to
Aspirin.

Diflunisal has changed absorption profile and increased duration of action.
Diflunisal is absorbed only in intestine; it is not soluble in gastric fluid. Thus,
gastric bleeding and GI upset is not as common. It lasts 3–4 times longer
than aspirin. The increase in potency is attributed to an increase in binding
to the receptor since it has a second aromatic ring SAR 2. The proximity of
the two phenyl rings allows for the ortho hydrogen van der Walls electron
radii to repel and thus keep the rings out of the same plane.
Fenemates

The Fenemates are derivatives of Anthranilic acid, an isoster of salicylic acid

The most potent analogs are those disubstituted at 2’ and 3’. This indicates that
activity resides in compounds with the substituent on the second ring that keep
it out of coplanarity by the ortho substituent

Mefenamic acid has only one substituent,
the 2’ methyl, that ensures non coplanarity

Meclofenamate sodium has two such
groups, the chlorine atoms, and thus more
molecules of Meclofenamate assume the
correct conformation and the drug is more
potent
MEFENAMIC ACID
Ponstel
O
MECLOFENAMATE Sodium
Meclomen O
OH
ONa
NH
NH
CH3
CH3
Cl
Cl
CH3

Meclofenamate is 25 times more potent thus normal dose for Meclofenamate
is 25 mg while the dose for Mefenamic acid is 250 mg.

Since this class offers no advantage over the salicylates with respect to
analgesic or anti-inflammatory actions, there is little interest in developing this
class
p-Aminophenols
O
H
N
O
CH3
H
N
O
CH3
Phenacetin
Acetanilide
O
CH3
H
N
CH3
ACETAMINOPHEN
Tylenol, Datril, Panadol
OH Liquiprin, Tempra

Useful for pain and fever, but not inflammation. They have an aromatic ring, but
do not have an acidic group ionizable at physiologic pH. Thus they do not comply
with SAR 1 possibly act by some other mechanism

The first drug Acetanilide is out of market due of toxicity (both blood and liver
disorders

Phenacetin (1887) was used for decades, but in the 1970s it was implicated in
cases of liver and nephrotoxicity and was removed from the market

Acetaminophen is also a very old drug, a metabolite of both phenacetin and
acetanilide, is a safe drug, producing much better tolerance and a lower
incidence of gastric bleeding compared to many of the other NSAIDs, probably
because of its apparently different mechanism of action

You know the chemistry of toxicity for both phenacetin and acetaminophen
Pyrazoles and Pyrazolidinediones
ANTIPYRINE
(Auralgan Otic)
Antipyrine is the prototype and its antipyretic
and analgesic activities were discovered by
accident.
Aminopyrine
O
O
CH3
N
N
N
N
CH3
H3C
N
H3C
CH3
CH3
Aminopyrine is an analog, more potent and
longer acting but both possess significant
incidences of agranulocytosis leading to death
and used only in otic drops
Dipyrone is a prodrug which spontaneously decomposes
in aqueous solutions to aminopyrine. It is banned in the US
but available in Mexico.
S ONa
N
H3C
Dichloralphenazone is a complex of Aminopyrine and
Chloral hydrate It is a common agent in many OTC
analgesics. It is a mild sedative used in migraine /tension
headache products.
O
O
N
N
O
CH3
CH3 Dipyrone
O
N
Cl
N
Cl
•
Cl
OH
H3C
Although it appears that SAR 1 does not apply, these
OH
CH3
drugs are able to tautomerize into enols, which in turn DICHLORALPHENAZONE
ionize. Thus they have an aromatic ring with an anionic Antipyrine • Chloral Hydrate
charge two atoms away.
O
Search for better drug
produced the
pyrazolidinediones which are
acidic because the bdiketone tautomrizes into an
acidic enol
N NH
pyrazole
HN NH
pyrazolidine
O
O
OH
HN NH
HN NH
pyrazolidinedione
O
O
N
N
CH3
N
O
O
Phenylbutazone
CH3
N
HO
Oxyphenbutazone
Phenylbutazone is equipotent to antipyrine, and more potent than aspirin for
treating inflammation. It has long half-life (72-84 hours). Serious toxicities, e.g.,
agranuylocytosis, peptic ulcers and bone marrow depression, limits its use in
long term therapy.
Oxyphenbutazone is its active metabolite with similar activity, equipotent but
less toxic, shorter half–life (half-life 48-72 hours) and better tolerated.
w-1 Hydroxyl is another metabolite with uricosuric activity but little anti–
inflammatory activity
The keto metabolite, Kebuzone, is marketed in Europe as a uricosuric agent.
Sulfinpyrazone is marketed in the US as a uricosuric.
The two phenyl rings are not coplanar due to their close proximity, on adjacent
nitrogens. The ortho hydrogens one each ring are effective at this close proximity
Arylacetic acid Derivatives
Satisfy SAR 1, SAR 2, SAR 4 as well as SAR 3 thus are generally more potent
than ASA. Indomethacin was synthesized in 1961 at Merck as part of a study of
indole derivatives as potential anti–inflammatory agents since Serotonin, which
contains the indole nucleus, is a potential mediator of inflammation. The indole
system and the phenyl ring are separated by one atom and thus two sigma bonds.
Theoretically it could exist in millions of conformation, but it does not due to skillful
molecular manipulations.
CH3 O
INDOMETHACIN
Indocin
O
H3C O
C
CH3
O
Cl
CH3 O
CH2 COOH
CH3
N
OH
N
CH2 COOH
O
N
O
CH3
C
Different conformers of Indomethacin
Cl
Cl
Illustrates SAR 3. Partial double bond character of amide
restrict rotation. 2-Methyl provides steric hindrance favoring
the active conformer and the hydrogen atoms at 7 and 2’
provide hindrance to ensure non coplanarity
Sulindac: Indomethacin has significant CNS side effects due
to the indole nucleus. Thus the heterocyclic nitrogen was
removed and a double bond introduced, giving the indene
derivative. Z isomer is active, lacks the CNS side effects and
causes less GI irritation but low water solubility. Introduction of
a fluoro and a methylsulfinyl increased solubility while retaining
potency. Sulindac is a prodrug. Its active form is the sulfide
metabolite which has a long half–life allowing for BID
administration. The phenyl is out of the plane
CH3 O
F
CH2 COOH
CH3
C
H
Cl
Indene analog of
Indomethacin
OH
CH3
H
H3 C
O
CH3
C
H
CH3 S
Sulindac
Clinoril
CH2 COOH
CH3
C
S
O
F
CH2 COOH
O
F
H
CH3 S
Sul indac
Sul fide of Sul indac
Clinically it has only about half the potency of Indomethacin in treating inflammation
and reducing fever, but is equipotent in analgesic effect. Since the drug is absorbed
as the inactive sulfoxide, it causes fewer GI disturbances (no prostaglandin
biosynthesis inhibition in the stomach). The thioether metabolite (shown at the
right) is longer-lived than the parent (ca. 16 hours).
Indole replaced with pyrrole
N
O
O
ONa
ONa
CH3
CH3
O
H3C
TOLMETIN Na
Tolectin
N
CH3
O
Cl
Zomepirac Na
[Zomax]
Tolmetin was designed to contain the three portions of Indomethacin deemed
necessary for activity, the carboxyl, the flat indole ring and an out of plane phenyl
Compared to Indomethocin, is there anything to ensure SAR 3, that one
conformer predominates and the two aromatic rings are non coplanar? Which is
more potent and why?
Tolmetin’s major metabolite is the carboxylic acid resulting from benzylic
hydroxylation and subsequent oxidation. It has a half–life of 30 to 60 minutes
To increase the duration of action the methyl was replaced with a chloro which
prevented metabolism at the phenyl ring. This drug was Zomepirac which was
marketed but eventually removed due to reports of severe anaphylactoid
reactions in patients sensitive to Aspirin.
O
O
OK
ONa
NH
NH
Cl
Cl
Cl
Cl
Diclof enac Na
Diclof enac K
Voltaren, (Arthrotec), Cataf lam
Solaraze
The SARs in Diclofenac sodium are similar to those discussed with the
Fenemates. Diclofenac is probably the most popular NSAID in the world. Its
mechanism of action may be a little different from the others. It is a COX inhibitor
like the rest, but it also seems to inhibit lipoxygenase to some degree. This could
account for its increased anti-inflammatory effectiveness and potency. The two Cl
groups are necessary to force the two rings out of plane with each other. It has a
profile of action similar to the others and favors anti-inflammation uses, rather
than analgesic uses.
Diclofenac is also available in combination with Misoprostol as Arthrotec™.
Why? The Sodium salt is a delayed release formulation while the Potassium salt
is used in a rapid release formulation.
Diclofenac sodium is available in a gel form (Solaraze) for the treatment of
actinic keratosis. The mechanism is unknown.
Arylpropioanic acid Derivatives
These agents illustrate SAR 4, 6 and 7
Activity resides in the S isomer. in vivo some of the inactive R isomer is
converted to the active S by isomerases, but not the S to R. One reference
states that 60% of an Ibuprofen and 100% of a Fenoprofen dose undergo
isomerization. Another reference states that S–Ibuprofen is 160 times more
active than R–Ibuprofen in vitro but they were equipotent in vivo.
IBUPROFEN
Motrin, Rufen, Advil, Nuprin,
CH3
(Vicoprofen)
3
O
O
O
OH
OH
OH
F
H3C
KETOPROFEN
Orudis, Oruvail CH3
FLURBIPROFEN
Ansaid
CH
O
CH3
Ibuprofen is the prototype, marketed as the racemate. Lacks second
aromatic ring (SAR 2) but possess a sec–butyl substituent that presumably
renders the drug slightly less potent. Its profile is much like other NSAIDs in
terms of GI distress.
Flurbiprofen resulted from a study of the SARs. The 3–fluoro substituent
helps ensure non–coplanarity. This compound had the most favorable
therapeutic profile and was first introduced as a topical product for ophthalmic
use (Ocufen). Later it was introduced for systemic use (Ansaid is reputed to
stand for Another NSAID). This drug is many times the potency of the other
drugs (100x phenylbutazone against inflammation), and is about half as potent
as methylprednisolone (an anti-inflammatory steroid).
Ketoprofen (1986): The great potential advantage of this drug is that it
inhibits the leukotriene pathway as well, although its structure does not predict
that. It is clinically less potent than Indomethacin, but has about the same GI
disturbance profile
SUPROFEN
Profenal
FENOPROFEN Calcium
Nalfon
CH3
CH3
O
O
OH
S
O
KETOROLAC Tromethamine
Toradol, Acular
Ca
++
O
O
N
O
NH3
O
O
HO
OH
OH
2
Suprofen (1985) is an isostere of Ketoprofen an analgesic for mild to
moderate pain. It was found to cause flank pain and transient renal failure and
was withdrawn in 1987. It then was reintroduced in 1989 for ophthalmic use in
lens replacement surgery to prevent iris inflammation.
Fenoprofen (1976) is less potent than many of the others for inflammation,
with some analgesic and antipyretic activity. It does not illustrate SAR 3. No
special advantage is shown by this drug.
Ketorolac is related to Indomethacin and Tolmetin because it has the
pyrrole ring, but is a cyclic propionic acid derivative (SAR 8), commercially
available as the tromethanime salt. The tromethamine moiety enhances water
solubility. The injectable formulation is incompatible with solutions of
conjugate acids like meperidine hydrochloride (precipitation). It is about half
as potent as Morphine when injected. After its success as a parenteral agent,
an oral agent was marketed.
NAPROXEN
Naprosyn
NAPROXEN Sodium
Anaprox, Aleve,
CH3
Naprelan
CH3
O
O
CH3
OH
O
CH3
CARPROFEN
Rimadyl
O
CH3
O
ONa
Cl
OXAPROZIN
Daypro
OH
O
O
NH
N
OH
Naproxen does not possess a second non coplanar ring (SAR 3).
The naphthyl rings are fused and aromatic thus flat and planar. It is
the only drug currently marketed in the optically pure form. This is not
due to resolution but is the result of the synthetic method used.
Interestingly the S isomer of Naproxen is (+) as most in this class are,
but the S isomer of the sodium salt is (–).
Carprofen is marketed as a veterinary analgesic. Does it have a
second non–coplanar ring, SAR 2?
Oxaprozin is an aryl propionic acid but is unique in that the propyl
is not branched.
Oxicams
Pfizer developed this class to produce non–carboxylic acid NSAIDS
PIROXICAM
Feldene
OH
N
O
S
O
MELOXICAM
Mobic OH O
O
N
H
CH3
N
N
O
S
N
N
H
S
CH3
CH3
O
Piroxicam is the first member of this family marketed, however it possess the
three structural requirements. The enolic hydroxyl is the acidic group and the
pyridyl ring is the second aromatic ring. Although it has good potency, the GI side
effects limit its usefulness. A typical half-life for Piroxicam is ca. 38 hours.
Meloxicam is structurally related to Piroxicam. Although Meloxicam is frequently
described in the literature as a selective COX-2 inhibitor, it is considerably less
selective for the COX-2 versus COX-1 isoenzyme when compared to Celecoxib
or Rofecoxib.
Miscellaneous
ETODOLAC
Lodine
H3C
H3C
H
N
NAMBUMETONE
Relafen
O
6–Methoxy–2–naphthylic acid
6–MNA
O
O
O
OH
O
O
CH3
CH3
OH
Etodolac can be considered a nonclassical bioisostere of the arylpropionic acids.
It is ca. 50x more potent than aspirin in inflammation, 33% as potent as
indomethacin. It shows a much better GI profile than aspirin or indomethacin and
this can be a therapeutic advantage. It is a unique compound. How many aromatic
rings does it have? Note the separation between the aromatic ring and the acid.
Nabumetone is a ketone and thus non–acidic (SAR1?). It is classed as an
Alkanone. It is a prodrug and must be activated by b–oxidation to 6–Methoxy–2–
naphthylacetic acid. Approximately 35% of a 1000mg dose is converted to 6–
MNA, which is structurally related to Naproxen, an arylacetic acid. But is only an
acetic acid derivative thus weaker than Naproxen. Further, not all the dose is
converted to 6–MNA. The advantages of this drug is less GI tract toxicity because
it is not acidic
Allopurinol is a structural analog of hypoxanthine
and thus is a xanthin oxidase inhibitor used to
treat hyperuricemia and its complications including
chronic gout as well as prophylaxis with
chemotherapeutic treatments, which can rapidly
produce severe hyperuricemia.
O
O
N
HN
HN
N
N
N
H
Hypoxanthene
N
N
H
Allopurinol
Drugs for Inflammatory Bowel Disease (Ulcerative Colitis)
Mesalamine or 5-aminosalicylic acid (5-ASA), and its prodrugs balsalazine
and olsalazine are anti-inflammatory drugs/prodrugs used to treat
inflammation of the digestive tract (ulcerative colitis) and mild-to-moderate
Crohn's disease. Mesalazine is a bowel-specific aminosalicylate drug that
acts locally in the gut and has its predominant actions there, thereby having
few systemic side effects. Balsalazine and olsalazine generate mesalamine
in the site of action. (How about salfasalazine??)
NaOOC
H2N
NaOOC
O
OH
HO
N
N
OH
HO
N
N
Mesalamine COOH
HN
Olsalazine
COONa
O
Balsalazine
ONa
COX - 2 Inhibitors
CELECOXIB
Celebrex
F 3C
O
N
N
S
NH2
O
O
REFECOXIB
Vioxx
VALDECOXIB
O
Bextra
O
S
O
CH3
CH3
O
N
S
NH2
DERACOXIB
Deramax
O
S
F
N
O
F
O
CH3
NH2
O
N
F
OCH3
Celecoxib was the first. Structurally it differs from other NSAIDS in that is only
weakly acidic. It does possess a sulfamyl group and has a warning about use in
patients with a sulfonamide allergy
Valecoxib is also a sulfamyl and its package insert contains the same caution. It
is this phenyl group which is inserted into the extra space in COX–2
Deracoxib is also acidic but is indicated for veterinary use
Rofecoxib is not acidic
Refecoxib and MI
One of the reasons given is that the endothelial cells express mainly
COX–2 whereas platelets express COX–1. Since Refecoxib is COX–
2 selective it allows for an overproduction of Thromboxane A2
(platelet).
Thromboxane is released by platelets and causes vasoconstriction
and platelet aggregation. Prostacycline is release by capillary
endothelium and causes vasodilatation and prevents platelet
aggregation. Normally these balance each other; The platelets use
COX-1 and the capillaries use COX-2. Thus COX-2 selective agents
unbalance the system favoring thromboxane.
However this is not the only factor in play since the other COX–2
selective agents have not shown the increase in MI
Study Guide

What are cyclooxygenase and peroxydase? What do you mean by
prostaglandin endoperoxide H2 synthase (PGHS)?

What are COX-1 and COX-2? What physiologically important prostaglandins
and thromboxanes are synthesized by them blocking of which gives clinical
effects of different NSAIDs?

What are different chemical categories of NSAIDs? List the nonselective and
COX-2 selective NSAIDs with structures.

Similarities and differences between COX-1 and COX-2 – with reference to
physiology, active site amino acids, size and shape of active site.

Diflunisal is a salicylic acid derivative yet does not cause much is gastric
bleeding and GI upset. Why?

Why low-dose, long term aspirin is recommended for the prevention of
strokes and heart attacks?

Describe the action and mechanism of action of acetaminophen. Is COX-3
important for its activity?
Study Guide Cont.

Are pyrazoles & pyrazolidinediones acids? What is their mechanism of
action?

Why indomethacin is highly potent analgesic yet toxic to CNS? Why
sulindac can be considered as its isostere without CNS effect? Is sulindac a
prodrug?

Why diclofenac and ketoprofen are highly potent anti-inflammatory agents?

Which stereoisomer of ibuprofen is biologically active? Why it is not
necessary to resolve the active form rather than administering the recemic
mixture?

The mercapturic acid conjugate is a sign of acetaminophen toxicity. Why?

Are the oxicams classified as COX-2 selective agents? Why or why not?

What is the active principle of sulfasalazine in IBS? Why it is replaced with
better alternatives? Which are they?

Why coxibs are selective to COX-2 and not bound to COX-1. Why the
coxibs have more CV risk than other NSAIDs?