Chapter 5

44 4

Non-narcotic analgesics &

related drugs

1
 Non steroidal anti-inflammatory drugs
(NSAIDs)

 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.

2
 Natural Eicosanoids
PGA2
O O PGB2 O PGC2
9 5 1
COOH COOH COOH
CH3 CH3 CH3
11 13 15 20
OH OH OH

HO PGD2 O PGE2 HO PGF2

COOH COOH COOH
CH3 CH3 CH3

O HO OH HO
OH OH

PGG2 PGH2 PGJ2

O O
COOH COOH COOH
CH3 CH3 CH3
O O
O
OOH OH OH

PGI2 Prostacycline TXA2 Thromboxane A2 TXB2

OH
COOH COOH
O
O CH3 COOH
O
CH3
OH HO O
CH3 OH

OH 3
OH
 Commercial Prostanoids

A. Ocular Hypertension & Glaucoma

BIMATOPROST LATANOPROST
HO Lumigan HO Xalatan
N CH3 O CH3
H
O CH3
O

HO HO OH
OH

TRAVOPOST UNOPROSTONE isopropyl

Travatan Rescula
HO HO
O CH3 O CH3

O CH3 O CH3
O
HO OH HO O CH3
CF3

4
 Commercial Prostanoids -II
B. Pulonary Hypertension
EPOPROSTENOL ILOPROST TREPROSTINIL sodium
PGI Ventavis Remodulin
Flolan ONa
COOH COOH
O OH
O H

CH3 CH3 O CH3

H
OH
HO OH HO OH

C. Other Uses

CARBOPROST MISOPROSTOL
Hemabate Cytotec,(Arthortec)
HO O O
CH3
COOH O
OH CH3
CH3 CH3

HO H3 C OH HO

ALPROSTADIL DINOPROSTONE
Prostglandin E1 Prostglandin E2
Prostin VR, Caverject, Edex, Muse Prostin E2, Prepidil, Cervidil
O O
COOH
COOH
CH3 CH3

HO 5
HO OH OH
 Prostaglandins - Nomenclature
Prostanoic acid PGE1 O PGE2 O PGE3
1 O
9
COOH COOH
COOH COOH
20
11 15
HO HO HO
OH OH 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.

6
 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.

7
 Prostaglandins - Biosynthesis
Phospholipase A 1
 Prostaglandins are biosynthesized Phospholipase A 2
O
from Arachidonic acid O O C
C O (CH2 )nCH 3
 Archidonic acid is found esterified as O O CH 3
a cell membrane phospholipid P
O N
O CH 3
Phospholipase C CH 3
 The concentration of free arachidonic
Phospholipase D
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 8
 THE EICOSANOIDS
The Arachidonic Acid Cascade

O
O O C
C O (CH2)nCH3
O
O CH3
P
N
O O CH3
H3 C
Lipoxins
Phospholipase A2 [[Link]]

Arachinate COOH
15–lipoxygenase Cytochrome P450 Epoxyeicosatriene acids
15–HPETE Dihydroxy acids
[EC [Link]]
Arachidonic acid Arachinate
Arachinate 12–lipoxygenase
5–lipoxygenase [EC [Link]]
[EC [Link]] Cyclooxygenase

5–HPETE COOH 12–HPETE

O
O
Leukotrienes
LTA4
O COOH

LTB4 LTC4 O LT = Leukotriene

PG = Prostaglandin
LTD4 LTF4 O COOH
O
TX = Thromboxane
LTE4 OOH
HETE = Hydroxyeicosatetraenoic acid
Prostaglandin G2 HPETE = Hydroperoxyeicosatetraenoic acid
Peroxidase

O COOH
O
Prostaglandins Thromboxanes
OH
TXA2 TXB2
PGA2 PGB2 PGC2 PGD2 Prostaglandin H2
9
PGE2 PGF2 PGI2
 O COOH OH

H2C
C H COOH COOH PGH2 is also
O
C H
OH
Arachidonic acid HO O converted into two
Malondialdehyde Hydroxyhepta OH
decatrienoic aacid
1 Thromboxane B2 unstable yet highly
HHT
HO O COOH active
COOH O COOH
OOH
O
O
thromboxanes (so
HO OH OH Prostaglandin G2 7 OH
Thromboxane A2
named because
19–Hydroxy Prostaglandin F2a
2
HO HO they were first
O COOH
COOH 3
O
6 COOH isolated from
HO OH
OH
Prostaglandin H2
O OH thrombocytes)
Prostaglandin F2a 5 Prostaglandin D2
O O 4
COOH COOH
COOH
O
HO OH OH HO OH
19–Hydroxy Prostaglandin E2 Prostaglandin E2

O O HO OH
COOH COOH Prostaglandin I2
Prostacyclin
1. Cyclooxygenase Prostaglandin
OH OH OH endoperoxide synthase
19–Hydroxy Prostaglandin A2 Prostaglandin A2 COOH 2. Peroxidase [EC [Link]]
O O Prostaglandin endoperoxide synthase
COOH COOH (cylcooxyenase domain)
HO Prostaglandin endoperoxide synthase
OH
OH OH OH 6–Keto– Prostaglandin F1a
(hydroperoxidase domain)
19–Hydroxy Prostaglandin C2 Prostaglandin C2
3. Prostaglandin F2a synthase [EC [Link]]
O
4. Prostaglandin E2 synthase [EC [Link]]
COOH 5. Prostaglandin I2 synthase [EC [Link]]
6. Prostaglandin D2 synthase [EC [Link]]
OH 10
7. Thromboxane A2 synthase [EC [Link]]
Prostaglandin B2
 Products of 5–Lipoxygenases
Leukotriene Biosynthesis
COOH

Arachidonic acid
1
OOH OH
S CH3 inhibited by COOH 2 COOH
O
N Zileuton
HO NH2 5–HPETE 5–HETE
1
O
1. 5–Lipoxygenase + FLAP [EC [Link]]
COOH 2. Peroxidase
C5H11 3. Leukotriene A4 epoxide hyrolase (LTA4 hydrolase) [EC [Link]]
Leukotriene A4 4. LTC4 synthetase (a glutathione–S–transferase) [EC [Link]]
5. g–Glutamyl transferase [EC [Link]]
3 4 6. Cysteinyl glycinase (an amino dipeptidase)

HO H
COOH
COOH
C5H11 OH C5H11 S
Leukotriene B4 CHCONHCH2COOH
NHCOCH2CH2CHCOOH
5 Leukotriene C4 NH 2

HO H
COOH HO H HO H
COOH COOH
C5H11 H S 6
CHCOOH C5H11 H S C5H11 H S
NH2 CHCONHCH2COOH CHCOOH
Leukotriene E4 NH2 NCOCH2CH2CHCOOH
Leukotriene D4
Leukotriene F4 11
NH 2
 Products of 15–Lipooxygenases
Lipoxin Biosynthesis

COOH

Arachidonic acid
1
COOH COOH
2

OOH OH
15–HPETE 15–HETE

OH OOH
COOH COOH
2
HPETE – Hydroperoxyeicosatetraenoic acid
HETE – Hydroxyeicosatetraenoic acid
OH OOH
5,15–HETE 5,15–HPETE

1 Arachinate 15–lipoxygenase [EC [Link]]

COOH
2 Peroxidase
O 3 Arachinate 5–Lipoxygenase [EC [Link]]

OH

HO OH HO OH OH
COOH COOH COOH

OH 12
OH OH OH
6S–Lipoxin A Lipoxin B 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 13
 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

14
 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.
15
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 COX-
1 does not
 COX-2 is constitutively expressed notably in the brain and kidney
16
 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 Intracellular
low pH higher pH
– + AR—COOH AR—COOH – +
AR—COO + H AR—COO + H

Unionized fraction Ionized fraction

predominates predominates

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 17
 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

18
 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
19
 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
20
 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 21
 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

22
 1. The Salicylates
 Salicylic acid is a natural product, present in the
bark of willow and poplar trees OH
OH
 The active ingredient, isolated by a French HO
O
O
pharmacist in 1827, was Salicin, oxidized to HO
OH
Salicylic acid
Salicin
 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.

23
ASPIRIN SODIUM SALICYLATE SODIUM THIOSALICYLATE CHOLINE SALICYLATE
O (Bisalate) O Rexolate O Anthropan O H3 C
H3C
N CH3
OH ONa ONa O

O OH SH OH
OH
H3C O
SALSALATE
MAGNESIUM SALICYLATE Salf lex, Disalcid Benorylate
Magan, Mobidin, (Trisalate) O
N CH3
O O O H
OH
C O
O O O
O
Mg
O O O O
H H
H3C O
OH

 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

24
 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
25
 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 CH2 NHCOCH2NCO

COOH O H COOH O + H+ COOH CH2

O CH3 O CH3 OH O

O O-
+
O CH326
 Salicylamide and Diflunisal
SALICYLAMIDE DIFLUNISAL
(Bisalate) Dolobid
F
O O
NH2 OH
F
OH 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. 27
 2. p-Aminophenols
O O O
H H H
N CH3 N CH3 N CH3

ACETAMINOPHEN
Phenacetin Tylenol, Datril, Panadol
Acetanilide O CH3 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
29
 3. Pyrazoles and Pyrazolidinediones
Antipyrine is the prototype and its antipyretic
ANTIPYRINE Aminopyrine
(Auralgan Otic)
and analgesic activities were discovered by
O accident.
O
N CH3
N N Aminopyrine is an analog, more potent and
N
N H3 C CH3 longer acting but both possess significant
H3C
CH3
CH3 incidences of agranulocytosis leading to death
and used only in otic drops
O O
Dipyrone is a prodrug which spontaneously decomposes
S ONa
N
in aqueous solutions to aminopyrine. It is banned in the US N O
N
H3C CH3
Dichloralphenazone is a complex of Aminopyrine and CH3 Dipyrone
Chloral hydrate It is a common agent in many OTC
analgesics. It is a mild sedative used in migraine /tension O
Cl
headache products. N Cl
• OH
N Cl
Although it appears that SAR 1 does not apply, these H3C
OH
drugs are able to tautomerize into enols, which in turn CH3
ionize. Thus they have an aromatic ring with an anionic DICHLORALPHENAZONE
Antipyrine • Chloral Hydrate
charge two atoms away.
30
 O O O OH
Search for better drug N NH HN NH HN NH HN NH
produced the pyrazole pyrazolidine pyrazolidinedione
pyrazolidinediones which are
O
acidic because the b- O
N
N
diketone tautomrizes into an CH3 N
CH3
N
acidic enol O
O
Phenylbutazone 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.
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
31
 4. 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.
CH 3 O CH 3 O
CH 2 COOH CH 2 COOH
INDOMETHACIN
Indocin
O
H3C O CH3 CH3
N N
OH
C C
CH3 O O
N

Cl Cl
O
Different conformers of Indomethacin
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
32
 O O

ONa OK
NH NH
Cl Cl Cl Cl

Diclof enac Na Diclof enac K

Voltaren, (Arthrotec), Cataf lam
Solaraze

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™.
The Sodium salt is a delayed release formulation while the Potassium salt is
used in a rapid release formulation.

35
 5. 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.

36
 IBUPROFEN FLURBIPROFEN KETOPROFEN
Motrin, Rufen, Advil, Nuprin, Ansaid Orudis, Oruvail CH3
CH3
(Vicoprofen) CH3 O
O
O
OH
OH
OH
F O
H3 C 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.
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

37
 NAPROXEN NAPROXEN Sodium CARPROFEN OXAPROZIN
Naprosyn Anaprox, Aleve, Rimadyl Daypro
CH3 CH3 CH3
Naprelan
O O O

OH ONa OH O
O O
Cl O
CH3 CH3 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 (–).
Oxaprozin is an aryl propionic acid but is unique in that the propyl
is not branched.

39
 6. Oxicams
Pfizer developed this class to produce non–carboxylic acid NSAIDS

PIROXICAM MELOXICAM
Feldene Mobic OH O N
OH O CH3
N S
N N H
H N
N S CH3
S CH3 O O
O 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.

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 7. Miscellaneous
ETODOLAC NAMBUMETONE 6–Methoxy–2–naphthylic acid
Lodine H3C Relafen O 6–MNA
H O O
H3C N
O
OH OH
O O

CH3 CH3

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.
Note the separation between the aromatic ring and the acid.

41
Allopurinol is a structural analog of hypoxanthine O O
and thus is a xanthin oxidase inhibitor used to HN N
HN
treat hyperuricemia and its complications including N
N
chronic gout as well as prophylaxis with N
H N N
H
chemotherapeutic treatments, which can rapidly Hypoxanthene Allopurinol
produce severe hyperuricemia.

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.
NaOOC NaOOC
H2N OH O O
HO N N OH HO N N
Mesalamine COOH HN ONa
COONa Balsalazine
Olsalazine 42
 COX - 2 Inhibitors
CELECOXIB REFECOXIB VALDECOXIB DERACOXIB
Celebrex O Vioxx O Bextra O Deramax O
NH2 CH3 NH2 NH2
S S CH3 S F S
N N
F 3C N O O O O O N O
F
N
O
F

CH3 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

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 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

44