Non- Steroidal Anti-Inflammatory

Drugs (NSAIDs)
LIU- School of Pharmacy
Spring Semester 2023-20244
PHAR450 – Medicinal Chemistry II
 Introduction
• NSAIDs are a class of drugs that relief pain, reduce inflammation
(redness and swelling) and bring down high temperature (fever).
• NSAIDs are used to treat a wide range of conditions: headaches,
painful periods, toothache, sprains and strains infections, such as
the common cold or the inflammation of the joints (arthritis) and
other tissues.
• NSAIDs act by inhibiting the production of prostaglandins,
chemical messengers responsible for pain and swelling of
inflammatory conditions.

PHAR 450- Spring 23/24 2

 Prostaglandins (PGs)
• PGs are naturally occurring unsaturated fatty acid derivatives
containing 20 Cs that include a cyclic ring structure =
cyclopentano fatty acid derivatives produced from
polyunsaturated fatty acids
• Class of PGs: Eicosanoids (unsaturated fatty acid derivatives) and
include:
-Prostaglandins -Thromboxanes
-Prostacyclin -Leukotrienes
• PGs are a family of mediators produced by the cells of the body in
response to illness or injury. They promote inflammation, pain,
and fever; support the blood clotting function of platelets; and
protect the lining of the stomach from the effects of acid.
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 **NSAID-Induced Asthma

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**Prostaglandins as Drugs
 MOA of NSAIDs
• The major mechanism by which the
NSAIDs elicit their therapeutic effects
(analgesic, antipyretic and anti-
inflammatory) is inhibition of PG
synthesis.

• NSAIDs competitively inhibit COX (COX1

and COX2), the enzymes that catalyze the
synthesis of PGs.

• Selective COX-2 inhibitors are NSAIDs

that selectively block the COX-2 enzyme,
thus, preventing the production of PGs
that often cause the pain and swelling of
inflammation and other painful
conditions without affecting the
protective mucus lining of the stomach,
as realized in non-selective COX
inhibitors. PHAR 450- Spring 23/24 5
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 MOA of NSAIDs
• Most NSAIDs, salicylates, arylalkanoic acids, oxicams or anthranilic
acid derivatives, possess the common structural features of an:
– Acidic center
– Aromatic or heteroaromatic ring
– Additional center of lipophilicity in the form of an:
⌑ Alkyl chain
⌑ Additional aromatic ring
• The active site of COX consists of:
– Cationic site to which the –COO- would bind through ionic bonding
– Flat area to which the indole ring would bind through Vander Waals forces
– Out-of-the-plane trough to which the benzene ring of the p-chlorobenzoyl
group would bind through hydrophobic or charge-transfer interactions
– Additional binding sites for CH3O- & C=O groups were suggested
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 NSAIDS - Aminophenols Derivatives
• Acetaminophen (paracetamol) is the only useful agent in this class used as
analgesic-antipyretic OTC medication; it is the metabolite of both aniline
(acetanilide and phenacetin) and less toxic than both anilines.
• It is weakly acidic in nature.
• Its analgesic activity is comparable to aspirin ⇒ individuals who are hypersensitive
to salicylates generally respond well to acetaminophen
• High Safety margin, and it is the drug of choice to treat fever in COVID-19 patients
• No useful anti-inflammatory activity ⇒ May be due to its greater inhibition of PG
biosynthesis in the CNS than in the periphery
• Weakly bound to plasma proteins

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 Metabolism & Toxicity
• Both acetanilide & phenacetin:
• are metabolized to acetaminophen
• undergo hydrolysis to yield aniline derivatives
that produce hydroxylamine derivatives ⇒
significant methemoglobinemia and hemolytic
anemia ⇒ removal from the U.S. market
• Acetaminophen is metabolized primarily by
conjugation reactions:
• O-sulfate conjugate ⇒ 1° metabolite in children
• O-glucuronide ⇒ 1° metabolite in adults
• Acetaminophen and phenacetin produce N-
hydroxyamide (minor produced CYP450) ⇒
N-acetyl-p-benzoquinoneimine (NAPQI)
(reactive toxic metabolite)⇒ nephrotoxicity
& hepatotoxicity
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PHAR 450- Spring 23/24 10
 Metabolism & Toxicity/Detoxification
• Quinone is detoxified by conjugation with hepatic glutathione.

• In cases of large doses or overdoses of acetaminophen, hepatic stores of glutathione

may be depleted (>70%), the reactive quinone interacts with nucleophilic functions,
primarily -SH groups, on hepatic proteins that results in formation of covalent
adducts and hepatic necrosis.

• Overdoses of acetaminophen yield to fatal hepatic necrosis, renal tubular necrosis

and hypoglycemic coma.

• Various sulfhydryl-containing compounds (N-acetylcysteine) were found to be useful

as antidotes to acetaminophen overdoses.

• N-acetylcysteine, serves as a substitute for the depleted glutathione, by enhancing

hepatic glutathione stores, or by enhancing disposition by nontoxic sulfate
conjugation. N-acetylcysteine may also inhibit the formation of the toxic
imidoquinone metabolite
PHAR 450- Spring 23/24 11
 Drug Interactions
• Hepatic necrosis develops at much lower doses of acetaminophen in some
heavy drinkers than would be expected due, perhaps, to:
– induction of CYP450
– depletion of glutathione stores
– abnormalities in the primary sulfate and glucuronide conjugation pathways
• Interactions with warfarin has been suggested (mechanism is not fully
elucidated). It may be:
– associated with competition for plasma protein binding sites because acetaminophen is a
weak acid and is weakly bound
– due to the induction of hepatic enzymes
• Effects of acetaminophen:
– ➘ in presence of enzyme inducers as barbiturates
– ➚ by metoclopramide and salicylamide
• Absorption of acetaminophen is:
– ➘ by polysorbate and sorbitol
– ➚ by anticholinergics and narcotic analgesic
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 NSAIDs
Salicylates

Arylalkanoic Acids

N-Arylanthralinic Acids

3,5- Pyrazolidinediones

Oxicams

Selective COX-2 Inhibitors

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 Salicylates
• Salicylates are derivatives of 2-hydroxybenzoinc acid (salicylic
acid).
• Salicylates have potent anti-inflammatory activity with mild
analgesic and anti-pyretic activities.
• Salicylates bind with higher affinity to COX-1
• Derivatives of salicylic acid began to receive medical attention
shortly thereafter.

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PHAR 450- Spring 23/24 15
 GI side effects

SAR of Salicylates
• Active moiety is the salicylate anion (R-COO-):
• Side effects of aspirin, particularly the GI effects, appear to be
associated with the COOH group
• Reducing acidity of -COOH ⇒ conversion to an amide ⇒
salicylamide:
• Maintains the analgesic actions of salicylic acid derivatives
• Eliminates the anti-inflammatory properties
• Substitution on either the carboxyl or phenolic
hydroxyl groups ⇒ may affect potency & toxicity
• Removal of –OH group ⇒ Benzoic acid ⇒ Weak activity
• Placing the phenolic -OH group meta- (C3) or para-
(C4) to the carboxyl group ⇒ No activity
• Substitution of halogen atoms on the aromatic ring ⇒
➚ potency & toxicity
• Substitution of aromatic rings at C5 ⇒ ➚ anti-
inflammatory activity ⇒ Diflunisal
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 Absorption of Salicylates
• Salicylates are rapidly absorbed on oral administration. Rate of
absorption & bioavailability depends on:
Gastric pH: Salicylates are weak acids, thus, mainly absorbed from the small
intestine and to a lesser extent from the stomach. Thus, gastric pH is an
important factor in the rate of absorption of salicylates.
Any factor ➚ gastric pH (e.g., buffering agents) ⇒ salicylate will be ionized ⇒ ➚
solubility of salicylates ⇒ ➚ absorption
Food contents present in the stomach➘ rate of absorption.
Formulation factors :
• Tablet formulations consisting of small particles are absorbed faster than those of larger
particle size
• Absorption of salicylate from rectal suppositories is slower and incomplete ⇒ Not
recommended when high levels are required
• Topical preparations of salicylic acid are effective in that the rate of salicylate absorption
from the skin is rapid
• Salicylates are highly bound to plasma protein albumin ⇒ drug-drug
interactions
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 Metabolism of Salicylates
• The initial route of metabolism is the
conversion to salicylic acid ⇒ excreted
in the urine as the free acid (10%)
• Conjugation with:
• Glycine ⇒ salicyluric acid = major
metabolite (75%)
• Glucuronic acid ⇒ glucuronide ether and
ester (15%)
• Small amounts of metabolites resulting
from aromatic hydroxylation ⇒ Not
active ⇒ e.g., Gentisic acid
Metabolism of salicylic acid and its derivatives. Glu =18
PHAR 450- Spring 23/24
glucuronide
conjugate, Gly = glycine conjugate.
 Side Effects of Salicylates
• GIT disturbances: nausea, vomiting, epigastric discomfort, intensification of
symptoms of peptic ulcer disease such as dyspepsia and heartburn,
gastric ulcerations, erosive gastritis, and GI hemorrhage occur in
individuals on high doses of aspirin
• At therapeutic doses used in anti-inflammatory therapy ⇒ Aspirin may lead to
GI bleeding

• The mechanism by which salicylates cause gastric mucosal cell damage may be
due to:
– Gastric acidity
– Ability of salicylates to damage the normal mucosal barrier which protects against the back
diffusion of H+
– Ability of salicylates to inhibit the formation of PGs, particularly the PGE series which
normally inhibit gastric acid secretion
– Inhibition of platelet aggregation ⇒➚ tendency toward bleeding ⇒ use prior to surgery or
tooth extraction is contraindicated
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 Salicylates Hypersensitivity
• Salicylate hypersensitivity, particularly to aspirin, is relatively uncommon but
must be recognized since severe and potentially fatal reactions may occur.
• Signs of aspirin hypersensitivity appear soon within administration and
include:
– Skin rashes - Watery secretions
– Urticaria - Vasomotor rhinitis
– Edema - Bronchoconstriction
– Anaphylaxis
• Aspirin-sensitive asthmatics are especially at high risk.
• Mild salicylism may occur after repeated administration of large doses.
• Symptoms include:
- Dizziness - Tinnitus (sensation of noise)
- Nausea - Vomiting
- Diarrhea - Mental confusion
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 Aspirin/Acetylsalicylic acid
• Stability of Aspirin:
– Stable in a dry environment
– Hydrolyzed to salicylic acid + acetic acid under humid or moist conditions
– Hydrolysis can also occur when aspirin is combined with:
• Alkaline salts
• Salts containing water of hydration
• Stable aqueous solutions of aspirin are thus unobtainable despite the addition
of modifying agents that tend to decrease hydrolysis.
• Despite the vast effort which has been expended in the search to find a “better”
aspirin, that is, one possessing:
– Fewer GI side effects
– Increased potency
– Longer DOA
– Inexpensive
– With antipyretic, analgesic & anti-inflammatory activity
• None has been discovered
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 Aspirin/Acetylsalicylic acid
• Aspirin is the only NSAID that covalently modifies COX by acetylating both:
- Ser-530 of COX-1 - Ser-516 of COX-2
• Aspirin is 10-100 X more potent against COX-1 than COX-2
• Aspirin is rapidly absorbed from the stomach and upper small intestine upon
oral administration largely intact but is rapidly hydrolyzed by plasma
esterases.
• Peak plasma levels are usually achieved within 2 hrs after administration.
• ➚ pH of the stomach by the addition of buffering agents ⇒ ➚ degree of
ionization ⇒ may affect absorption
• Aspirin is indicated (dose-related):
– For the relief of minor aches and mild to moderate pain
– For arthritis and related arthritic conditions
– To reduce the risk of transient ischemic attacks in men (low-dose)
– For myocardial infarction prophylaxis (low-dose)
Coadministration of AspirinPHAR
and Other NSAIDs???
450- Spring 23/24 23
PHAR 450- Spring 23/24 24
 Salicylamide
• Salicylamide: much less acidic than other salicylic acid derivatives
• The major advantages of salicylamide relative to aspirin are:
– Its general lack of gastric irritation
– Its use in individuals who are hypersensitive to aspirin
• Where as salicylamide is reported to be as effective as aspirin as an analgesic-
antipyretic and is effective in relieving pain associated with arthritic
conditions, it does not appear to possess useful anti-inflammatory activity.
• Absorbed from the GI tract on oral administration. Rapidly metabolized to
inactive metabolites by intestinal mucosa, but not by hydrolysis. Excretion
occurs rapidly, primarily in the urine. Thus, activity appears to reside in the
intact molecule.
• ~40-55% plasma protein bound
• It competes with other salicylates and acetaminophen for glucuronide
conjugation decreasing the extent of conjugation of these other agents
PHAR 450- Spring 23/24 25
 Salicylate Salts

• These salts are used primarily to decrease GI disturbances because they

form stable aqueous solutions
• Na+ salicylate:
– is half as potent, on a weight basis, as aspirin as an analgesic & antipyretic
– produces less GI irritation and equivalent blood levels
– is useful in patients exhibiting hypersensitivity to aspirin
– does not affect platelet function
• It generates salicylic acid in the GIT accounting for some GI irritation 
Na+ bicarbonate is sometimes given concomitantly to reduce acidity.
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 Salicylate Salts
• Magnesium salicylate has a low incidence of GI side effects.
• Both Na+ and Mg2+ salicylates should be used cautiously in patients
whom excessive amounts of these electrolytes might be detrimental.
• Na+ thiosalicylate:
– is indicated for rheumatic fever, muscular pain and acute gout
– is available as a solution for IM injection.
• Choline salicylate has lower GI SE than aspirin and has been shown to
be particularly useful in treating juvenile rheumatoid arthritis where
aspirin was ineffective.
• It is absorbed more rapidly than aspirin and produces higher salicylate
plasma levels.

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Salsalate (Disalcid)
• Salsalate is a dimer of salicylic acid.
• It is insoluble in gastric juice but is soluble in the small intestine where
it is partially hydrolyzed to two molecules of salicylic acid and then
absorbed.
• It does not cause GI blood loss and can be given to aspirin-sensitive
patients.

Diflunisal (Dolobid)
• Diflunisal used as an analgesic and to treat rheumatoid arthritis and
osteoarthritis.
• Diflunisal is metabolized primarily to ether and ester glucuronide
conjugates.
• t½ 3-4 X greater than that of aspirin
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 Arylalkanoic Acids
- Aryl Acetic Acids
- Aryl Propionic Acids
• This class is the largest group of NSAIDs
• The arylalkanoic acids, to various extents, inhibit the COX-1 & COX-2 with
varying degrees of selectivity ⇒ Inhibition of PG biosynthesis.
• Agents of this class share a number of common structural features.
• Specific SARs for each drug or drug class will be presented separately, where
appropriate.
• All of the arylalkanoic acids are highly bound to plasma proteins
• Most commonly observed interaction is that b/w the arylalkanoic acid and
oral anticoagulants (warfarin) ⇒ Co-administration may prolong prothrombin
time
• Co-administration of aspirin ➘ plasma levels of arylalkanoic acids
PHAR 450- Spring 23/24 29
 General SAR/Arylalkanoic Acids
• All nonselective COX inhibitors possess a center of acidity which can be
represented by:
• Carboxylic acid function (RCOOH)
• Enolic function (Alkenolic derivative)
• Hydroxamic acid function (RCONROH)
• Sulfonamide (R1SO2NHR2)
• Tetrazole ring (RCHN4)
• The relationship of this acid center to the –COOH function of arachidonic
acid is obvious.
• Center of acidity: Activity of ester & amide derivatives of carboxylic acids is
generally attributed to the metabolic hydrolysis products. i.e., Nabumetone:
Non-acidic drug but active ⇒ Activity is attributed to its active acid
metabolite
• Center of acidity is generally located 1C adjacent to a flat surface
represented by an aromatic (aryl or heteroaryl) ring
- 2 or 3 Cs ⇒ generally ➘ activity
PHAR 450- Spring 23/24 30
 General SAR/Arylalkanoic Acids
• Substitution of a -CH3 group on the C atom b/w the acid center & the
aromatic ring ⇒ α-methyl acetic acid or 2-substituted propionic acid
analogs = class name: “profens” ⇒ ➚ anti-inflammatory activity.
• Substitution of groups larger than -CH3 ⇒ ➘ activity
• Incorporation of -CH3 in an alicyclic ring system does not drastically
affect activity
• Introduction of a -CH3 group ⇒C* ⇒ R/S enantiomers ⇒ (S)-(+)-
enantiomers is responsible for the anti-inflammatory activity
• When propionic acid is administered as a racemic mixture (R/S) ⇒
conversion of R to the active S-enantiomer

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Structures of Aryl-
and
Heteroarylacetic
Acid Derivatives

PHAR 450- Spring 23/24 32

 Indomethacin
• Indomethacin is one of the commonly used and most
effective NSAIDs to reduce fever (more than aspirin and
acetaminophen), pain (10 X > Aspirin), stiffness and
swelling.
SAR of Indomethacin/Indole
• Acylation of the indole nitrogen with aliphatic or aralkyl
carboxylic acids ⇒ Amide derivatives less active than
those derived from benzoic acid
• N-Benzoyl derivatives substituted in the para-position
(with F, Cl, F3C- or H3C- S groups) are the most active
• Indole ring nitrogen is not essential for activity ⇒ 1-
benzylidenylindene analogs ⇒Sulindac ⇒ active
PHAR 450- Spring 23/24 33
 SAR of Indomethacin
• Substituents at 5-position of the indole
ring ⇒ CH3O-, -F, dimethylamino, - CH3,
allyloxy, CH3CO- ⇒ More active than the
unsubstituted indole ring
• Substitution of alkyl groups (especially
–CH3) at the α-position generates:
– Propionic acid derivatives ⇒ equiactive
analogs
– C* ⇒ R/S ⇒ (S)-(+)-enantiomer displays
the anti-inflammatory activity

PHAR 450- Spring 23/24 34

All metabolites are inactive.
 Sulindac
• Designed and synthesized to produce an analog free of the side
effects (particularly GI irritation) associated with indomethacin.

• It is a “prodrug”, thus, results in an active metabolite that inhibits

the COX system ⇒ ~8 X > aspirin

• In anti-inflammatory and antipyretic assays ⇒ about one-half as

potent as indomethacin

• In analgesic assays ⇒ Equipotent

PHAR 450- Spring 23/24 35
 SAR of Sulindac
• Replacement of the indole ring with the indene ring system leads to a
derivative with:
Useful anti-inflammatory activity
Less CNS and GI side effects
Poor water solubility ⇒ Crystalluria

• Replacement of the N-p-chlorobenzoyl with a benzylidene function ⇒

active derivatives

• Replacement of 5-methoxy group of the indene isostere with a F atom ⇒ ➚

analgesic effect

• Replacing p-Cl atom with a sulfinyl group ⇒ ➚ water solubility

PHAR 450- Spring 23/24 36
 SAR of Sulindac
Stereochemistry
• Benzylidene isostere contains a double bond ⇒ Z/E isomers ⇒(Z)-isomer is a much
more potent anti-inflammatory agent than (E)-isomer
• Both indomethacin & sulindac assume similar conformations at the active site of COX

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Tolmetin Sodium
• Indication: Rheumatoid arthritis, juvenile rheumatoid arthritis, and osteoarthritis
• MOA:
– Inhibits PG biosynthesis
– Inhibits polymorph migration
– ➘ capillary permeability

SAR of Tolmetin
• Tolmetin has a pyrrole ring instead of the indole ring in indomethacin
• Replacement of the 5-p-toluoyl group with a p-chlorobenzoyl moiety ⇒ little effect on
activity
• Introduction of a –CH3 group in the 4-position of the pyrrole ring ⇒ 4-methyl-5-p-
chlorobenzoyl analog = Zomepirac ⇒ ~4X > tolmetin Zomepirac (1980) = analgesic ⇒
severe anaphylactic reactions particularly in patients sensitive to aspirin ⇒ removed
from the market in 1983
• Substitution of –CH3 at the α-position
⇒ propionic acid analogue ⇒ slightly less potent than tolmetin
PHAR 450- Spring 23/24 38
 Metabolism
• Tolmetin is extensively metabolized to
dicarboxylic acid ⇒ Inactive

• ~15-20% is excreted unchanged

• 10% is excreted as the glucuronide

conjugate

• Conjugates of the dicarboxylic acid

metabolite account for the majority of the
remaining administered drug
PHAR 450- Spring 23/24 39
 Diclofenac Sodium
• It is the most widely used NSAID in the world.

• Diclofenac has structural characteristics of both arylalkanoic acid and the anthranilic acid
classes of anti-inflammatory agents

• It displays anti-inflammatory (2X> Indomethacin & 450X > Aspirin), analgesic (6X >
Indomethacin & 40X > Aspirin), and antipyretic (2X > Indomethacin & 350X > Aspirin)
properties.

• Diclofenac is unique among the NSAIDs in that it has three possible MOAs:
1. Inhibition of the COX system (3-1000X more potent than other NSAIDs on a molar basis)
⇒ ➘ production of PGs & thromboxanes
2. Inhibition of the lipoxygenase pathway ⇒ production of leukotrienes
3. Inhibition of arachidonic acid release (PLA2) and stimulation of its reuptake ⇒ reduction
of arachidonic acid availability
PHAR 450- Spring 23/24 40
 SAR of Diclofenac
• SAR is not extensively studied
• The two o-Cl groups force the
anilino-phenyl ring out of the
plane of the phenylacetic acid
portion
⇒ Twisting effect
⇒ Important in the binding of
NSAIDs to the active site of the COX
Major
(Less active)

PHAR 450- Spring 23/24 41

Metabolism of Diclofenac
 Etodolac - SAR
• Alkyl groups at R1 and an acetic acid function at R2 ⇒ ➚ anti-inflammatory
activity

• Lengthening the acid chain, or ester or amide derivatives ⇒ inactive

• Substitution of –CH3 at the α-position ⇒ propionic acid analogue ⇒ inactive

• ➚ chain length of R1 to ethyl or n-propyl ⇒ derivatives 20X more potent than

methyl

• Substituents at the 8-position (R3) ⇒ Active ⇒ Among the most active: 8-ethyl, 8-
n-propyl, and 7-fluoro-8-methyl derivatives
PHAR 450- Spring 23/24 42
 Nabumetone
• A new class of non-acidic prodrugs ⇒ rapidly metabolized after absorption to
a major active metabolite

• Gastric damage produced by NSAIDs generally involves a dual insult

mechanism

• Nabumetone being non-acidic:

– Does not produce a significant 1º insult
– Is an ineffectual inhibitor of COX in gastric mucosa, thus producing minimum secondary
insult
– The result is that gastric side effects of nabumetone appear to be minimized

• Once the parent drug enters the circulatory system, however, it is metabolized
to an active metabolite, 6-methoxy-naphthalene-2-acetic acid (6MNA) (which
is an effective inhibitor of PG synthesis in joints
PHAR 450- Spring 23/24 43
 Nabumetone - SAR
• Introduction of –CH3 or –CH2CH3 groups on the butanone side chain ⇒ ➘ anti-inflammatory activity

• Converting the ketone to a dioxolane ⇒ retention of activity

• Converting the ketone to an oxime (C=NOH) ⇒ ➘ activity

• Removal of the CH3O- group at the 6-position ⇒ ➘ activity

• Replacement of the CH3O- with a –CH3 or Cl group ⇒ active compounds

• Replacement of the CH3O- with hydroxyl, acetoxy or N-methylcarbamoyl groups, or positional

isomers of the methoxy group at the 2- or 4-positions ⇒➘ activity

• The active metabolite, 6MNA, is closely related structurally to naproxen, differing only by the lack of
an α-methyl group. The ketone precursor [4-(6- methoxy-2-naphthyl) pentan-2-one] that would be
expected to produce naproxen as a metabolite, was inactive in chronic models of inflammation
PHAR 450- Spring 23/24 44
Metabolism of Nabumetone

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Aryl- and Heteroaryl Propionic Acids

PHAR 450- Spring 23/24 46

 Ibuprofen
• Ibuprofen became the 1st prescription NSAID to become available:
As an OTC analgesic in almost 30 years
Under a number of trade names

SAR of Ibuprofen
• Substitution of an α-CH3 group on the alkanoic acid portion of acetic
acid derivatives:
↗ anti-inflammatory actions
↘ many side effects

• For example, Ibufenac (p-iso-butylphenyl-acetic acid) =

acetic acid analogue of ibuprofen is:
Less potent
More hepatotoxic than ibuprofen

PHAR 450- Spring 23/24 47

 SAR of Ibuprofen
Arylpropionic acids have C* ⇒ Stereochemistry ⇒
important role in both in vivo and in vitro activities of these
agents:
– (+)-enantiomer has greater activity in vitro than (-)-isomer

– For the inhibition of PG synthesis R < S, but in vivo are

equiactive

– (+)-enantiomer of ibuprofen, and of most of the arylpropionic

acids under investigation, has been shown to possess the (S)-
absolute configuration = S-(+)-enantiomer
PHAR 450- Spring 23/24 48
 Absorption and Metabolism
• Ibuprofen is rapidly absorbed on oral administration
• Ibuprofen is extensively bound to plasma proteins ⇒ drug-drug
interactions
• Metabolism involves primarily oxidation of the p-isobutyl side chain,
followed by oxidation of the 1º alcohol to the corresponding carboxylic
acid ⇒ All metabolites are inactive
• (R) (-)-enantiomer is inverted to (S) (+)-enantiomer in vivo ⇒
observation that the two enantiomers are bioequivalent in vivo ⇒ same
for other arylpropionic acids (ketoprofen, benoxaprofen, fenoprofen and
naproxen)

PHAR 450- Spring 23/24 49

 Fenoprofen Calcium
• Fenoprofen is less potent in anti-inflammatory assays than ibuprofen,
indomethacin, ketoprofen or naproxen

• It also possesses analgesic & antipyretic activity

• Fenoprofen is marketed as a racemic mixture ⇒ no differences between
the in vivo anti-inflammatory or analgesic properties of the individual
enantiomers due to the ability of (R)-(-)-arylpropionic acids to undergo
inversion to the (S) (+)-enantiomers may be involved

• Like other NSAIDs, in vitro PG synthesis assays indicate that the (S) (+)-
enantiomer > (R) (-)-isomer
PHAR 450- Spring 23/24 50
SAR of Fenoprofen
• Placing the phenoxy group in the ortho- or para position of the
arylpropionic acid ring ⇒ ↘ activity

• Replacement of the oxygen bridge between the two aromatic rings

with a C=O group ⇒ Ketoprofen

Metabolism
• Fenoprofen is rather extensively metabolized, primarily through
glucuronide conjugation with the parent drug and the 4’-hydroxy
metabolite
PHAR 450- Spring 23/24 51
 Ketoprofen
• Ketoprofen, unlike many NSAIDs, inhibits:
– The synthesis of leukotrienes & leukocyte migration into inflamed joints
– Biosynthesis of PGs
– Stabilizes the lysosomal membrane during inflammation ⇒ ➘ tissue destruction
– Anti bradykinin (pain mediator) activity has also been observed

• Ketoprofen has anti-inflammatory, antipyretic & analgesic properties

• Its ability to produce gastric lesions is almost similar to indomethacin

Oxaprozin
• It is used for acute and long-term use in the management of signs and
symptoms of osteoarthritis and rheumatoid arthritis
PHAR 450- Spring 23/24 52
 Naproxen
• Order of gastric ulcerogenic activity: Sulindac < Naproxen < Aspirin,
Indomethacin, Ketoprofen and Tolmetin
SAR
• In a series of substituted 2-naphthylacetic acids, substitution in the 6-position
⇒ maximum anti-inflammatory activity:
 Small lipophilic groups such as Cl, CH3S, and CHF2O in the 6-position ⇒ active analogues ⇒ CH3O
being the most potent
 Larger groups were found to be less active
• Derivatives of 2-naphthylpropionic acids are more potent than the
corresponding acetic acid analogues
• Replacing the -COOH with functional groups capable of being metabolized to
the carboxyl function (e.g.-CO2CH3, -CHO or -CH2OH) ⇒ retention of activity
• (S) (+)-isomer is the more potent enantiomer
PHAR 450- Spring 23/24 53
 Flurbiprofen
• Most potent substituted
phenylalkanoic acids ⇒ 2-(4-
biphenylyl) propionic acids
• In 1987 when it was
introduced as the Na+ salt as
Ocufen ⇒ 1st topical NSAID
indicated for ophthalmic use in
the U.S.
• Ocufen is used to inhibit intra-
operative miosis induced by
PGs in cataract surgery ⇒
flurbiprofen is an inhibitor of
PG synthesis PHAR 450- Spring 23/24 54
 Ketorolac Tromethamine
• Ketorolac (1990) represents a cyclized heteroarylpropionic acid derivative
with the α-CH3 group being fused to the pyrole ring.
• Indications:
 Peripheral analgesic for short-term use
 Relief of ocular itching caused by seasonal allergic conjunctivitis
 Exhibits anti-inflammatory & antipyretic activity
• Its analgesic activity resembles that of morphine ⇒ used as alternative to
narcotic analgesia
• It is highly plasma protein bound
• Ketorolac is metabolized to the p-hydroxy derivative and to conjugates that
are excreted primarily in the urine

PHAR 450- Spring 23/24 55

 N-Arylanthranilic Acids (Fenamic Acids)
• The anthranilic acid class is the result of the application of classical
medicinal chemistry bioisosteric drug design concepts since these
derivatives are nitrogen isosters of salicylic acid
Mefenamic acid
• Modest anti-inflammatory activity ⇒ it is one-half as potent as flufenamic
acid
• Meclofenamic acid ⇒ primarily used as an antirheumatic agent &
analgesic.

PHAR 450- Spring 23/24 56

 N-Arylanthranilic Acids/Fenamic Acids
• Structurally, the fenamic acids fit the
proposed active site of COX⇒ they have
an acidic function connected to an
aromatic ring along with an additional
lipophilic binding site = N-aryl
substituent

• The greater anti-inflammatory activity

of meclofenamic acid compared to that
of mefenamic acid correlates well with
the ability to inhibit PG synthesis
PHAR 450- Spring 23/24 57
 General SAR
• Substitution on the anthranilic acid ring ⇒ ↘ activity
• Monosubstitution:
– In the UV erythema assay for anti-inflammatory activity ⇒ Order of activity is 3’
> 2’ >> 4’ ⇒ with 3’-CF3 derivative (flufenamic acid) being particularly potent
• Disubstitution ⇒ two substituents are the same ⇒ 2’,3’- derivative
appears to be the most potent
• Substituents on the N-aryl ring which force this ring to be non-coplanar
with the anthranilic acid ring ⇒ ➚ binding at this site ⇒ ➚ activity

PHAR 450- Spring 23/24 58

 General SAR
• NH-moiety of anthranilic acid is essential for activity ⇒
replacement of the NH function with O, CH2, S, SO2, N-CH3 or N-
COCH3 ⇒ ➘ activity

• -COOH moiety
– The position, rather than the nature, of the acidic function is critical for
activity:
 Anthranilic acid derivatives (ortho-) ⇒ active
 meta- & para- aminobenzoic acid analogs ⇒ inactive

• Replacement of the -COOH with the isosteric tetrazole moiety ⇒

little effect on activity
PHAR 450- Spring 23/24 59
 Mefenamic Acid
• It is the only fenamic acid derivative that produces
analgesia centrally and peripherally
• Mefenamic acid is absorbed rapidly following oral
administration
• Highly bound to plasma proteins and has a plasma t½ of
2-4 hrs

• Metabolism occurs through regioselective oxidation of

the 3’- methyl group and glucuronidation of mefenamic
acid and its metabolites ⇒ inactive metabolites:
– 3’-hydroxymethyl metabolite (primarily as the
glucuronide)
– Dicarboxylic acid (glucuronide conjugate)

PHAR 450- Spring 23/24 60

 Meclofenamate Sodium
• It is rapidly and almost completely absorbed following oral administration
• It is highly bound to plasma proteins and has a plasma t½ = 2-4 hrs
• Metabolism involves:
– Oxidation of the methyl group ⇒ active metabolite ⇒ Anti-inflammatory
activity
– Aromatic hydroxylation
– Monodehalogenation
– Conjugation

PHAR 450- Spring 23/24 61

 Oxicams
• Oxicams (4-hydroxy-1,2-benzothiazine carboxamides) are new
enolic acid class of NSAIDs possessing anti-inflammatory and
analgesic properties.

• Designed and synthesized by the Pfizer group in an effort to

produce:
– Non-carboxylic acid
– Potent
– Well-tolerated anti-inflammatory agents

PHAR 450- Spring 23/24 62

 General SAR
• 4-hydroxy-1,2-benzothiazine
carboxamides series

• R1 = methyl substituent ⇒ optimum

activity

• R = aryl or heteroaryl substituent since

alkyl substituents are less active

• Oxicams are acidic compounds with

pKa’s 4-6
PHAR 450- Spring 23/24 63
 Piroxicam
• Readily absorbed on oral administration
reaching peak plasma levels in about 2 hrs
• Highly bound to plasma proteins (99.3%)
• Piroxicam is extensively metabolized where
the major metabolites are:
– Hydroxylation of the pyridine ring and
subsequent glucuronidation, other
metabolites being of lesser importance
– Aromatic hydroxylation at several
positions of the aromatic benzothiazine
ring but not at the 8-position
– Ring contraction following amide
hydrolysis and decarboxylation
eventually yields saccharin
• All of the known metabolites of piroxicam are
inactive.
PHAR 450- Spring 23/24 64
 Meloxicam
• Meloxicam is a new oxicam derivative approved as a selective COX-2
inhibitor for the treatment of osteoarthritis

• Meloxicam = COX-2 inhibitor but it is less selective than either of the

two (celecoxib & rofecoxib = COX-2 inhibitors) in vitro studies

• Meloxicam is readily absorbed when administered orally

• It is highly bound to plasma protein

• It is extensive metabolized in the liver primarily by CYP2C and to a

lesser extent by CYP3A4

PHAR 450- Spring 23/24 65

 Selective COX2 Inhibitors - Overview
• Classical NSAIDs share similar side effect profiles, particularly the GI
bleeding and renal toxicity, many of which have been attributed to the
nonselective inhibition of COX.
• COX-2 > COX-1 binding site restricts access by larger, relatively rigid
side-chain substituents, such as sulfamoyl or sulfonyl side chains
usually seen in the selective COX-2 inhibitors.
• In addition to their role in reducing the incidence of GI side effects, COX-
2 selective inhibitors play other potential therapeutic use treatment of
Alzheimer’s disease and various carcinomas: COX-2 appears to be
induced in inflammatory plaques that are evident in the CNS in
Alzheimer’s disease
PHAR 450- Spring 23/24 66
PHAR 450- Spring 23/24 67
Selective COX2 Inhibitors

PHAR 450- Spring 23/24 68

PHAR 450- Spring 23/24 69
 Selective COX2 Inhibitors
COX-2 selectivity doesn’t yield an increased safety profile relative to
NSAIDs.
• Two highly COX-2 selective inhibitors, rofecoxib and valdecoxib,
were pulled from the US market due to an unacceptably high risk
of cardiovascular morbidity.
• Thromboembolic events: coronary and cerebrovascular
• COX-2 inhibition disturbs the balance between prostacyclines
&thromboxanes
• COX-2 inhibition in the kidney reduces glomerular filtration and
can lead to renal failure.

PHAR 450- Spring 23/24 70

 Celecoxib
• Celecoxib is currently indicated for the relief of signs and symptoms of
osteoarthritis and rheumatoid arthritis
• Celecoxib is at least as effective as:
– Naproxen in the symptomatic management of osetoarthritis
– Naproxen and diclofenac in the symptomatic treatment of rheumatoid arthritis
– And is less likely to cause adverse GI effects

• Unlike aspirin, celecoxib does not exhibit antiplatelet activity

• Concomitant administration of aspirin and celecoxib may increase the incidence
of GI side effects.
• Another notable potential drug interaction with celecoxib is its ability, like other
NSAIDs, to reduce the blood pressure response to angiotensin-converting
enzyme inhibitors.
PHAR 450- Spring 23/24 71
 Etoricoxib
Study its:
- SAR
- Indications
- Compare it with celecoxib
- Does it affect platelet aggregation?

PHAR 450- Spring 23/24 72

Marketed as a racemic mixture, with S-isomer being the most active. Phenoxy
group best to be in meta-position because ortho and para position reduce
activity. This info is about:
A. Fenoprofen
B. Meclofenamate
C. Piroxicam
D. Celecoxib
Which of the following produces active Sulfide metabolites?
A.Ketoprofen
B.Naproxen
C. Pyroxicam
D.Sulindac
Which of the following NSAIDs is associated with minimal gastric side effects:
A.Ketoprofen
B.Naproxen
C. Pyroxicam
D.Nabumetone
PHAR 450- Spring 23/24 73