The document discusses COX-1 and COX-2 inhibitors. It notes that there are two forms of the cyclooxygenase enzyme, COX-1 and COX-2, which are involved in inflammation. COX-1 has beneficial effects and is present in most tissues, while COX-2 is primarily found at sites of inflammation. COX-1 inhibitors selectively inhibit COX-1, while COX-2 inhibitors selectively inhibit COX-2. Many classes of non-steroidal anti-inflammatory drugs act as COX inhibitors, including indoles, fenamates, oxicams, pyrazolones, and anilides. Selective COX-2 inhibitors like cele

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COX-1 AND COX-2 INHIBITORS
Presenting by,
Mr. Purushotham K N
Asst.professor
Dept. of Pharm. Chemistry
SACCP. ACU
2021-2022

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Cyclooxygenase (COX) is an enzyme that
forms prostaglandins, prostacyclins, and
thromboxanes—substances called prostanoids that
are responsible for the inflammatory response.
COX is known as a rate-limiting enzyme because it
serves as the major pathway or key for the formation
of these prostanoids.

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Cyclooxygenases (COX-1 and COX-2) are key enzymes in the
conversion of arachidonic acid to prostaglandins and other lipid
mediators. Because it can be induced by inflammatory stimuli, COX-
2 has been classically considered as the most appropriate target for
anti-inflammatory drugs. siologic functions

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• There are actually two forms of the cyclooxygenase enzyme: COX-1
and COX-2. Both are involved in inflammation, but only COX-1 has
a beneficial effect on the body as well.
• COX- 1 is known to be present in most of the tissues in your body. In
the gastrointestinal tract, COX-1 maintains the normal lining of the
stomach and intestines, protecting the stomach from the digestive
juices.The enzyme is also involved in kidney and platelet function.
• COX-2, on the other hand, is primarily found at sites of inflammation

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• COX 1 inhibitor is a non-steroidal anti-inflammatory drug that inhibits
cyclooxygenase-1 enzyme expressed constitutively in most tissues while COX
2 inhibitor is a non-steroidal anti-inflammatory drug that inhibits
cyclooxygenase-2 enzyme expressed in areas of inflammation.
• Non-steroidal anti-inflammatory drugs (NSAIDS) usually provide anti-
inflammatory, analgesic, and antipyretic effects. They are used in the
treatment of a variety of diseases. Non-steroidal anti-inflammatory drugs
inhibit a particular rate-limiting enzyme called cyclooxygenase (COX) involved
in the production of prostaglandins. Two isoforms of this enzyme have been
identified: COX 1 and COX 2.
• COX 1 inhibitor and COX 2 inhibitor are two non-steroidal anti-inflammatory
drugs involved in the inhibition of cyclooxygenase 1 (COX 1) and
cyclooxygenase 2 (COX 2), respectively.

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Aryl and Heteroarylacetic Acids
Classification
• indene/indoles,
• pyrroles
• oxazoles

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Indene and Indole Acetic Acids
Indomethacin Structure

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Synthesis of Indomethacin

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Indene and Indole Acetic Acids
Sulindac Structure

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Ketolorac

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Anthtranilates (fenamates)

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Mefenamic Acid

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Meclofenamic Acid

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©M. S. Ramaiah University of Applied Sciences
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Oxicams (“Enol Acids”)
• Oxicams (Piroxicam and Meloxicam) are characterized by the 4-
hydroxybenzothiazine heterocycle.
• The acidity of the oxicams is attributed to the 4-OH with the
enolate anion being stabilized by intramolecular hydrogen-bonding
to the amide N-H group.
• These compounds are acidic (pKa = 6.3).

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Oxicams (“Enol Acids”)
• The oxicams are primarily ionized at physiologic pH and acidity is
required for COX inhibitory activity.
• Examples include Piroxicam and Meloxicam

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Piroxicam

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Meloxicam

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Phenylpyrazolones
Pyrazole
• Simply double unsaturated compound containing 2 N’s
and 3 C’s in the ring with the nitrogen atoms
neighbouring

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Phenylpyrazolones
Pyrazole – Reduction products
Pyrazoline Pyrazolidine

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Pyrazoline Substitution Products
5 – Pyrazolone 3,5-pyrazolidinedione

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Phenylpyrazolones
Phenylbutazone

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Oxyphenbutazone

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Silphinpyrazone

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SAR’s
• Pharmacologic activity of the 3,5-pyrazolidinedione derivatives are
closely related to their Acidity (the Acidic H at 4-position). The
dicarbonyl functions at 3- and 5- positions enhance the acidity of
the Hydrogen at the 4-position.
• Eliminating the acidic proton at the 4-position abolishes anti-
inflammatory activity.
• Enhancing the acidity too much leads to a decrease in anti-
inflammatory activity while other effects like uricosuric effects and
sodium retention

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SAR’s
• A single alkyl group at the 4-position enhances anti-inflammatory
with the most activity being given by the n-butyl substituent.
• Substitution of the 2- phenylthioethyl group at the four position
produces anti-gout drug sulphinpyrazone

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Anilides [p-aminophenol Derivatives]
• Introduced as analgesics after the discovery of the powerful
antipyretic activities of aniline
• The anilides are simple acetamides of aniline (Aminobenzene),
which may or may not contain a 4-hydroxy or 4-alkoxy group.
• Anilides do not possess the carboxylic acid functionality and
therefore they are classified as neutral drugs and possess little
inhibitory activity against cyclooxygenase.

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Anilides [p-aminophenol Derivatives]
• They are believed to act as scavengers of hydroperoxide
radicals.
• Acetanilide was first introduced and was found to be too toxic
causing jaundice.
• Phenacetin was withdrawn recently due to Nephrotoxicity.
• Paracetamol remains the only useful member of this group
(introduced in1891)

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SAR’s
• Esterification of the phenolic functional groups with
methyl or propyl groups produce derivatives with greater
side effects than the ethyl derivative.
• Substituents on the Nitrogen atom, which reduce the
basicity, also reduce activity unless the substituent is
metabolically labile e.g., acetyl.
• Amides derived from aromatic acid e.g. N-Phenyl
benzamide's (Benzanilide) are less active or even inactive

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Synthesis of Paracetamol
• Preparation of paracetamol involves treating an amine (p-
aminophenol) with an acid anhydride (acetic anhydride) to form an
amide (p-acetamidophenol).

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Selective COX-2 Inhibitors
• Prostaglandins that mediate inflammation, fever and pain are
produced solely COX-2 (Highly inducible by inflammation)
• Selective Cox – 2 inhibitors are devoid of side effects such as gastric
ulcer and it does not affect the normal functioning of the platelet,
uterus and renal system.

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Celecoxib

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Rofecoxib

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Valdecoxib

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Summary
• The non-steroidal anti-inflammatory drugs (NSAIDs) are widely
used for the treatment of minor pain and for the management of
edema and tissue damage resulting from inflammatory joint
disease (arthritis).
• The major mechanism by which the NSAIDs elicit their therapeutic
effects (antipyretic, analgesic, and antiinflammatory activities) is
inhibition of prostaglandin (PG) synthesis.
• Most NSAIDs are mainly COX-1 selective (e.g., aspirin, ketoprofen,
indomethacin, piroxicam, sulindac).

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