cyclooxygenase inhibitors, topic of medicinal chemistry

1. Miss. Aarti V. Shingan
M. Pharm in pharmaceutical Chemistry

2.  Known as :prostaglandin-endoperoxide
synthase(PTGS)
 Responsible for formation of prostanoides
1.prostaglandin,
 2.thamboxen,
 3.prostacylin.
 Involved in the inflammtory Responce.

3.  Contains two separate active sites for
prostaglandin synthase
 One side contains the cyclooxygenase active
 The Opposite active side active side contains
peroxidase active site which is Involved in
activating the heme group neccesory for
cyclooxygenase reaction
 It has two forms COX-1 and COX-2.

4.  Continiously stimulate by the body
 Constitutive (its concentration in the body
remain stable)
 creates prostaglandin uses for basic house
keeping throughout the body
 Prostaglandin stimulate normal body
function such as stomach mucous
production, regulation of gastric acid and
kidney water

5.  Induced ( normally not in present in cells)
 Built only in special cells (Ex: lung cells)
 Used for singnaling pain and inflamation
 Produces prostaglandins for inflammtory
responce
 Stimulated only as part of immune
responce
 Production is stimulated by inflammtory
cytokines and growth factors

8. Flurbiprofen Ibuprofen
Tolmetin

9. Indomethacin Ketoprofen

10. IUPAC Name :
1-(p-Chloro benzoyl) 5-
methoxy indole-3-acitic
acid

11. Properties :
Colour: pale yellow
appearance: crystalline powder
solubility: soluble in water sparingly soluble in alcohol
M.P : 155-162 0C
chemical formula: C19H21ClNNaO7
Assay: the sample in acetone and pass nitrogen for 15 min
and titrate with 0.1M NAOH using phenolphthalein as
indicator.

12. 1. The centre of acidity is usually located one carbon atom
adjecent to a flat surface represented by an aromatic or hetero
aromatic ring .
2. The distance between these centre is critical because
increasing this distance to two or three carbon generally
decreasing activity.
3. Increasing acidity of of COOH group Increasing activity.
4. Substitution of methyl group on the carbon atom separating
the aromatic ring leads to the enhancement of anti-
inflammatory activity.

13. P –methoxy
phenyl hydrazine hydrazone
indomethacin

14. Mechanism of action :
indomethacin ,a non –steroidal anti-inflmmatory drug
(NSAIDs) ,it is a selective COX-1 inhibitor
the enzyme that participate in prostaglandin synthesis
from archidonic acid
Prostaglandin are hormone like molecule normally found in
the body , where they have a wide variety of effects, some
of which leads to pain ,fever, and inflammation.
By inhibiting the synthesis of prostaglandins , indomethacin
can reduce pain, fever, and inflammation.

15. Medical uses:
 indomethacin is an analgesic,antipyretic and anti-
inflammatory . Clinical indication for indomethacin
include :
 Joint diseases : rheumatoid arthritis ,oateoarthritis
,gouty arthritis ;Headaches etc
Adverse effect: peptic ulcer ,dypepsia,heartburn,mild
dirrhea ,edema9swelling due to fluid retention ) ,
hyperkalemia(highpotassiumlevel), hypernatremia(high
sodium level ) .

16.  IUPAC Name :
2-(4-isobutyl
phenyl) propionic
acid

17. Properties :
Colour: colourless ,
appearance: crystalline powder
solubility: insoluble in water, soluble in most organic
solvents like alcohols, acetone,and dichloromethane.
M.P : 75-780C
chemical formula: C13H18O2
Assay: Dissolve the sample in methanol and titrate
against 0.1M NaOH USING Phenolphthalin indicator as
indicator ,until colour is obtained .

19. Mechanism of action: it is a non –steroidal anti-inflmmatory
drug (NSAIDs) ,it is a selective COX-1 inhibitor
the enzyme that participate in prostaglandin synthesis
from archidonic acid
Prostaglandin are hormone like molecule normally found in
the body , where they have a wide variety of effects, some
of which leads to pain ,fever, and inflammation.
By inhibiting the synthesis of prostaglandins , ibuprofen
can reduce pain, fever, and inflammation

20. Medical uses:
 Ibuprofen is used primarily to treat fever (including post-
vaccination fever),
 mild to moderate pain (including pain relief after surgery),
painful menstruation, osteoarthritis, dental pain,
headaches, and pain from kidney stones.
 About 60% of people respond to any NSAID; those who do
not respond well to a particular one may respond to
another.
 It is used for inflammatory diseases such as juvenile
idiopathic arthritis and rheumatoid arthritis.
 It is also used for pericarditis and patent ductus arteriosus.

21. Adverse effects :
 include nausea, dyspepsia, diarrhea, constipation,
gastrointestinal ulceration/bleeding, headache, dizziness,
rash, salt and fluid retention, and high blood pressure.
 Infrequent adverse effects include esophageal ulceration,
heart failure, high blood levels of potassium, kidney
impairment, confusion, and bronchospasm.Ibuprofen
can exacerbate asthma

22.  IUPAC name :
2-(6-methoxy
2-naphthyl)
propionic acid

23. Properties :
Colour: white
appearance: crystalline powder
solubility insoluble in water, soluble in most organic
solvents like methanol,ethanol.
M.P : 155-162 0C
chemical formula: C19H21ClNNaO7
Assay: dissolve the sample in a mixture of water and
methanol(1:3)and titrate with 0.1M NAOH using
phenolphthalein as indicator.

25. Mechanism of action: it is a non –steroidal anti-
inflmmatory drug (NSAIDs) ,it is a selective COX-1
inhibitor
the enzyme that participate in prostaglandin synthesis
from archidonic acid
Prostaglandin are hormone like molecule normally found
in the body , where they have a wide variety of effects,
some of which leads to pain ,fever, and inflammation.
By inhibiting the synthesis of prostaglandins , naproxen
can reduce pain, fever, and inflammation.

26. Medical uses :
Inflammatory sources of pain that may respond to
naproxen's anti-inflammatory activity are conditions
 such as migraine,
 osteoarthritis,
 kidney stones,
 rheumatoid arthritis,
 psoriatic arthritis,
 gout,
 ankylosing spondylitis,
 menstrual cramps, tendinitis, and bursitis.

27. adverse effects:
include
 dizziness, drowsiness,
 headache,
 rash,
 bruising,
 gastrointestinal upset.
 Heavy use is associated with increased risk of end-
stage renal disease and kidney failure.

28.  IUPAC Name:2-
(1-methyl-5-(4-
methylbenzoyl)-
1H-pyrrole2-
yl)acetate

29. Properties :
Colour: light yellow,
appearance: crystalline powder
solubility soluble in water, slightly soluble
solvents like methanol,ethanol.
M.P : 155-157 0C
chemical formula: C15H15NO3

31. Mechanism of action:
 Although the mechanism of action of tolmetin is
unknown, research involving humans and animals has
shown that tolmetin does not achieve anti-inflammatory
response by stimulation of the adrenal or pituitary gland,
 but it has shown tolmetin restrains prostaglandin
synthetase in vitro and reduces plasma levels of
prostaglandin E, possibly causing the anti-inflammatory
response.

32. Medical uses: Is used alone or with other treatment to reduce
pain , swelling, and joint stiffness from rheumatoid arthritis and
osteoarthritis . It is used for juvenile rheumatoid arthrites
Adverse effect:
 Tolmetin can increase the risk of heart or circulatory conditions
such as heart attacks and strokes. It should not be taken shortly
before or after coronary artery bypass surgery.
 Tolmetin can also increase the risk of gastrointestinal conditions
such as perforation or bleeding, which is fatal. Antacids can be
taken with tolmetin to relieve stomachaches that often occur.
 Overdose can result in drowsiness, nausea, epigastric pain, and
vomiting

33. Adverse effect:
 Tolmetin can increase the risk of heart or circulatory
conditions such as heart attacks and strokes.
 It should not be taken shortly before or after coronary
artery bypass surgery.
 Tolmetin can also increase the risk of gastrointestinal
conditions such as perforation or bleeding, which is fatal.
Antacids can be taken with tolmetin to relieve
stomachaches that often occur.
 Overdose can result in drowsiness, nausea, epigastric pain,
and vomiting.

35. IUPAC Name:
4-[5-(4-methyl phenyl)3-
(trifluoro)1Hpyrazolyl)
Benzene sulphonamide
Drug name :CELEBREX

36. Properties :
Colour: pale yellow
appearance: crystalline powder
solubility: soluble in water sparingly soluble in
alcohol
M.P : 157-159 0C
chemical formula: C17H14FNO2S

37.  A para-sulfamoylphenyl at position 1 of the pyrazole was
found to have a higher potency for COX-2 selective inhibition.
 At the 3-position of the pyrazole, a trifluoromethyl or
difluoromethyl provides superior selectivity and
potencyCelecoxib is compound 22;
 the 4-sulfamoylphenyl on the 1-pyrazol substituent is
required for COX-2 inhibition and the 4-methyl on the 5-
pyrazol system has low steric hindrance to maximize potency,
 while the 3-trifluoromethyl group provides superior
selectivity and potency.
 To explain the selectivity of celecoxib, it is necessary to
analyze the free energy of binding difference between the
drug molecule and COX-1 compared to COX-2 enzymes

39.  Celecoxib is used for osteoarthritis, rheumatoid
arthritis, acute pain, musculoskeletal pain,
painful menstruation, ankylosing spondylitis, and to reduce
the number of colon and rectal polyps in people with familial
adenomatous polyposis.
 It may also be used in children with juvenile rheumatoid
arthritis who are older than two years of age and weigh more
than 10 kg (22 lb).
Mental illness
 Tentative evidence supports its use in treating a number of
psychiatric disonrders, including major depression, bipolar
disorder, and schizophrenia.
 Familial adenomatous polyposis

40. Adverce effect:
 Cardiovascular events: NSAIDs are associated with an increased
risk of serious (and potentially fatal) adverse cardiovascular
thrombotic events, including myocardial infarction and stroke
 Gastrointestinal events: NSAIDs may increase risk of serious
gastrointestinal (GI) ulceration, bleeding, and perforation (may
be fatal). These events may occur at any time during therapy
and without warning.
 Use cautionHematologic effects: Anemia may occur;
monitor hemoglobin or hematocrit in people on long-
term treatment. Celecoxib does not usually
affect prothrombin time, partial thromboplastin
time or platelet counts; it does not inhibit platelet
aggregation at approved doses.
 with a history of GI disease (bleeding or ulcers).

41. IUPAC Name:
4[4(methylsulfonyl)p
henyl]-3phenylfuran-
2 furonone

42. Properties :
Colour: light yellow
appearance: crystalline powder
solubility: . Soluble in 1- octanol ,soluble in water
sparingly soluble in alcohol , acetone
M.P : 155-162 0C
chemical formula: C17H14O4S

44. ROFICOXIB
Mechanism of action
Cyclooxygenase (COX) has two well-studied isoforms,
called COX-1 and COX-2. COX-1 mediates the
synthesis of prostaglandins responsible for protection
of the stomach lining, while COX-2 mediates the
synthesis of prostaglandins responsible for pain and
inflammation.
By creating "selective" NSAIDs that inhibit COX-2, but
not COX-1, the same pain relief as traditional NSAIDs
is offered, but with greatly reduced risk of fatal or
debilitating peptic ulcers. Rofecoxib is a selective
COX-2 inhibitor, or "coxib"

45.  Medical uses :Rofecoxib is a nonsteroidal
anti-inflammatory drug that was used in the
treatment of osteoarthritis, acute pain
conditions, and dysmenorrhoea.
 Adverce effect:Aside from the reduced
incidence of gastric ulceration, rofecoxib
exhibits a similar adverse effect profile to
other NSAIDs.

46. Thank you