Non steroidal anti inflamatoryNSAIDs 2016 (1).pdf

cific in its activity upon those innervations which categorically activate both functionalities, namely :
(a) GI-motility ; and (b) gastric secretion. Interestingly, based on the extremely specific nature of its
pharmacological activity on the gastric functions actually renders diphemanil particularly beneficial
in the control, management and treatment of peptic ulcer. Besides, its inherent lack of atropine-like
effects makes this specific usage relatively less painful in comparison to several other antispasmodic
drugs.
Note. The methylsulphate salt is considered to be the best in terms of its stability in comparison to its corresponding halides e.g., Cl–
(hygroscopic) ; Br–
and I–
(toxic reactions).
7.8.7.2. Methixene Hydrochloride
The ‘drug’ essentially exhibits both antihistaminic and direct antispasmodic activities. It has
been duly observed that the drug is invariably absorbed from the GI-tract. It subsequently gets excreted
through the urine, partly as its corresponding isomeric sulphoxides or their metabolites ; and a reasonable quantum as unchanged product.
Methixene hydrochloride has been profusely indicated in such preparations that may ultimately
relieve gastro-intestinal spasms.
7.8.7.3. Glycopyrronium Bromide
It is a quaternary ammonium antimuscarinic agent having marked and pronounced peripheral
effects that are quite akin to those of atropine. It has been found that approximately 10–25% of the
‘drug’ gets absorbed from the GI-tract when administered orally. It penetrates the blood brain barrier
(BBB) rather very poorly. It gets ultimately excreted in bile and urine.
7.8.7.4. Diphemanil Methylsulphate
The ‘drug’ is quite active for the symptomatic management and subsequent control of visceral
spasms. It may also cause enough relief from the ensuing painful and distressing spasms of the biliary
and the genitro-urinary systems. Importantly, it also finds its adequate usage for the treatment of symptomatic bradycardia.
8. GANGLIONIC BLOCKING AGENTS
Langley first studied the action of drugs on the autonomic ganglia with the alkaloid nictoine
obtained from Nicotiana tabacum. Subsequently, some other alkaloids were also found to possess similar effects, namely ; coniine from the poison Hemlock obtained from Conicum maculatum, gelsemine
from the yellow jasmine and lobeline from the lobelia, a native of America.
Generally, ganglionic blocking agents normally exert their action by competing with acetylcholine from the cholinergic receptors present in the autonomic postganglionic neurons. In fact, the ganglia
of either of the sympathetic and parasympathetic nervous systems are cholinergic in character, these
therapeutic agents interrupt the outflow through both these systems. Therefore, it is not practically possible to accomplish a complete therapeutic block of the autonomic outflow to a specific locus without
encountering a few undesirable but unavoidable ‘side effects’ that may arise as a consequence from the
blockade of other ensuing a

1. Med chem of Non-Steroidal Anti-
Inflammatory Drugs (NSAIDs)
Med chem I by [email protected]
1

2. NSAIDs…
•These drugs are of different chemical structures and are used for
treatment of inflammatory and painful conditions and have
antipyretic activity
•Used to treat gout, Prophylaxis of heart disease, prophylaxis of
colorectal cancer and used to treat alzheimers disease.

•Also have side effects like gastro intestinal ulcer, blockage of platlet
agregates, inhiition of prostaglandin mediated renal function,
inhibition of uterine motility and hypersensitivity reaction
M
6. Prophylaxis of colorectal cancer
7. Treatment of Alzheimer’s Disease
Treatment of gout
5. Prophylaxis of heart disease (myocardial infarction
and stroke)
6. Prophylaxis of colorectal cancer
7. Treatment of Alzheimer’s Disease

Med chem I by [email protected]
2

4. NSAIDs…
•Prostaglandins contribute to sign and symptoms of inflammatory
processes including pain and edema





•Pain: PGI2 and PGE2-sensitizes Nerve endings to bradykinin,
histamine and sustance P
•Inflamation:PGI2, PGD2 and PGDE2 are vasodilators that cause
edema
•PGI2 causes protection of gastric mucosa
•PGE2 used to maintain renal blood flow but cause fever
•PGI2 and PGD2 inhibit platelet aggregation while TXA2 stimulate
platelet aggregation

COOH COOH
O
HO
Arachidonic acid Prostaglandins
Med chem I by [email protected]
4

5. NSAIDs…
The non-steroidal anti-inflammatory drugs can be divided:
MOA: Inhibit cyclooxgenase (COX)
Three types of COX
Cox-1-Constitutively expressed where inhibition leads to adverse effect
Cox -2-Inducibly expressed at sites of inflammation by inflamatory
mediatirs---NSAIDs should be COX-2 selective to treat pain,
inflammation and fever
COX-3-Inducile and causes inflammation and found in brain
-Non-selective inhibition of COX-1 and COX-2 result unwanted side
effect like gastric ulcer, platelet aggregation…

1.Salicylates
2.Para-aminophenol derivatives
3.pyrazolone and pyrazolidinediones derivatives
4.Arylacetic acids
5.Arylpropionic acids
6.Anthranilic acid derivatives
7.Arylsulfonamides
Med chem I by [email protected]
5

6. NSAIDs…
1. Salicyates



• Are derivatives of salicylic acid and are two types (I and II)
• Posses analgesic, antipryetic and anti-inflamatory activity






• Type I represents those that are formed by modifying the carboxyl group.
• Type II (a and b) represents those that are substitution on the hydroxyl group of
salicylic acid
•The derivatives were introduced to prevent gastric symptom and undesirable
tests of some common salt of salicylate
•Asprin is the only irreversible inhibitor C
OH
O
OH
1
2
3
4
5
6 C
OH
O
OR C
OR
O
OH C
O
O
OH
CR
O
Type I Type IIa Type IIb
Salicylic acid
Med chem I by [email protected]
6

7. NSAIDs…
Structure activity relationship
•The active moiety appears to be the salicylate anion
•Reduction of the acidity of the carboxylic group of the salicylate retain
analgesic effect eliminating anti-inflammatory (Salicylamide)
•Shift of phenolic OH group to meta or Para to carboxyl abolish activity
•Halogen atom substitution on the aromatic ring enhances potency &
toxicity
•Hydrophobic substituent at 5 position of salicylic acid improved activity C
O
O
OH
CCH
3
O C
OH
O
NH
2 C
OH
O
OH
F
F
Aspirin Salicylamide Diflunisal
Med chem I by [email protected]
7

8. •Salicylates are useful in the treatment of gouty arthritis
• because salicylates promote the excretion of uric acid.
• The ability of salicylates to inhibit platelet aggregation, therefore,
aspirin can be used as anti-thrombotic agent.
• An additional study suggested that aspirin and other NSAIDs
might be protective against colon cancer.
•Generally, salicylates inhibit the biosynthesis of prostaglandins at
the cyclooxygenase stage.
 Acetylsalicylic acid (Aspirin) is the only NSAID that covalently
modified COX by acetylating Ser-530 of COX-1 and Ser-516 of COX-
2.
 However, aspirin is 10-100 times more potent against COX-1 than
COX-2.

10. Pharmakokinetics-Salicylates are orally absorbed rapidly primarily
from intestine and to some extent in stomach
Generally, esters such as acetylsalicylic acid (ASA) appear to be
absorbed more slowly, yet 70% of aspirin is absorbed within an
hour and absorption is complete within 4 hours.
Metabolism
Salicylic acid and drugs like ASA that are converted to salicylic
acid undergo a variety of secondary metabolic transformations
including: glycine conjugation to yield salicyluric acid, ring
hydroxylation and carboxyl and phenol glucuronide conjugation.
The salicylates and their metabolites are eliminated by renally.
Diflunisal is cleared primarily by phenol and
carboxyl O-glucuronidation similar to the salicylates

11. Metabolism of Salicylates

12. Diflunisal metaolism

13. NSAIDs…
2. Para- aminophenol derivatives
•Are para aminophenol derivatives



•Introduced as analgesics after the discovery of the powerful
antipyretic activities of aniline
•They possess analgesic and antipyretic but not anti-
inflammatory activity
•Paracetamol is a prototype NH
2
OH OH
NHCCH
3
O
Med chem I by [email protected]
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14. NSAIDs…
•The anilides are simple acetamides of aniline
(Aminobenzene), which may or may not contain a 4-hydroxy
or 4-alkoxy group.
•Based on the discovery that phenacetin and acetanilide have
powerful antipyretic property
•Both are converted to paracetamol and are more toxic NHCCH
3
O
OH
NHCCH
3
O
OC
2H
5
NHCCH
3
O
Acetanilide Paracetamol Phenacetin
Med chem I by [email protected]
14

15. •Anilides do not possess the carboxylic acid
functionality and therefore they are classified as
neutral drugs and possess little inhibitory activity
against cyclooxygenase.
•They are believed to act as scavengers of
hydroperoxide radicals.

Med chem I by [email protected]
15

16. NSAIDs…
Structure activity relationship
–Amino phenols are less toxic than corresponding aniline derivatives
–Eterification of phenolic hydroxyl group with methyl or propyl group
produce more toxic derivative than ethyl
–Nitrogen substituents that reduce its basicity reduce activity unless it
is metabolically removed
–Amides derived from aromatic acid e.g. N-Phenyl benzamide's
(Benzanilide) are less active or even inactive

•Paracetamol overdose causes sever hepatotoxicity with
necrosis and liver failure
Med chem I by [email protected]
16

17. •Metabolism of paracetamol

18. •Normally acetaminophen is metabolized by N-
deacetylation and glucuronidation. However, in an
acute overdose, a minor metabolic pathway takes
precedence when the normal pathway is saturated,
giving rise to a reactive species known as the
"arylating intermediate".
•This intermediate reacts rapidly with GSH, resulting in
a complete depletion of glutathione.
•This leaves the liver defenseless against reactive
intermediates produced by the mixed function
oxidases, and against the arylating intermediate itself.
•The result is a dramatic hepatotoxicity.
•This process may be reversed by administration of
acetylcysteine, which preferentially reacts with
reactive species and protects the liver until GSH can be
resynthesized.

19. NSAIDs…
3. 3, 5-pyrazolidinediones


•The most important once are phenylbutazone and
oxyphenylbutazone (its metabolite) N
H
NH
O
O
1
2
34
5 N
N
O
OH
3CH
2CH
2CH
2C N
N
O
OH
3CH
2CH
2CH
2C
OH
Phenylbutazone Oxyphenylbutazone
Med chem I by [email protected]
19

20. NSAIDs…
Structure activity relationship
–Hydrogen atom at C4 is acidic & this is enhanced by the two-ketone
groups
•Decreasing /eliminating acidity abolishes activity
–If acidity increases too much uricosuric activity increases while anti-
inflammatory decreases
–Single alkyl substituent at C4 enhances anti-inflammatory activity
•n-butyl is the most active
–The presence of two phenyl groups in the ring nitrogen is not
important for anti-inflammatory & analgesic activity
–Pyrrole and isoxazole analogue of phenylbutazone retain activity NH
pyrrole
O
N
isoxazole
Med chem I by [email protected]
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21. •Substitution of the 2- phenylthioethyl group at the four
position produces anti-gout drug sulphinpyrazone

Med chem I by [email protected]
21

22. NSAIDs…
4. Arylalkanoic acids
ARC
H
H
COH
O ARC
CH
3
C
H
OH
O
Aryl or Hetero-aryl acetic acid analogs
Aryl or Hetero-aryl propionic acid analogs

Med chem I by [email protected]
22

23. NSAIDs…
Structure activity relationship
•All agents have an acidic and aromatic center
•Derivatives of aryl or heteroaryl acetic/propionic acid
correlates with carboxylic acid and double bond at position C5
and C8 of arachidonic acid
•The activity of ester & amide derivatives of carboxylic acid is
due to its metabolic hydrolysis
•The center of acidity is located one carbon atom from the
aromatic ring
–This distance is critical
–Increase distance to two or three carbons generally diminishes activity
Med chem I by [email protected]
23

24. NSAIDs…
•Methyl substitution on the carbon atoms separating the
acid and aromatic group increases anti-inflammatory
activity
•Groups more than methyl decrease anti-inflammatory activity
•A second area of lipophilicity non-coplanar with aromatic
ring enhances activity
•This lipophilic area corresponds to the double bond of C11 of
arachidionic acid
Med chem I by [email protected]
24

25. NSAIDs… N
O
Cl
11
8
5
14
OH
O
OH
O
Med chem I by [email protected]
25

26. •The α-carbon in aryl/hetroarylpropanoic acids is chiral and the S-
(+)- enantiomer of the profens is the more potent cyclooxygenase
inhibitor.
•Most profen products, except naproxen , are marketed as the
racemates.
•The profens undergo a metabolic inversion at the chiral carbon
involving stereospecific transformation of the inactive R
enantiomers to the active S-enantiomers.
•This is believed to proceed through an activated (more acidic α-
carbon) thioester intermediate. Normally only the S-(+) isomer is
present in plasma. ARC
CH
3
C
H
OH
O

27. Actions
These compounds are antiinflammatory agents with analgesic and antipyretic
activity.
Generally the profens are considered to be slightly “COX-1 selective”; naproxen
appears to be more selective for COX-
2 than other members of this series.
They are used for Rheumatoid Arthritis (RA), Osteoarthritis (OA) and as analgesics
and antipyretics. They should not be used during pregnancy or nursing; they can
enter fetal circulation and breast milk.).
They produce less GI ulceration than the salicylates, but may cause some
thrombocytopenia, headache, dizziness, fluid retention edema.
Absorption and Distribution:

These agents are well absorbed orally with high oral bioavailabilities and peak
plasma times of 1-2 hours.
Only ketoprofen and naproxen provide slower peak plasma levels.
All of the profens >99% bound by plasma proteins.

Metabolism:
All of these agents are carboxylic acids and thus are cleared, in part, as
acylglucuronides (inactive).
The other metabolic transformations different for profens under-go are
determined by the structure of the additional lipophilic functionality present in
each compound

28. Ibuprofen Fenoprofen
Flurbiprofen
The substitution of an -methyl on the alkanoic acid portion of acetic acid enhances
anti-inflammatory actions and reduces side effects
Med chem I by [email protected]
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30. •Metabolism and epimerization of fenprofen

31. •Metabolism and epimerization of ketoprofen

32. •Metabolism of naproxen-marketed as S(+)
naproxen

33. NSAIDs…
5. Aryl and heteroarylacetic acids –derivatives of acetic acid N
CH
2
CO
Cl
CH
3
CO
2H
H
3CO CH
S
CH
2CO
2H
CH
3
F
O
CH
3
Indomethacin Sulindac
Med chem I by [email protected]
33

34. NSAIDs…
Structure activity relationship
•N-benzoyl derivatives substituted in the para-position with
fluoro, chloro, trifluoromethyl, or thiomethyl group are the
most active
•The 5 –position of the indole ring is most flexible with regard
to the nature of substituent, which enhances activity.
–Substituents such as methoxy, fluoro, dimethylamino, methyl, allyloxy, and
acetyl are more active than un-substituted indole ring
•The presence of an indole nitrogen is not essential for activity
because the corresponding 1-benzylidenyl indene analogs
(e.g., sulindac) are active
–Sulindac is biososter of indomethacin
Med chem I by [email protected]
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35. Indomethacin: contains a benzoylated indole nitrogen. The methyl group at
the 2 position of the indole ring prevents free rotation about the C-N bond and
keeps the two aromatic rings in the correct relationship for COX binding and
therapeutic activity.





Pks: Well absorbed orally and should be taken with meals to
reduce GI upset. Peak plasma levels are attained within 1-2 hours and half-
life is 4.5 hours.
The metabolism of indomethacin involves glucuronidation
of the carboxyl group along with demethylation (increasing resemblance to 5-
HT and CNS toxicity) and glucuronidation of the resulting phenol.

36. Metabolism of indomethacin

37. It is used for Rheumatoid Arthritis (RA), Osteoarthritis (OA),
ankylosing spondylitis(pain inflamed spine), to suppress uterine
contraction (preterm labor), and to promote closure of patent ductus
arteriosus in neonates (premature infants).
Sideeffect:
GI ulceration and hemorrhage (these limit use).
CNS toxicity ranging from headaches to delusions to psychoses and
suicidal tendencies occur along with bone marrow depression: aplastic
anemia and thrombocytopenia.

38. Sulindac
The relationship between aromatic rings observed for
indomethacin is preserved by restricted rotation about the
carbon-carbon double bond in sulindac.
 In this agent the indole N has been eliminated which reduces the
drugs resemblance to 5-HT and therefore fewer CNS side effects
are seen.
This compound has pharmacologic actions similar to
indomethacin
However, sulindac is a prodrug function; it is reduced to a
sulfide which is 50X more active.

39. •Sulindac Kinetics: Rapidly and extensively absorbed when given
orally within 1 to 2 hours. The half-life for sulindac is 7-8 hours.
The active sulfide has half-life of 18 hrs.
•Sulindac Metabolism:
Sulindac is a prodrug and therefore must be converted to an
active form. This activation requires reduction to the sulfide
which is then capable of inhibiting cyclooxygenase.
•Alternatively, sulindac may be oxidized to the inactive sulfone.
In the case of sulindac, glucuronidation of the carboxyl group
may still occur but since the methoxy group has been replaced by
a F substituent, no ring demethylation
•Therapeutic use
sulindac is used for RA, OA, acute gout and to inhibit uterine
contractions.
Side effect:
Overall sulindac produces less GI ulceration, probably as a result
of its prodrug function.
Some CNS toxicity, hepatic damage and prolongs clotting time

40. Sulindac metabolism

41. •Tolmetin and ketorolac are pyrole derivative acetic acid derivative NSADs



















•Tolmetin is Non-selective COX inhibitor with actions similar to
other members in this class and it is used for RA, and OA.
•It is the shortest acting member of this class due in part to rapid
Phase I oxidation of the para-methyl group to a benzylic alcohol
initially and eventually to the acid.
•These metabolites are subsequently glucuronidated and
eliminated. As a result of this, tolmetin’s half-life is typically less
than 5 hours.

42. •Ketorolac Lacks this benzylic methyl group is not susceptible to the
type of oxidation observed for tolmetin and as a result its half-life is
longer (4-6 hours). Metabolism of tolmetin and ketorolc is shown
elow

43. •Alkanones are prodrugs of acetic acid analogue NSAIDs-
Nabumetone is an example where its metabolism is below

44. NSAIDs…
5. Arylanthranilic acid derivatives(fenamates)
–The anthranilic acid derivatives are nitrogen isosters of
salicylic acid
–Are the results of the application of bioisosteric drug
design NH
2
COOH NH
COOH
1
4
2
3
5
6
1'
2'
3'
4'
5'
6'
anthranilic acid
Structure of arylanthilic acids C
OH
O
OH
3
Salicylic acid
Med chem I by [email protected]
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45. NSAIDs… NH
COOH
CH
3
CH
3 NH
COOH
CF
3 NH
COOH
CH
3
Cl
Mefenamic acid Flufenamic acid
Meclofenamic acid
Med chem I by [email protected]
45

46. NSAIDs…
Structure activity relationship

•Substitution on the anthranilic acid ring generally reduces
activity while substitution of the N-aryl ring can lead to
conflicting results
•The most active once have a small alkyl or halogen substituent
at 2’, 3’ and/or 6’ position of the N-aryl moiety
•Among disubstituted N-arylfenamates 2’ and 3’ derivatives
are most active
•These Substituents serve to force the N-aryl ring out of co-
planarity with anthranilic acid
Med chem I by [email protected]
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47. NSAIDs…
SAR …

•NH moiety is essential for activity
•Replacement of NH with O, CH
2, S, SO
2, NCH
3 or NCOCH
3
significantly reduces activity
•The position rather than the nature of the acidic function is
critical for activity
• Replacement of carboxylic acid function with isosteric
tetrazole moiety has little effect on activity NH
N
N
N
tetrazole
Med chem I by [email protected]
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48. Actions:
•The anthranilates have primarily anti-inflammatory with some
analgesic and antipyretic activity and are non-COX selective
•The anthranilates are used as mild analgesics and
occasionally to treat inflammatory diseases.
• Diclofenac is used for RA, OA, and analgesic,
•Meclofenanamte for RA (as a secondary agent), and Mefenamic
acid as an analgesic for dysmennorhea.
•The utility of the class of agents is limited by a number of adverse
reactions including nausea and vomiting, diarrhea, ulceration,
headache, drowsiness and hematopoietic
toxicity.

49. •Diclofenac is twice as potent as indometacin and 450 times more
potent as asprin because
Inhibition of prostaglandins more than indomethacin
 inhibition of lipooxygenase and decrease production of proinflamatory
leucotrienes
inhibition of release of arachidonic acid and stimulate its reuptake









•The function of the chlorine atoms are to force the two rings out of
planarity

50. •Metabolism of diclofenac

51. Different amino acids at the active sites of COX-1 and Cox-2
COX-1 COX-2

52. Selective COX-2 inhibitors
•All COX-2 inhibitors are diaryl-5-membered heterocycles.
•Celecoxib has a central pyrazole ring and two adjacent
phenyl substituents, one containing a methyl group and
the other a polar sulfonamide moiety
– the sulfonamide binds to a distinct hydrophilic region
that is present on COX-2 but not COX-1.
•Rofecoxib and Valdecoxib contain a central furanone ring
and central oxazole ring, respectively
•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.

Med chem I by [email protected]
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53. Med chem I by [email protected]
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54. Actions:
•The COX-2 inhibitors have analgesic, antipyretic and inflammatory
activity comparable to NSAIDs and are used therapeutically in OA
(all), RA (celecoxib and Valdecoxib), acute pain (Celecoxib,
Rofecoxib) and primary dysmenorrhea (all).
•These compounds produce less GI ulceration and hemorrhage than
NSAIDs due to their COX-2 selectivity.
• Also they do not inhibit platelet aggregation and have minimal
renal and CV side effects.
•These drugs should not be used in 3rd trimester of pregnancy since
they promote closure of ductus arteriosus.
Absorption and Distribution:
All three COX-2 inhibitors are well absorbed and provide peak plasma
levels within 3 hours. Celecoxib and Valdecoxib are more acidic
(sulfonamide versus sulfone) and are more highly bound by plasma
proteins.

55. •Metabolism:
Celecoxib - efficiently metabolized, the benzylic methyl.
Rofecoxib - its double bond may be reduced to yield two different
stereoisomeric dihydro metabolites that are inactive.