1. Pharmaceutical Chemistry II Lecture 5 - NSAIDS
Joseph O. Oweta | PHC 3201

2. Introduction
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).
A number of these drugs possess antipyretic activity in addition to
having analgesic and anti-inflammatory actions, and thus have utility in the treatment of fever.
Some of the primary indications for NSAID therapy include: Rheumatoid arthritis, osteoarthritis (OA), acute gouty arthritis, ankylosing spondylitis, dysmenorrhea and tissue damage resulting from inflammatory joint disease (arthritis).

3. Differing roles of COX-1 and COX-2 enzymes.

4. Mechanism of Action No.1
The major mechanism by which the NSAIDs elicit their therapeutic effects (antipyretic,analgesic, and antiinflammatory activities) is inhibition of prostaglandin (PG) synthesis.
Specifically NSAIDs competitively (for the most part) inhibit cyclooxygenases(Prostaglandin synthetase), the enzymes that catalyze the synthesis of cyclic endoperoxidesfrom arachidonic acid to form prostaglandins.

5. Mechanism of Action No. 2
Generally, the NSAIDs inhibit both COX-1 and COX-2.
Most NSAIDs are mainly COX-1 selective (e.g., aspirin, ketoprofen, indomethacin, piroxicam, sulindac).
Others are considered slightly selective for COX-1 (e.g., ibuprofen, naproxen, diclofenac) and…
Others may be considered slightly selective for COX-2 (e.g., etodolac, nabumetone, and meloxicam).

6. Mechanism of Action No. 2
The mechanism of action of celecoxib and rofecoxib is primarily selectiveinhibition of COX-2;
NB: at therapeutic concentrations, the COX-1 isoenzyme is not inhibitedthus GI toxicity may be decreased.

7. Mechanism of Action No. 2
Other mechanisms that may contribute to NSAID antiinflammatory activity include
the reduction of superoxide radicals,
induction of apoptosis,
inhibition of adhesion molecule expression,
decrease of nitric oxide synthase,
decrease of proinflammatory cytokine levels (tumornecrosis factor-α, interleukin-1),
modification of lymphocyte activity, and
alteration of cellular membrane functions.

8. Mechanism of pyrexia
Antipyretic activity of NSAIDs results from inhibition of prostaglandin E2 (PGE2) synthesis in circumventricular organs in and near the preoptic hypothalamic area.
Infections, tissue damage, inflammation, graft rejection, malignancies, and other disease states enhancethe formation of cytokines that increase PGE2 production.
PGE2 triggers the hypothalamus to promote increase in heat generation and decreases in heat loss.

9. Biosynthetic pathways of prostaglandins and the mechanism of drugs which inhibit their production

10. Classification of NSAIDS
Salicylates
Propionic acids (Profens)
Aryl and heteroarylacetic acids
Anthranilates (Fenamates)
Oxicams (“Enol Acids”)
Phenylpyrazolones
Anilides.

11. General Structure and Property of NSAIDS

12. General Structure and Property of NSAIDS
In general, NSAIDs structurally consist of an acidic moiety (carboxylic acid, enols)attached to a planar, aromatic functionality.
Some analgesics also contain a polar linking group, which attaches the planar moiety to an additional lipophilic group.

13. Chemical/ pharmacologic properties
All are relatively strong organic acids with pKa in the 3.0–5.0 range. Most, but not all, are carboxylic acids.
Thus, salt forms can be generated upon treatment with base and all of these compounds are extensively ionized at physiologic pH.
The acidic group is essential for COX inhibitory activity.

14. Chemical/ pharmacologic properties
The NSAIDs differ in their lipophilicities based on the lipophilic character of their aryl groups and additional lipophilic moieties and substituents.
The acidic group in these compounds serves a major binding group (ionic binding) with plasma proteins.
Thus all NSAIDs are highly bound by plasma proteins (drug interactions).

15. Chemical/ pharmacologic properties
The acidic group also serves as a major site of metabolism by conjugation.
Thus a major pathway of clearance for many NSAIDs is glucuronidation (and inactivation) followedby renal elimination

16. 1. Salicylates
The salicylates are derivatives of 2-hdroxybenzoic acid(salicylic acid).
They were discovered in 1838 following the extraction of salicylic acid from willow bark.

17. Salicylates
The salicylates have potent antiinflammatory activity with mild analgesic and antipyretic activities.
These compounds are mainly COX-1 selective—they are bound with higher affinity to COX-1.
The therapeutic and some of the toxic actions (i.e. gut) of aspirin can be related to its ability to inhibit COX-1 in various tissues.

18. 2-hydroxybenzenecarboxylate.
Sodium Salicylate
2-hydroxybenzenecarboxylate.
relief of pain, rheumatic fever and symptomatic treatment of gout.

19. Magnesium Salicylate
Magnesium salicylate is prepared by mixing of salicylic acid with sufficient quantity of magnesium oxide in isopropanol and water mixture

20. Salicylamide
o-hydroxybenzamide.

21. Phenylsalicylate (salol)
Phenyl salicylate is prepared by esterification of salicylic acid with phenol.

22. Salicylates continued…. Acetylsalicylic acid
Is an acetyl derivative of salicylic acid.
Acetyl salicylic acid (aspirin) can be prepared by the reaction between salicylic acid and acetic anhydride.
…the hydroxyl group on the benzene ring in salicylic acid reacts with acetic anhydride to form an ester functional group.

23. Acetyl Salicylic Acid
Thus, the formation of acetyl salicylic acid is referred to as an esterification reaction.
This reaction requires the presence of an acid catalyst.

24. Flufenisol acetyl-5-(4-fluorophenyl) salicyclic acid
Flufenisol is more potent, long acting NSAID and produces less gastric irritation.

25. Proprionic Acid Derivatives (Profens)

26. Proprionic Acid Derivatives (Profens)
…are often referred to as the “profens” based on the suffix of the prototype member, ibuprofen.
Like the salicylates these agents are all strong organic acids(pKa = )and thus form water soluble salts with alkaline reagents.
The arylpropionic acids are characterized by the general structure Ar—CH(CH3)—COOH which conforms to the required general structure.
All of these compounds are predominantly ionized at physiologic pH and more lipophilic than acetyl salicylic acid or salicylic acid.

27. Proprionic Acid Derivatives (Profens)
The α-CH3 substituent present in the profens increases cyclooxygenase inhibitory activity and reduces toxicity of the profens.
The α-carbon in these compounds is chiral and the S-(+)-enantiomer of the profens is the more potent cyclooxygenase inhibitor.
Sinister Vs Rectus whilts looking at enantiomers from via the chiral centre.

28. 2-(4-(2-methylpropyl)phenyl)propanoic acid
Ibuprofen
2-(4-(2-methylpropyl)phenyl)propanoic acid

29. Fenoprofen

30. Flurbiprofen
Systematic Name?

31. Ketoprofen and Naproxen

32. Synthesis of Ibuprofen.

33. Two of the most popular ways to obtain ibuprofen are the Boot process and the Hoechst process.
The Boot process is an older commercial process developed by the Boot Pure Drug Company, and the Hoechst process is a newer process developed by the Hoechst Company.
Most of these routes to ibuprofen begin with isobutylbenzene and
use Friedel-Craft’s acylation.
The Boot process requires six steps, while the Hoechst process,
with the assistance of catalysts, is completed in only three steps.

34. Assignment Draw the structure of Naproxen
Give a systematic name for the structure above
Describe the synthesis of Naproxen.

35. Aryl and Heteroarylacetic Acids Chemistry and General Structure
These compounds are also derivatives of acetic acid, but in this case the substituent at the 2-position is a heterocycle or related carbocycle.
This does not significantly effect the acidic properties of these compounds.

36. Aryl and Heteroarylacetic Acids Classification
indene/indoles,
pyrroles
oxazoles

37. Indene and Indole Acetic Acids Indomethacin SAR’s and Structure1 2 2
1. The carboxyl group is essential for anti-inflammatory activity.
2. Presence of methoxy (position 5) group on the ring (5 or 6), methyl (2), dimethylamino group (5) in indole moiety of indomethacin exhibit activity.
3. Presence of chlorine or fluorine or CF3 groups at para position of phenyl group also exhibits anti-inflammatory activity. 3

38. Synthesis of Indomethacin

39. Indene and Indole Acetic Acids Sulindac Structure

40. Indene and Indole Acetic Acids Sulindac
Describe the synthesis of Sulindac
Draw the structure of etodolac

41. Ketolorac Can you identify the chemical class of this drug molecule?
Name and draw the structure of an oxazole acetic acid

42. Anthtranilates (fenamates)
Actions. The anthranilates have primarily antiinflammatory with some analgesic and antipyretic activity and are non-COX selective.
The anthranilates are used as mild analgesics and occasionally to treat inflammatory disorders.
Diclofenac is used for rheumatoid arthritis, osteoarthritis and post-operative pain and mefenamic acid as an analgesic for dysmenorrhea.
The utility of this class of agents is limited by a number of adverse reactions including nausea vomiting, diarrhoea, ulceration, headache, drowsiness and hematopoietic toxicity.

43. Mefenamic Acid

44. Meclofenamic Acid

45. Diclohlorophenyl Acetic Acid
Draw the structure of diclofenac
Describe the synthesis of diclofenac.

47. 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).

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

49. Piroxicam

50. Meloxicam

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

52. Phenylpyrazolones Pyrazole – Reduction products
Pyrazoline
Pyrazolidine

53. Pyrazoline Substitution Products
5 – Pyrazolone
3,5-pyrazolidinedione

54. Phenylpyrazolones
Phenylbutazone

55. Oxyphenbutazone

56. Silphinpyrazone

57. 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

58. 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

59. Assignment
Read and make notes about the synthesis of phenylbutazone from diethyl malonate

60. Anilides and COX 2 Inhibitors

61. 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.

62. 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)

64. 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

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

66. 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.

67. Celecoxib

68. Rofecoxib

69. Valdecoxib