Anti inflammatory agents

notes for medicinal chemistry I

1. Anti-Inflammatory Agents MRS.REKHA AMIT BHALERAO Department of Pharmaceutical Chemistry PES MODERN COLLEGE OF PHARMACY, FOR LADIES, Moshi - 412015

2. The non-steroidal antiinflammatory 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 antiinflammatory 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 Introduction

3. Cycloxygenase enzyme There are Two COX isoenzymes have been identified these are: COX-1 and COX-2 . COX-1 constitutive enzyme is present in a wide variety of cell types and influences the “housekeeping” functions of prostaglandins. This activity is particularly important in the gastrointestinal (GI) tract, the kidneys, and the circulatory system. COX-2 is inducible enzyme, is found in only a few cell types, especially macrophages and other leukocytes, fibroblasts, and endothelial cells, including those of the vascular system. COX-2 is involved in those aspects of the inflammatory process that are mediated by prostaglandins.

4. Role of COX Enzyme Any Inflammatory stimulus activates COX-2 inducible enzyme which synthesizes PGI2, PGE2, in Macrophages, Leukocytes, Fibroblasts, Endothelial cells which causes Inflammation. cyclooxygenases (Prostaglandin synthetase ) the enzymes that catalyze the synthesis of cyclic endoperoxides from arachidonic acid to form prostaglandins.

5. Mechanism of Action 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 inhibit cyclooxygenases also called Prostaglandin synthetase . Generally, the NSAIDs inhibit both COX-1 and COX-2. Most NSAIDs are mainly inhibit 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 ). The mechanism of action of celecoxib and rofecoxib is primarily selective inhibition of COX-2; at therapeutic concentrations, the COX-1 isoenzyme is not inhibited thus GI toxicity is decreased .

6. Classification The NSAIDs are classified on basis of chemical structure as follows : Salicylates : Aspirin, Sodium Salicylate Propionic acid derivatives ( Profens ): Ibuprofen Aryl acetic acids derivatives : Diclofenac , Indolacetic acid derivatives: Indomethacin , Sulindac Anthranilates ( Fenamates ): Mefenamic acid Oxicams (“ Enol Acids ”): Piroxicam Phenylpyrazolone derivatives: Phenyl butazone Anilides derivatives: Paracetamol Pyralopyralo Derivative: Ketorolac II. Preferential COX2 Inhibitors

7. Salicylates The salicylates are derivatives of 2-hydroxybenzoic acid (salicylic acid). They were discovered in 1838 following the extraction of salicylic acid from willow bark. Salicylic acid was used medicinally as the sodium salt but replaced therapeutically in the late 1800s by acetylsalicylic acid (Aspirin). Mechanism of Action: 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 and participate in transacetylation reactions in vitro. Examples: Sodium Salicylate ,, Acetyl Salicylic acid (Aspirin), Phenyl salicylate

8. Sodium S alicylate Sodium salicylate is sodium 2-hydroxybenzenecarboxylate. It occurs as a white, crystalline powder or small, colorless crystals or shiny flakes, freely soluble in water, sparingly soluble in alcohol and practically insoluble in ether. Sodium salicylate is employed for the relief of pain, rheumatic fever and symptomatic treatment of gout. Sodium salicylate

9. Acetylsalicylic acid ( Aspirin) Properties: Aspirin occurs as colorless crystals or powder. It is slightly soluble in water and soluble in alcohol, chloroform, ether and glycerin . Aspirin is stable in dry air but in presence of moisture, it hydrolyses slowly into salicylic acid and acetic acid. Aspirin is acidic and produces effervescence with carbonates and bicarbonates . Use. Aspirin is used as an antipyretic, analgesic and antirheumatic .

10. Phenyl Salicylate ( Salol ): Phenyl Salicylate is prepared by esterification of salicylic acid with phenol. Phenyl Salicylate is available as white crystalline powder with aromatic odor . It is insoluble in water but freely soluble in alcohol, ether, chloroform, acetone and fixed oils . Phenyl Salicylate

11. Propionic acid derivatives ( Profens ) The arylpropionic acids are characterized by the general structure Ar —CH(CH3)—COOH which conforms to the required general structure. These compounds are referred to as the “ profens ” based on the suffix of the prototype member, ibuprofen. These agents are strong organic acids ( pKa = 3.0-5.0)and thus form water soluble salts with alkaline reagents .. All of these compounds are predominantly ionized at physiologic pH and more lipophilic than acetyl salicylic acid or salicylic acid. The alpha -CH3 substitutent present in the profens increases cyclooxygenase inhibitory activity and reduces toxicity of the profens . The alpha-carbon in these compounds is chiral and the S-(+)- enantiomer of the profens is the more potent cyclooxygenase inhibitor. Mechanism of Action: Generally the profens are considered to be slightly “COX-1 selective”; They are used for rheumatoid arthritis , oesteoarthiritis and as analgesics and antipyretics . Examples: Ibuprofen

12. Aryl acetic acid derivatives 2-[2-(2,6-dichloroanilino)phenyl]acetic acid is a Diclofenac . Which is an example of aryl acetic acid derivatives.

13. Indol acetic acid derivatives Indomethacin : Indomethacin contains a benzoylated indole nitrogen. Indomenthacin was introduced in 1964 as a powerful anti-inflammatory, analgesic agent. Chemically, indomethacin is 1-(p- chlorobenzoyl )-5-methoxy-2-methylindole-3-acetic acid. Indomethacin is “COX-1 ” selective” and produces primarily antiinflammatory actions with some analgesic and antipyretic activity. It is used for rheumatoid arthritis, oesteo arthritis, ankylosing spondylitis , to suppress uterine contraction, and to promote closure of parent ductus artiosus in neonates (premature infants ). Sulindac : In this agent the indole nitrogen has been eliminated which makes the drug resemblance to 5-HT and therefore fewer CNS side effects are seen. This compound has pharmacological actions similar to indomethacin (COX-1 selective and antiinflammatory primarily ). It is used for rheumatoid arthritis, osteoarthritis, ankylosing spondylytis , acute gout and to inhibit uterine contractions.

14. Anthranilates ( Fenamates ) Anthranilates are N-aryl substituted derivatives of anthranilic acid or N - anthranilic acid derivative. Which is a bioisostere of salicylic acid. These agents retain the acidic properties that are characteristic of this class of agents. The most active fenamates have small alkyl or halogen substituents at the 2′, 3′ and/or 6′ position of the N-aryl moiety ( meclofenamate is 25 times more potent than mefenamate ). Among the disubstituted N-aryl fenamates the 2 ′, 3 ′-derivatives are most active suggesting that the substituents at the 2′, 3′-positions serve to force the N-aryl ring out of coplanarity with the anthranilic acid. Hence this steric effect is proposed to be important in the effective interaction of the fenamates at their inhibitory site on cyclooxygenase .

15. Mechanism of action : The anthranilates have primarily antiinflammatory with some analgesic and antipyretic activity and are non-COX selective. The anthranilates are used as mild analgesics. Examples: Mefenamic Acid . Mefenamic Acid

16. Oxicam Derivatives (“ 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 NH group. These compounds are acidic ( pKa = 6.3). Mechanism of Action: Selective COX-2 inhibitor These agents used in treatment of rheumatoid arthritis and osteoarthritis. Examples: Piroxicam

17. Phenylpyrazolones This class of agents are characterized by the 1-aryl-3,5-pyrazolidinedione structure. The presence of a proton which is situated α to two electron with drawing carbonyl groups renders these compounds acidic. The pKa for phenylbutazone is 4.5. Oxyphenbutazone is a hydroxylated metabolite of phenylbutazone . Example: Phenylbutazone

18. Anilides The anilides are simple acetamides of aniline, 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 . Example: Acetoaminophen or Paracetamol

19. Pyrralo-Pyrrole derivatives Ketorolac is a potent analgesic and modest antiinflammatory active drug. It inhibits Prostaglandine synthesis. Ketorolac is frequently used in postoperative, dental and acute musculoskeletal pain. Ketorolac

20. Summary 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. The NSAIDs are characterized by the following 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. 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 ). 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) followed by renal elimination.

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