Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) PDF

# Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) ## Introduction Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are a class of drugs that relieve pain, reduce inflammation (redness and swelling), and bring down a high temperature (fever). They are used to treat a wide range of conditions, including...

# Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) ## Introduction Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are a class of drugs that relieve pain, reduce inflammation (redness and swelling), and bring down a high temperature (fever). They are used to treat a wide range of conditions, including: * Headaches * Painful periods * Toothache * Sprains and strains * Infections, such as the common cold or the flu * Inflammation of the joints (arthritis) and other tissues NSAIDs work by blocking the production of prostaglandins, chemical messengers that are often responsible for the pain and swelling of inflammatory conditions. **Types of Analgesics** * **Narcotic analgesics**: analgesics that have CNS effect. * **Non-Narcotics**: analgesics that do not have CNS effect. ## Market Share of Pain Medications in 2009 The following table shows the market share of pain medications in 2009: | Medication | Market Share | |---|---| | Local anesthetics | 5% | | COX2 inhibitors | 7% | | Weak opioids | 7% | | Strong opioids | 29% | | Anti-depressants | 11% | | Anti-convulsants | 13% | | NSAIDs | 28% | The total world pain market in 2013 is estimated to be above $25 billion. ## Mechanism of Actions for NSAIDs * **Prostaglandins** are the mediators of inflammation. The inflammatory response is the body's natural response that occurs immediately following tissue damage. * **NSAIDs** are irreversible inhibitors of cyclooxygenase activity, thus they prevent the formation of prostaglandins and consequently reducing the signs and symptoms of inflammation. * **Prostaglandins** are a family of chemicals that are produced by the cells of the body in response to illness or injury. They promote inflammation, pain, and fever; support the blood clotting function of platelets; and protect the lining of the stomach from the effects of acid. * **Prostaglandins** are unsaturated carboxylic acids, consisting of a 20 carbon skeleton that also contains a five member ring. They are biochemically synthesized from the fatty acid, arachidonic acid. ## What is the Basic Difference Between Traditional NSAIDs and COX-2 Inhibitors? * **Prostaglandins** are made by two different enzymes, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). * The **prostaglandins** made by the two different enzymes have slightly different effects on the body. * **Selective COX-2 inhibitors** are NSAIDs that selectively block the COX-2 enzyme and not the COX-1 enzyme. Blocking this enzyme prevents the production of prostaglandins by the COX-2 enzyme that often cause the pain and swelling of inflammation and other painful conditions. Because they selectively block the COX-2 enzyme and not the COX-1 enzyme, these drugs are uniquely different from traditional NSAIDs, which usually block both COX-1 and COX-2 enzymes. * With **traditional antiinflammatory drugs** such as aspirin, inflammation is reduced by blocking Cox-2, but the protective mucus lining of the stomach is also reduced because Cox-1 is blocked, which can cause stomach upset, ulceration, and bleeding from the stomach and intestines. * **Drugs** that selectively block COX-2 do not present the risk of injuring the stomach that medications also blocking COX-1 can. ## COX Isoform Functions |COX-1 | |COX-2| |---|---|---| | **Prostaglandins** | **Prostaglandins** | | Thromboxane A2 | Prostacyclin (PGI2) | |---|---|---| | * GI cytoprotection* | * Pain* | * Renal function ('constitutive')* | | * Platelet aggregation* | * Inflammation* | * Vasodilation* | | * Vasoconstriction* | * Fever* | * Inhibits platelet aggregation* | | * Renal function* | | * GI mucosal integrity & ulcer healing * | |**Physiologic** | **Inflammatory** | **Physiologic** | ## Classification of NSAIDs * **Salicylic acid derivatives**: aspirin, sodium salleylate, Imunisal, chalino-magnesium trisalleylate, salsalate, salley lealleytle acid, sulfasalazine, elastazine * **Para-aminophenol derivatives**: acetaminophen * **Indole & Indene acetio acids**: Indomethacin, oulindae, etodal, * **Anthranilic acids (fenamaten)** : mefenamie aeld, mestietenamie said * **Alkanones**: nabumeton * **Arvipropionic acida** : Ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, exaprozin * **Heteroaryl acetic acida**: talmetin, dielofenac, keteralse * **Enolic acids**: oxleams (piroxicam, tenoxicam, meloxicam), pyrazolidinediones (phenylbutazone, exyphenthatrazone) * **Propionic Acid Derivative**: ibuprofen, flurbiprofen, naproxen * **Pyrrolealkanoic Acid Derivative**: tolmetin * **Phenylalkanoic Acid Derivative**: flurbiprofen * **Indole Derivative**: indomethacin * **Fenamate**: meclofenamic acid * **Pyrazolone Derivative**: phenylbutazone * **Oxicam**: piroxicam * **Phenylactic Acid Derivative**: diclofenac * **Naphtylactic Acid Prodrug**: nabumetone ## Examples of NSAIDs * **Aspirin**: 2-acetoxybenzoic acid * **Diflunisal (Dolobid)**: 2',4'-difluoro-4-hydroxybiphenyl -3-carboxylic acid * **Indometacin (Indocin)**: 2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy -2-methyl-1H-indol-3-yl)acetic acid * **Diclofenac (Voltaren)**: 2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid * **Etodolac (Lodine)**: (RS)-2-(1,8-Diethyl-4,9-dihydro-3H- pyrano[3,4-b]indol-1-yl)acetic acid * **Sulindac (Clinoril)**: {(12)-5-fluoro-2-methyl-1-[4-(methylsulfinyl) benzylidene]-1H-indene-3-yl)acetic acid * **Ibuprofen (Motrin)**: (RS)-2-(4-(2-methylpropyl)phenyl) propanoic acid * **Ketoprofen (Orudis)**: (RS)-2-(3-benzoylphenyl)propanoic acid * **Paracetamol**: N-(4-hydroxyphenyl)acetamide * **Mefenamic acid**: 2-(2,3-dimethylphenyl)aminobenzoic acid * **Nabumetone (Relafen)**: 4-(6-methoxy-2-naphthyl)-2-butanone * **Naproxen (Aleve, Naprosyn)**: (+)-(S)-2-(6-methoxynaphthalen-2-yl) propanoic acid * **Phenylbutazone**: 4-butyl-1,2-diphenyl-pyrazolidine -3,5-dione * **Celecoxib (Celebrex)**: 4-[5-(4-Methylphenyl)-3-(trifluoromethyl) pyrazol-1-yl]benzenesulfonamide * **Piroxicam (Feldene)**: (8E)-8-[hydroxy-(pyridin-2-ylamino)methylidene]- 9-methyl-10,10-dioxo-1006-thia-9-azabicyclo[4.4.0] deca-1,3,5-trien-7-one ## NSAIDs - Salicylate Derivatives * **Salicylates** are derived from Salicylic acid, which is a monohydroxybenzoic acid, and are nonsteroidal anti-inflammatory drugs. * They inhibit the synthesis of prostaglandin and other mediators in the process of inflammation and have anti-inflammatory, antipyretic and analgesic properties. **Chemical Structures of Salicylate Derivatives** * **Salicylate**: $M+ = Na+ $ (Sodium), $M+ = 1/2 Mg2+$ (Magnesium) * **Acetylsalicylate**: $OC-CH3$ * **Sodium Thiosalicylate**: $$SH$$ * **Salicylamide**: $$NH2$$ * **Salicylic acid (2-Hydroxybenzoic acid)**: $$OH$$ **Salicylic acid derivatives and their chemical structures** * **Methyl Salicylate**: $$O-CH3$$ * **Salsalate**: $$OH$$ * **Diflunisal**: $$F$$ * **Olsalazine**: $O$ * **Fendosal**: $OH$ * **Sulfasalazine**: $HN$ **Structure Activity Relationship of Salicylates** * Salicylates generally act by virtue of their content of salicylic acid. * The carboxylate anion is required for anti-inflammatory action. * Salicylamide HAS ANALGESIC action but LACKS INFLAMMATORY action. * Substitution on the carboxyl or hydroxyl groups change the potency or toxicity of salicylate compounds. * Hydroxyl group should be ortho with respect to carboxylic group. * Halogen substitution enhances activity however make them toxic as well. * Substitution with hydrophobic aryl groups at the 5- position of the ring improves anti inflammatory activity. **Chemical Structures** * **Salicylic acid**: $$OH$$ * **Acetylsalicylic acid**: $$OH$$ * **Diflunisal**: $$OH$$ ## Synthesis of Salicylic Acid **Kolbe-Schmitt Reaction** $$ONCOONHO, COOH$$ $$OH$$ * The yield is about 90% at 150-160 °C and 5 bar (7atm) CO₂ pressure. ## Synthesis of Acetylsalicylic Acid (Aspirin) The synthesis of aspirin is classified as an esterification reaction: $$ \begin{aligned} CH3 & \qquad \qquad \qquad \qquad \qquad \qquad \qquad CH3 \\ & \qquad \qquad \qquad \qquad \qquad O & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad O & \qquad \qquad \qquad \qquad \qquad \qquad \qquad O \\ & \qquad \qquad \qquad \qquad C & \qquad \qquad \qquad \qquad \qquad \qquad \qquad || & \qquad \qquad \qquad \qquad \qquad \qquad \qquad || & \qquad \qquad \qquad \qquad C & \qquad \qquad \qquad \qquad \qquad \qquad \qquad O & \qquad \qquad \qquad \qquad \qquad O \\ & \qquad \qquad \qquad \qquad CH3 & \qquad \qquad \qquad \qquad \qquad + & \qquad \qquad HO & \qquad OH & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \longrightarrow & \qquad \qquad \qquad \qquad \qquad HO & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad O \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad O & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad O \\ & \qquad \qquad \qquad \qquad \qquad C & \qquad \qquad \qquad \qquad \qquad || & \qquad \qquad \qquad \qquad \qquad C & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad C & \qquad \qquad \qquad \qquad \qquad || & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad C & \qquad \qquad \qquad \qquad \qquad O & \qquad \qquad \qquad \qquad \qquad O \\ & \qquad \qquad \qquad \qquad \qquad CH3 & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad + & \qquad \qquad \qquad \qquad \qquad H3C & \qquad \qquad \qquad \qquad \qquad O & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad H \\ & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad O & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad CH \\ \qquad \qquad \qquad \qquad ACETIC & \qquad \qquad \qquad \qquad \qquad SALICYLIC & \qquad \qquad \qquad ACETYL- & \qquad \qquad \qquad \qquad ACETIC ACID \\ \qquad \qquad \qquad \qquad \qquad ANHYDRIDE (AA) & \qquad \qquad \qquad \qquad \qquad ACID (SA) & \qquad \qquad \qquad \qquad \qquad SALICYLIC ACID (ASA) \end{aligned} $$ *Aspirin has analgesic, antipyretic, anti-inflammatory, and antiplatelet effect.* ## The Mechanism-of-Action of Aspirin * Aspirin (acetylsalicylic acid) covalently and irreversibly modifies both Cox-1 and Cox-2 by acetylating Serine-530 in the active site. * Acetylation of Cox-1 creates a steric block that prevents the binding of arachidonic acid at the cyclooxygenase active site. * Acetylation of Cox-2 retains the cyclooxygenase activity although the reaction produces a novel product 15-R-HETE. ## Metabolism of Acetylsalicylic Acid * **Glucuronic acid and glycine conjugation** * **Hydroxylation** * **Conjugation** * **Methylation at 3- position** slows metabolism via hydrolysis of acetyl group. * **Glycine conjugation**. ## Synthesis of Diflunisal (Dolobid) * Diflunisal can be made from 2,4-Difluoro-4-nitrobiphenyl; * The first nitro group is reduced to phenol followed by Kolbe-Schmidt reaction $$ \begin{aligned} F & \qquad \qquad \qquad \qquad \qquad \qquad \qquad NO2 & \qquad \qquad \qquad \qquad \qquad \qquad \longrightarrow & \qquad \qquad \qquad \qquad \qquad \qquad F & \qquad \qquad \qquad \qquad \qquad \qquad \qquad OH \\ & \qquad \qquad \qquad \qquad \qquad F & \qquad \qquad \qquad \qquad \qquad \qquad \qquad F & \qquad \qquad \qquad \qquad \qquad \qquad \qquad F \\ & \qquad \qquad \qquad \qquad \qquad \qquad \qquad 1. Red . \qquad \qquad \qquad \qquad \qquad \qquad \qquad 2. HNO3/Δ & \qquad \qquad \qquad \qquad \qquad \qquad Kolbe-Schmidt & \qquad \qquad \qquad \qquad \qquad \qquad CO2 & \qquad \qquad \qquad \qquad \qquad \qquad F & \qquad \qquad \qquad \qquad OH & \qquad \qquad \qquad \qquad \qquad \\ \qquad \qquad \qquad \qquad \qquad \qquad \qquad & \qquad \qquad \qquad \qquad \qquad \qquad F & \qquad \qquad \qquad \qquad \qquad F & \qquad \qquad \qquad \qquad \qquad \qquad F & \qquad \qquad \qquad \qquad \qquad \qquad COOH & \qquad \qquad \qquad \qquad \qquad \qquad & \qquad \qquad \qquad \qquad \qquad \qquad 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid \end{aligned} $$ * Diflunisal metabolizes in kidneys through glucuronide conjugation. ## NSAIDs -The Para-amino Phenol Derivatives * **Acetaminophen (Tylenol; paracetamol; N-acetyl-p-aminophenol)** is the active metabolite of **phenacetin (acetophenetidin)**, a so-called coal tar analgesic. In-vivo, phenacetin is converted to acetaminophen. Phenacetin is no longer available in the United States. **Chemical Structures** * **Phenacetin**: $$ \begin{aligned} & \qquad HNCH3 &\qquad \qquad \qquad \qquad \qquad \qquad \qquad OCH &\qquad \qquad \qquad \qquad \qquad \qquad \qquad O-CH2GH3 \\ & \qquad HNCH3 &\qquad \qquad \qquad \qquad \qquad \qquad \qquad OH &\qquad \qquad \qquad \qquad \qquad \qquad \qquad NH-COCH2-CH-CH3 \\ & \qquad N-(4-Etoxyphenyl)acetamide &\qquad \qquad \qquad \qquad \qquad \qquad \qquad N-(4-Hydroxyphenyl)acetamide &\qquad \qquad \qquad \qquad \qquad \qquad \qquad N-(4-Etoxyphenyl)-3-hydroxybutyramide \\ & \qquad \text{Phenacetin} & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \text{Acetaminophen} & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \text{Bucetin} \end{aligned} $$ * **Acetaminophen** is effective as an analgesic and an antipyretic. * It has WEAK Anti-inflammatory action, possibly due to its weak inhibition of cyclooxygenase (as measured in the presence of high concentrations of peroxide found in Inflammatory lesions) and hence its weak inhibition of prostaglandin synthesis. ## Synthesis of Paracetamol * The nitro group on 4-nitrophenol was reduced with sodium borohydride. The resultant 4-aminophenol is then acetylated with acetic anhydride. **Chemical Structures** $$ \begin{aligned} & \qquad \qquad \qquad & \qquad \qquad & \qquad \qquad & & \qquad \qquad \\ & \qquad OH &\qquad \qquad \qquad OH &\qquad \qquad \qquad OH &\qquad \qquad \qquad \longrightarrow &\qquad \qquad \qquad OH \\ & \qquad OH &\qquad \qquad \qquad OH &\qquad \qquad \qquad OH &\qquad \qquad \qquad \longrightarrow &\qquad \qquad \qquad OH \\ & \qquad OH &\qquad \qquad \qquad NO2 &\qquad \qquad \qquad NO2 &\qquad \qquad \qquad \longrightarrow &\qquad \qquad \qquad NO2 \\ & \qquad OH &\qquad \qquad \qquad NO2 &\qquad \qquad \qquad NO2 &\qquad \qquad \qquad \longrightarrow &\qquad \qquad \qquad NH2 \\ & \qquad OH &\qquad \qquad \qquad NH2 &\qquad \qquad \qquad NH2 &\qquad \qquad \qquad \longrightarrow &\qquad \qquad \qquad NH2 \\ & \qquad \qquad \qquad & \qquad \qquad & \qquad \qquad & & \qquad \qquad \\ & \qquad NO2 &\qquad \qquad \qquad \text{dil. H₂SO₄} &\qquad \qquad \qquad \text{HNO3} &\qquad \qquad \qquad \text{NaBH4} &\qquad \qquad \qquad \text{Acetic anhydride} \\ \end{aligned} $$ ## Metabolism of Paracetamol * **Glucuronidation** * **Sulfation** * **Monooxygenase hydroxylation** * **Rearrangement** * **Glutathione conjugation** * **Reaction with proteins and nucleic acids** ## NSAIDs - Pyrazolone and Pyrazolidinedione Derivatives * 1-phenyl-2,3-dimethyl-3-pyrazolin-5-one and 1,2-diphenylpyrazolidin-3,5-dione derivatives The following drugs have been in clinical use for many years and include: * **Phenylbutazone** * **Oxyphenbutazone** * **Aminopyrine** * **Kebuzone** * **Dipyrone (metamizole)** Phenylbutazone was introduced in 1949 for the treatment of arthritis. Although not a first-line drug, it is the most important from the therapeutic point of view, while the others are not used today. ## Pyrazolidinedione Derivatives - Phenylbutazone * **Phenylbutazone** is a nonsteroidal anti-inflammatory drug (NSAID) effective in treating fever, pain, and inflammation in the body. * **Phenylbutazone** has analgesic and antipyretic effects with similar potency as aminophenazone and phenazon. it has enhanced antiinflammatory effects and is used to treat rheumatoid arthritis. **Chemical Structure of Phenylbutazone** $$ \begin{aligned} & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \text{Phenylbutazone} & \qquad \qquad \qquad \qquad \qquad \qquad \\ & \qquad \qquad \qquad \qquad \text{4-butyl-1,2-diphenyl-pyrazolidine-3,5-dione} & \qquad \qquad \qquad \qquad \qquad \qquad \end{aligned} $$ **Synthesis**: Phenylbutazone and its derivatives could be prepared from condensation of n-butylmalonic acid ester like substituted malonic acid esters and 1,2-diphenylhydrazine $$ \begin{aligned} & \qquad \qquad \qquad H & \qquad \qquad \qquad \qquad \qquad \qquad \qquad O & \qquad \qquad \qquad \qquad \qquad COOC2H5 & \qquad \qquad \qquad \qquad \qquad NH & \qquad \qquad \qquad \qquad \qquad C2H5ONa & \qquad \qquad \qquad \qquad \qquad H9CCH & \qquad \qquad \qquad \qquad \qquad \qquad + & \qquad \qquad \qquad \qquad \qquad ONN & \qquad \qquad \qquad \qquad \qquad H9CCH & \qquad \qquad \qquad \qquad \qquad booc2H5 & \qquad \qquad \qquad \qquad \qquad \qquad \qquad NH & \qquad \qquad \qquad \qquad \qquad \qquad \longrightarrow & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \qquad \text{Phenylbutazone} \end{aligned} $$ ## Pyrazolone Derivative - Dipyrone (Novalgene, Metamizole sodium) * Dipyrone is a drug that has analgesic, anti-inflammatory, and antipyretic properties. * It is associated with acute condition involving a severe and dangerous leukopenia (lowered white blood cell count). **Synthesis**: Aminoantipyrene reacts with benzaldehyde to give aldimine intermediate, which is methylated with dimethylsulfate followed by hydrolysis to give N-methylamino antipyrene. In the presence of formaldehyde and sodium bisulfate dipyrone is synthesized through Eschweiler-Clarke methylation reaction. $$ \begin{aligned} & \qquad \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad \\ & \qquad CH3 &\qquad CH3 &\qquad CH3 & \qquad CH-N & \qquad CH & \qquad CH-N & \qquad (CH)SO4 & \qquad CHO & \qquad CH3 & \qquad H3C-OSO & \qquad CH \\ & \qquad CH3 &\qquad CH3 & \qquad CH3 & \qquad CH3 & \qquad CH3 & \qquad CH3 & \qquad 0 & \qquad CH & \qquad 0 & \qquad CH & \qquad CH \\ & \qquad HN &\qquad CH & \qquad CH-N & \qquad CH & \qquad CH-N & \qquad 0 & \qquad N & \qquad CH3 & \qquad CH3 & \qquad CH3 & \qquad CH3-N \\ & \qquad H2O &\qquad CH3 & \qquad OH & \qquad N & \qquad CH3 & \qquad NaHSO3/CH2O & \qquad CH3 & \qquad CH2SO3Na & \qquad ONN & \qquad CH3 & \qquad CH3 & \qquad CH3-N \\ %& \qquad \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad \\ \end{aligned} $$ ## SAR for Pyrazolidinediones (and phenylbutazone) * The butyl group of carbon 4 may be replaced by propyl or allyl and show similar activity. * The meta substitution of the aryl ring are inactive but para substitution such as CH3, CI, NO2 or OH retains activity. * Replacement of nitrogen in pyrazolidines with oxygen yield isoxazole analog which is as active as pyrazolidine derivatives. * Decreasing pKa values of phenyl butazone analogs have shorter half lives decreasing anti inflammatory activity. * Substitution of Hydrogen at C-4 by methyl group or others destroys anti inflammatory activity since it is important to have a dicarbonyl group that could be enolized. * If *pyrazolidine* ring is replaced with *cyclopentane* or *cyclopenten* the resulting compounds are inactive. $$ \begin{aligned} & \qquad \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad \\ & \qquad \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad \\ \qquad \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad \\ & \qquad \text{phenylbutazone} & \qquad \qquad & \qquad \qquad & \qquad \qquad \\ \end{aligned} $$ ## NSAIDs - N-Arylanthranilic acid derivatives (Fenamates) * The fenamates are derivatives of N-phenylanthranilic acid. * They have no clear advantages over other NSAID's and frequently they cause side effects such as diarrhea. **Chemical Structures** * **Mefenamic acid**: $$COOH$$ * **Meclofenamate sodium**: $$COO-Na+$$ * **Flufenamic acid**: $$COOH$$ *Fenamates are N containing analogues of salicylates* ## Fenamates-Mefenamic acid * **Mefenamic acid** is an anti-inflammatory painkiller (NSAID). * It is used to treat painful conditions such as arthritis, pain associated with heavy menstrual bleeding, and pain after surgical operations. * **Mefenamic acid** is a competitive inhibitor of COX-1 and COX-2, which are responsible for the first step in prostaglandin biosynthesis. **Chemical Structure** $$ \begin{aligned} & \qquad CH3 \qquad \qquad \qquad \qquad \qquad \qquad 2-(2,3-dimethylphenyl)aminobenzoic acid \end{aligned} $$ **Synthesis**: The synthesis of Mefenamic acid is via reaction of 2-chlorobenzoic acid and 2,3-dimethylaniline . $$ \qquad \qquad \qquad \qquad \qquad \qquad \qquad \text{طلعية} $$ $$ \begin{aligned} & \qquad \qquad \qquad COOH & \qquad \qquad \qquad NH & \qquad \qquad \qquad K2CO3 & \qquad \qquad \qquad + & \qquad \qquad \qquad o-chlorobenzoic acid & \qquad \qquad \qquad 2,3-dimethylaniline & \qquad \qquad \qquad \longrightarrow & \qquad \qquad \qquad \text{HCl} & \qquad \qquad \qquad COOK & \qquad \qquad \qquad COOH \\ & \qquad \qquad \qquad \text{J/Med. Chem., 1968, 11, 111} & \qquad \qquad & \qquad \qquad & \qquad \qquad & & \qquad \qquad & & \qquad \qquad & & \qquad \qquad & \text{m.p. 229°C} \end{aligned} $$ ## NSAIDs - Heteroaryl Acetic Acids and Propionic Acid Derivatives * An important class of NSAID drugs, classified according to aryl and heteroaryl acetic acid derivative. * They are typically used for treatment of rheumatoid arthritis. **Chemical Structures** * **Indole and Indene Acetic Acids (Arylalkanoic acids)** * **Propionic Acid Derivatives** * **Heteroaryl Acetic Acids** * **Enolic acids** * **Alkanones: Nabumetone** ## NSAIDs - Indole and Indene Acetic Acids (Arylalkanoic acids) **Chemical Structures** * **Indomethacin**: $$ \begin{aligned} & \qquad \text{Indomethacin} & \qquad \qquad \qquad \text{Sulindac} & \qquad \qquad \qquad \text{Etodolac} \\ & \qquad \longrightarrow & \qquad \qquad \qquad \text{Becomes an -H} & \qquad \qquad \qquad \end{aligned} $$ * **Indomethacin**: is a methylated indole derivative. * **Sulindac (Clinoril)**: is a non-indole and contains a sulfoxide and is a PRODRUG since it is unlikely that this form has any pharmacological activity. Most of the activity resides in its sulfide metabolite, which is more than 500 times more potent as an inhibitor of cyclooxygenase than sulindac. ## Indole and Indene Acetic Acids (Arylalkanoic acids) - Indometacin * Indometacin is one of the commonly used and the most effective NSAIDs to reduce fever, pain, stiffness, and swelling. **Chemical Structure** $$ \begin{aligned} & \qquad \text{Indometacin} & \qquad \qquad \qquad \qquad \qquad \qquad \qquad \text{2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid} \end{aligned} $$ **Synthesis**: The synthesis of indometacin is through the reaction of methyl 4-oxopentanoate (methyl levulinate) and p-methoxy- phenylhydrazine hydrochloride. These compounds react giving methyl 5-methoxy-2-methyl indole-3-acetate, which undergoes acylation with p-chlorobenzoyl chloride to give indomethacin. $$ \begin{aligned} & \qquad \qquad \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad & \qquad \qquad \\ & \qquad CHO & \qquad \qquad \qquad NHNH, HCl & \qquad \qquad \qquad CH2CH2COOCH, & \qquad \qquad \qquad CHO & \qquad \qquad \qquad O-C & \qquad \qquad \qquad CH\\ & \qquad Piridin & \qquad \qquad \qquad C1 & \qquad \qquad \qquad C2H5OH/HCI & \qquad \qquad \qquad CH3O & \qquad \qquad \qquad CO CI & \qquad \qquad \qquad C1 \\ & \qquad \longrightarrow & \qquad \qquad \qquad \longrightarrow & \qquad \qquad \qquad CH2COOH & \qquad \qquad \qquad CH3 & \qquad \qquad \qquad CHCOOCH3 & \qquad \qquad \qquad -CH2 & \qquad \qquad \qquad H \\ \end{aligned} $$ ## Structure Activity Relationship of Indomethacin * **Branching** **-CH3** has no effect on activity. * Very flexible position as **-OCH3, F, N(CH3)2CH2, -acetyl, -allyloxy** are also active. * **Replacement with acidic functions** decreases activity. **Higher the acidity, greater the activity.** * **Amides** are inactive. * **-CH3** Is more active than phenyl. * **Indole ring N** is not essential as **C** version indene analog (Sulindac) is also active. * **Replacement of N-benzoyl with alkanoyl or arylalkanoyl** gps. decreases activity. **p-Cl to -for-CF3 retains activity.** ## Structure Activity Relationship for Indole Derivatives * **Carboxyl group** is necessary for anti inflammatory activity. If carboxylate group is exchanged with hydroxyl type groups there is a decrease in activity. Antirheumatic activity increases with acidity. * **Changing aromatic acyl group** at position 1 with alkyl, aliphatic acyl or alkyl group lowers activity. * **Substituting halogen, CF3 or SCH3 groups** at para position of 1-benzoyl ring increases activity. * **Methyl group** at position 2 forces the molecule to have a cis conformation therefore has pronounced effect on activity relative to aryl group. * **The bond at 3-acetic acid chain** can freely rotate. Hydrogen or methyl substitution at a-position of the side chain gives similar activity whereas α,α-dimethyl or hydroxyl substitution lowers activity. **S isomers are more effective.** * **Substitution at position 5 of the indole ring** is feasible and methoxy, dimethylamino, acetyl, methyl and fluoro substituents improve activity. * **Arylidene indenyl isostere** shows similar activity as indole compounds. **Cis isomer exhibits higher activity then trans compound.** ## Biotransformation of Indomethacin * **O-demethylation** * **Deacytolation** * **Hydrolysis** * **Glucuronidation** * Under in vivo condition inhibation of prostaglandin synthesis by indomethacin is more effective than phenylbutazone, however they show