Medicinal Chemistry: Chapter 9 Nonsteroidal Antiinflammatory Drugs

Introduction to Inflammation and Therapeutic Drugs

• Definition of Inflammation: A basic pathological process resulting from tissue damage caused by various inflammatory stimuli within the body. It serves as a vital defense mechanism against infection.
• Treatment Categories for Inflammation:
  • Steroidal Anti-inflammatory Drugs: These include corticosteroids.
  • Nonsteroidal Anti-inflammatory Drugs (NSAIDs).

Historical Development of Non-Steroidal Anti-Inflammatory Drugs

• 1950s–1960s (Twentieth Century): The clinical application of drugs including Phenylbutazone, Indomethacin, and Ibuprofen gained attention, shifting the research focus toward developing new NSAIDs.
• Early 1970s: The mechanism of action for NSAIDs was finally characterized: they work by inhibiting cyclooxygenase (COX), thereby blocking the biosynthesis of prostaglandins ($PG$).
• 1990s: Researchers developed several NSAIDs with strong selectivity for the COX-2 isozyme. However, the safety of these selective inhibitors has become a subject of increasing scrutiny during clinical use.

Mechanism of Action for NSAIDs

1. Metabolism of Arachidonic Acid (AA) and Inflammatory Mediators

• Initial Trigger: When a cell membrane is stimulated, the enzymes phospholipase $A_2$ and phospholipase $C$ catalyze the hydrolysis of phospholipids from the membrane reaching the release of Arachidonic Acid ($AA$).
• Biotransformation Pathways of Arachidonic Acid:
  • Cyclooxygenase (COX) Pathway: AA is oxidized and metabolized into Prostaglandins ($PG$) and Thromboxanes ($TX$).
  • Lipoxygenase (LOX) Pathway: AA is catalyzed by lipoxygenase to form Leukotrienes ($LT$).
• These metabolites are central to the occurrence and progression of inflammation.

2. Inflammatory Mediators in Detail

Prostaglandins (PG)

• Structure: A class of unsaturated fatty acids containing $20$ carbon atoms, featuring a five-membered ring and two side chains.
• Classification: Categorized into nine types (PGA, PGB, PGC, PGD, PGE, PGF, PGG, PGH, PGI) based on substituents and double bond positions on the ring.
• Physiological Effects:
  • $PGE_2$, $PGI_2$, and $PGD_2$: Act as strong vasodilators, improve vascular permeability, and synergize with other mediators to advance inflammation.
  • $PGE_2$: Known as one of the most potent thermogenic substances, causing fever by increasing body temperature.

Leukotrienes (LT)

• Structure: Hydroxyl acids containing $20$ carbon atoms, classified as LTA, LTB, LTC, LTD, LTE, etc.
• Physiological Effects:
  • $LTC_4$, $LTD_4$, and $LTE_4$: Increase vascular permeability, promote plasma exudation, and lead to edema.
  • $LTB_4$: Identified as the strongest known leukocyte chemoattractant, causing leukocyte aggregation and aggravating inflammation.
• Biosynthesis: AA is metabolized via $5-LOX$ to generate $5$-hydrogen peroxide eicosane-tetraenoic acid ($5-HPETE$), the precursor to leukotrienes.

3. Enzyme Targets: COX and LOX

Cyclooxygenase (COX)

• Located in the endoplasmic reticulum of mammalian cells.
• COX-1: A constitutive "prototype" enzyme found in the gastrointestinal tract and kidneys. It promotes the synthesis of physiological PGs to regulate normal cellular activities.
• COX-2: An inducible isozyme with very low activity in normal conditions. During inflammation, its expression increases significantly, leading to high PG levels, tissue damage, and pain.
• Comparison: Both are similar in structure and sequence length. Most traditional NSAIDs inhibit both, leading to side effects like gastrointestinal ulcers (due to COX-1 inhibition).
• COX-2 Selectivity: Selective inhibition of COX-2 aims to eliminate side effects associated with COX-1 inhibition while maintaining anti-inflammatory efficacy.

Lipoxygenase (LOX)

• Catalyzes the formation of leukotrienes from AA. $LTC_4$, $LTD_4$, and $LTE_4$ are primary components of allergic slow-reacting substances.
• Dual Inhibitors: Because equilibrium constraints exist between metabolites of COX and $5-LOX$, researchers are developing dual inhibitors to block both pathways, potentially improving efficacy and reducing the side effects of pure COX inhibitors.

Antipyretic Analgesics

• Mechanism: Act on the hypothalamus's thermoregulatory center to reduce febrile body temperature to normal. They do not affect the temperature of healthy individuals.
• Efficacy: Effective for chronic dull pain (headache, toothache, neuralgia, arthralgia). Ineffective for severe traumatic pain or visceral smooth muscle colic.
• Chemical Classes: Anilines, Salicylic acids, and Pyrazolones.

1. Anilines

Historical Context

• Acetanilide: Introduced in 1886 as "antipyretic ice"; eliminated due to high toxicity.
• Phenacetin: Widely used but abolished globally (eliminated in China in 1983) due to carcinogenicity and toxicity.

Acetaminophen (Paracetamol)

• Chemical Name: $N$-(4-hydroxyphenyl)acetamide.
• Clinical Use: Antipyretic and analgesic; preferred for patients sensitive to aspirin and common in anti-cold combinations.
• Chemical Properties:
  • Weakly acidic and stable in air.
  • Aqueous stability is pH-dependent; most stable at $pH = 6$ with a half-life of $21.8$ years at $25^{\circ}C$. Poor stability in strongly acidic or alkaline conditions.
  • Hydrolysis: Humid conditions cause hydrolysis into p-aminophenol, which undergoes oxidative degradation to imidoquinone, resulting in a dark color.
• Synthesis Methods:
  • Method 1: Nitration of phenol followed by reduction and acetylation.
  • Method 2: Reduction and acetylation of nitrobenzene.
  • Method 3: Beckmann rearrangement of p-hydroxyacetophenone oxime.
• Metabolism:
  • Primary pathways: Glucuronic acid and sulfate conjugation.
  • Minor pathway (via CYP enzymes): Formation of $N$-hydroxyacetaminophen, which converts to the toxic metabolite $N$-acetyliminoquinone.
  • Toxicity: If glutathione is depleted, $N$-acetyliminoquinone binds to liver proteins, causing liver necrosis and kidney failure. N-acetylcysteine or cysteine can be used as an antidote.

2. Salicylic Acids

Aspirin (Acetylsalicylic Acid)

• History: Salicylic acid ($pKa = 3.0$) was irritant to the GI tract. Acetylsalicylic acid was synthesized in 1859 and applied clinically as Aspirin in 1899.
• Chemical Name: $2$-(acetoxy)benzoic acid; $pKa = 3.5$.
• Instability: Hydrolyzes to salicylic acid and acetic acid when wet. Salicylic acid then oxidizes, turning the product light yellow, red-brown, or dark brown. Alkali, light, heat, and trace metal ions accelerate this process.
• Synthesis Side Effects: The byproduct acetylsalicylic anhydride must be controlled below $0.003\%$ (W/W) to prevent allergic reactions.
• Pharmacology:
  • Irreversible Inhibition: The acetyl group in aspirin acetylates the serine residue in the COX active center, blocking PG biosynthesis.
  • Antiplatelet Effect: Inhibits Thromboxane ($TXA_2$) synthesis in platelets, used to prevent cardiovascular diseases.
  • Side Effects: Gastric bleeding (due to loss of protective PG in the gastric wall) and allergic asthma (linked to the loss of PGE-mediated bronchial dilation).

Aspirin Derivatives and Prodrugs

• Lysine Aspirin: Good absorption, high water solubility for injections, less GI irritation.
• Aluminum Aspirin: Used to reduce gastric irritation.
• Salicylamide: Retains analgesic effect with almost no GI irritation but loses anti-inflammatory activity.
• Benorilate (Paracetamol/Aspirin ester): A prodrug with no gastric irritation, suitable for children/elderly.
• Diflunisal: Analgesic/anti-inflammatory activity $4$ times stronger than aspirin; long half-life ($8$-$12$ hours); used for arthritis/cancer pain.

3. Pyrazolones

• Stucture: $N_2$-arylpyrazolone derivatives.
• Properties: Strong antipyretic/analgesic effects but no anti-inflammatory activity.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

1. Nonselective NSAIDs

3,5-Pyrazolidinediones

• Example: Phenylbutazone ($pKa = 4.4$) and Hydroxybuzone ($pKa = 4.5$).
• The carbonyl groups at positions 3 and 5 enhance the acidity of the hydrogen at position 4, increasing anti-inflammatory activity.

Arylalkanoic Acids

• Aryl Acetic Acids:
  • Indomethacin: Acts on COX; anti-inflammatory activity is $2.5$ times stronger than Phenylbutazone. Derived from structural analogies to serotonin and tryptophan.
  • Nabumetone: A non-acidic keto-prodrug metabolized in the liver to active 6-methoxy-2-naphthalene acetic acid. Selectively acts on COX-2.
  • Fenbufen: A prodrug metabolized to biphenylacetic acid to reduce GI reactions.
• Arylpropionic Acids:
  • Characteristics: Derived from plant growth hormones; good efficacy with low GI irritation but possible hepatotoxicity.
  • SAR (Structure-Activity Relationship): The $\alpha$-carbon is chiral. Generally, the (S)-isomer is more active than the (R)-isomer.
  • Ibuprofen (Paracetamol): $2$-(4-(2-methylpropyl)phenyl)propionic acid. In vivo, the R-(-) isomer undergoes configuration reversal to the active S-(+) form. Usually administered as a racemic mixture.
  • Naproxen: (S)-$\alpha$-methyl-6-methoxy-2-naphthalene acetic acid.
  • Intensity of Action (Relative): Ibuprofen ($0.1$), Flurbiprofen ($5$), Ketoprofen ($1.5$), Naproxen ($1$), Indobufen ($2$).

Anthranic Acids

• Also known as "acid extinguishers"; hydroxyl of salicylic acid is replaced with an amino group (Mefenamic acid, Meclofenac, Flunisin). Limited clinical use due to side effects.

1,2-Benzothiazides (Oxicams)

• Contains an enol-type hydroxyl group; acidic ($pKa = 4\text{ to } 6$).
• Piroxicam: Long-acting, well-tolerated. Stronger analgesic effect than ibuprofen/naproxen.
• Others: Meloxicam (high COX-2 selectivity, low ulcer risk), Tenoxicam, Lornoxicam.
• SAR: Enol hydroxyl is essential; activity order: aromatic heterocyclic $>$ aromatic ring. Benzene ring replacement with thiophene ring retains activity.

2. Selective COX-2 Inhibitors

• Rationale: Eliminate GI side effects by selectively sparing COX-1.
• Generations:
  • First Generation: Celecoxib ($400$-fold selective for COX-2), Rofecoxib.
  • Second Generation: Valdecoxib, Etoricoxib, Imrecoxib.
• Structural Characteristics: Two benzene rings connected orthoxially to an aromatic/unsaturated ring (cis-stilbene structure). A methylsulfonyl or aminosulfonyl group para-attached to a benzene ring is the essential pharmacophore for COX-2 selectivity, acting on the Valine 523 side pocket.
• Imrecoxib: Developed in China using the "moderate inhibition" principle to balance activity and cardiovascular risk. Approved May 2011.
• Safety Concerns:
  • Rofecoxib was withdrawn after $5$ years due to cardiovascular events.
  • Mechanism of Risk: Inhibition of COX-2 blocks vascular-protective $PGI_2$ while unregulated COX-1 continues to produce $TXA_2$, promoting platelet aggregation and vasoconstriction.

Agents Used to Treat Gout

• Gout: A purine metabolism disorder resulting in hyperuricemia and sodium urate crystal deposition in joints.
• Uric Acid Pathway: Adenine/Guanine $\rightarrow$ Hypoxanthine/Xanthine $\xrightarrow{Xanthine\,Oxidase}$ Uric Acid.

1. Drugs Inhibiting Uric Acid Production (Xanthine Oxidase Inhibitors)

• Allopurinol: Analogue of hypoxanthine. Metabolized to active Oxypurinol ($70\%$); both inhibit XO.
• Febuxostat: A non-purine XO inhibitor.

2. Drugs Promoting Uric Acid Excretion

• Mechanism: Inhibit uric acid reabsorption in proximal renal tubules.
• Drugs:
  • Probenecid: Competitive reabsorption inhibitor.
  • Benbromarone: Potent uric acid lowering agent.
  • Lesinurad (Lesnorel sodium): URAT1 inhibitor.
• Risk: Can cause renal colic due to crystal deposition in the urinary tract.

3. Drugs for Acute Gout Treatment

• Colchicine: Preferred drug for acute attacks; selective anti-inflammatory effect but narrow safety window and significant side effects.
• Others: NSAIDs, Glucocorticoids.