Medicinal Chemistry II: Analgesics and Non-Steroidal Anti-Inflammatory Drugs

Comprehensive practice flashcards on analgesics and NSAIDs, detailing chemical classifications, mechanisms of action, and structure-activity relationships (SAR).

Where are prostaglandins produced following induction by bacterial pyrogens, and how do interleukins affect body temperature?

Prostaglandins are produced in the CNS; interleukins affect the hypothalamus (which regulates body temperature) by signaling it to raise the temperature by a few degrees.

What therapeutic uses of anti-inflammatory agents are listed in the introduction?

They are used to cure or prevent inflammation caused by prostaglandins, and to treat minor aches, fever, rheumatic fever, rheumatoid arthritis, and osteoarthritis.

At which point in the inflammatory cascade do steroids act to prevent arachidonic acid formation?

Steroids inhibit the enzyme phospholipase.

What is the general mechanism of action of most NSAIDs on cyclooxygenase (COX)?

They serve as reversible, competitive inhibitors of cyclooxygenase (COX) activity.

How does aspirin differ in its inhibition of cyclooxygenase compared to other NSAIDs?

Aspirin inhibits COX enzymes irreversibly by acetylating them, blocking the conversion of arachidonic acid to unstable $PG\text{-}2$, which is the rate-determining step in prostaglandin synthesis.

Which drugs belong to the pyrazolidinedione derivatives class?

Phenylbutazone, oxyphenbutazone, and sulphinpyrazone.

Which drugs are classified under anti-gout drugs in the lecture notes?

Colchicine, allopurinol, and probenecid.

In the SAR of salicylates, what happens if the phenolic hydroxyl group is removed or placed at the meta or para position relative to the carboxyl group?

Removing the phenolic hydroxyl group or placing it meta or para to the carboxyl group abolishes activity.

What effect does converting the carboxyl group ($-COOH$) of salicylic acid to an amide have on its pharmacological profile?

Converting it to an amide (salicylamide) retains the analgesic action of salicylic acid but renders it devoid of anti-inflammatory properties.

What is the name and chemical designation of this salicylic acid derivative substituted at the 5-position?

Diflunisal ($5\text{-(}2,4\text{-difluorophenyl) salicylic acid}$).

Identify this salicylate derivative that retains analgesic action but lacks anti-inflammatory activity:

Salicylamide.

What salicylate dimer is represented by this chemical structure?

Salsalate.

Identify this mutual prodrug used in the treatment of ulcerative colitis:

Sulphasalazine.

How is sulphasalazine activated in the large intestine and what are its active metabolites?

It is cleaved into $5\text{-aminosalicylic acid}$, which inhibits prostaglandin synthesis, and sulphapyridine, which is useful for treating infection.

What pharmacological actions do para-aminophenol derivatives possess, and what do they lack?

They possess analgesic and anti-pyretic actions but lack anti-inflammatory activity.

Identify this para-aminophenol analgesic and antipyretic compound:

Paracetamol (acetaminophen).

Identify this para-aminophenol ether derivative:

Phenacetin.

According to the SAR of para-aminophenol derivatives, how does etherification with methyl or propyl groups compare to an ethyl group?

Etherification with methyl or propyl groups produces derivatives with greater side effects than the ethyl derivative (phenacetin).

How does salicylanilide differ in pharmacological activity from other aniline-related analgesics in Table 22-7?

Salicylanilide is not an analgesic; it is an antifungal agent.

What are anthranilic acid derivatives considered in relation to salicylic acid?

They are nitrogen isosteres of salicylic acid.

In disubstituted anthranilic acid derivatives with identical substituents, which substitution pattern is the most effective?

The $2',3'\text{-disubstituted}$ pattern (e.g., mefenamic acid).

Identify this $2',3'\text{-disubstituted}$ anthranilic acid derivative:

Mefenamic acid.

What is the effect of replacing the $-NH-$ moiety of anthranilic acid with $-O-$, $-CH_2-$, $-S-$, $-SO_2-$, or $-NCH_3-$?

It significantly reduces activity, demonstrating that the $-NH-$ moiety is essential for activity.

Identify this anthranilic acid derivative that possesses 25 times greater anti-inflammatory activity than mefenamic acid:

Meclofenamate sodium (meclofenamic acid).

In the SAR of arylalkanoic acid derivatives, what is the required distance between the center of acidity and the aromatic ring?

The center of acidity must be located one carbon atom adjacent to the aromatic or heteroaromatic ring; increasing this distance to two or three carbons diminishes activity.

What is the effect of substituting a methyl group on the carbon atom separating the aromatic ring and the carboxylic acid group in arylalkanoic acids?

A methyl group tends to increase anti-inflammatory activity (e.g., ibuprofen, ketoprofen, fenoprofen), but groups larger than methyl decrease activity.

Identify this indole acetic acid derivative:

Indomethacin.

In indole acetic acid derivatives, is the indole ring nitrogen strictly essential for activity?

No, because the benzylidenylindene analogue sulindac is also active.

Which enantiomer exhibits anti-inflammatory activity in indole acetic acid derivatives?

Only the $S(+)$ enantiomer.

What clinical and toxicity advantages are offered by selective COX-2 inhibitors over non-selective NSAIDs?

They decrease gastrointestinal side effects (gastric bleeding, ulcers, and possibility of colon cancer) and renal toxicity, and are also used to treat Alzheimer's disease.

What are the chemical core classifications of celecoxib, rofecoxib, and valdecoxib?

Celecoxib is a diarylpyrazole derivative, rofecoxib is a diarylfuran derivative, and valdecoxib is a diarylisoxazole derivative.

What characteristic side chain is typically present in the chemical structures of selective COX-2 inhibitors?

A sulfamoyl or sulfonyl side chain.