Organic Chemistry Compound

Antihistamines

• Antazoline: has local anesthetic effect and is used in eye preparations
• Clemizole: has anti-histaminic effect
• Propylamine derivatives:
  • Pheniramine: N,N-dimethyl-3-phenyl-3-(2-pyridinyl)propanylamine
  • Chlorpheniramine: mainly used as maleate salt
  • Bromo-pheniramine: 3 times more active than ethylene diamine class
• Phenothiazine: replacing N atom with SP2 carbon
• Cyproheptadine (Periactine): has antihistaminic and sedative effects
• Azatadine: has antihistaminic effect
• Ketotifen (Zaditen): mast cell stabilizer, used as anti-histaminic with long duration of action
• Olopatadine (Patanol): mast cell stabilizer, used to treat itching associated with allergic conjunctivitis

2nd Generation H-1 blockers

• Characteristics:
  • Improved peripheral H-1 selectivity
  • Little affinity to central muscarinic and adrenergic receptor
  • Long acting mainly due to formation of active metabolites
  • Chemically unrelated
  • More hydrophilic, so have decreased CNS side effects
• Terfenadine (Triludan): used for treatment of allergic conditions, but not used anymore due to life-threatening arrhythmia
• Fexofenadine (Telfast): active metabolite of Terfenadine

H-2 receptor antagonists

• Ranitidine (Zantac): 100 times more potent than Cimetidine
• Nizatidine (Axid): commonly used for treatment of heartburn and peptic ulcer
• Famotidine (Famotac / Pepcid): 15-20 times more potent than Ranitidine
• Lafutidine: chemical name and synthesis
• Roxatidine (Roxit): chemical name and synthesis

SAR of H-2 receptor antagonists

• Basic heteroaromatic ring (if imidazole, free NH is essential)
• Replacement for the imidazole ring with other heteroaromatic rings resulted in other useful analogs
• Flexible intermediate chain in which the NH side chain must be separated by 4 carbons or equivalent atoms from the heterocyclic ring
• Terminal polar non-basic group (Urea like end group)
• N-cyanoguanidine substituent
• Nitromethylene group replaces N-cyanoimino group in the substituted guanidine analogs, increasing potency

Proton Pump Inhibitors (Anti-Ulcer agents)

• More effective than H-2 blockers in suppressing gastric acid secretion
• Irreversibly inhibit the H+/K+ ATPase enzyme
• General structure of a proton-pump inhibitor: methyl or unsubstituted
• Mechanism of action: conversion to achiral products which react with a cysteine group in H+/K+ ATPase, thereby inhibiting the ability of parietal cells to produce gastric acid

Proton Pump Inhibitors

• Omeprazole (Losec): prototype of this group, used for treatment of dyspepsia, peptic ulcer, gastroesophageal reflux, and Zollinger-Ellison syndrome
• Esomeprazole (Nexium): enantiomer of Omeprazole
• Rabeprazole (AcipHex):
• Lansoprazole (Prevacid):
• Pantoprazole (Pantoloc):

SAR of Proton Pump Inhibitors

• Substituted Benzimidazole, substituted pyridine, and sulfinyl chain connecting the two rings are essential for activity
• Benzimidazole substitution with electron-donating group increases activity
• Benzimidazole substitution with electron-withdrawing group decreases activity
• 4-Methoxy group on pyridine ring increases biological activity
• 4-Fluoro alkoxy substitution on pyridine ring results in strong inhibitory activity

H-3 receptor antagonists

• Drugs used to inhibit action of histamine at the H3 receptor
• H3 receptors are primarily found in the brain and are inhibitory autoreceptors
• H3-antihistamines have stimulant and cognition-modulating effects