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Other ester prodrugs soluble O O-Na+ Drug O O Drug OH + OH O Na+O- O H+ O O O Sodium succinate prodrug Sodium succinate Unstable: use immediately More stable: less prone to hydrolysis by water Drug O O O S O-Na+ Sulfatase Drug OH HO + O O S O-Na+ Sulfate prodrug Drug O HO O P O-Na+ Phosphate prodrug Phosphatase Drug OH HO + HO O P O-Na+ Amine derivatives as prodrugs Amides not used due to high stability Most common amine derivative used is a Mannich Base prodrug H3C CH3 HN S N O CH3 Water CH3 CO2H N O H2N H N O OH N(CH3)2 OH Tetracycline O O H O H H3C + H2C N OH O -H2O H3C CH3 Acetone O H H + HN Iminium ion O OH O Formaldehyde NH2 OH O N CH3 CH3 + CO2H Ampicillin Hetacillin H3C O S N(CH3)2 OH H N O O H O H O Rolitetracycline - A prodrug of N tetracycline with increased water solubility Pyrrolidine Mannich Base Chemistry Mannich Reaction - This is nucleophilic addition reaction of an aldehyde and at least a secondary amine to produce what is known as a schiff base on protonation and elimination of a water molecule. The Schiff base is often stabilized by resonance. The addition of a carbanaion to the schiff base gives another base called the Mannich base. The Mannich base formed can readily eliminate the secondary amine to give the synthetic usefulness of the reaction, but when primary amines or ammonia are used the hydrogen on nitrogen atom can participate in a further reaction to give more complex products. Azo Prodrugs •Bacterial reductases reductive cleavage • Release of 2 amine compounds • Occurs in colon discourages small intestine systemic absorption • Concentrates the drug at the desired site of action Sulfapyridine CO2H NHSO2 N N NHSO2 OH N NH2 N Sulfasalazine - Azulfidine® - Pharmacia & Upjohn Sulfonamide antibiotic and antiinflammatory Used to treat Ulcerative colitis, rheumatoid arthritis + CO2H H2N OH 5-aminosalicylic acid Carbonyl prodrugs Aldehyde and ketone derivatives Little clinical utility with one exception N Acidic urine pH N N N O + 6 H H 4 NH3 Methenamine hippurate Hiprex® - Hoechst Marion Roussel Urex ® - 3M Pharmaceuticals plus a number of combos Used for prophylaxis or suppression/elimination of frequent UTI– Bioprecursor Prodrugs Do NOT contain a carrier or promoiety Contain latent functionality – Metabolically or chemically transformed into an active drug– Types of activation at are predictable– Oxidative (most common method) • Reductive• Phosphorylation (antiviral agents) • Oxidation Example – Nabumetone – Relafen® – Smith Kline Beecham– O CH3 CH3O Series of oxidative decarboxylation Non-steroidal antiinflammatory Use: Arthritis OH CH3O O Active form of the drug that inhibits Prostaglandin biosynthesis by cyclooxygenase