Kinetics of alkaline hydrolysis of the monoethyl ester of adipic acid
Other ester prodrugs - soluble Unstable: use immediately More stable: less prone to hydrolysis by...
6
Other ester prodrugs - soluble Unstable: use immediately + Drug O O O O-Na+ Sodium succinate prodrug H+ Drug OH O O O Na+O- O O OH Sodium succinate Drug O P O O-Na+ O H Drug OH P O O-Na+ O H O H + Phosphatase Phosphate prodrug Drug O S O O O-Na+ Drug OH Sulfatase S O O O-Na+ O H + Sulfate prodrug More stable: less prone to hydrolysis by water
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Transcript of Other ester prodrugs - soluble Unstable: use immediately More stable: less prone to hydrolysis by...
Other ester prodrugs - soluble
Unstable: use immediately
+DrugO
O
O
O-Na+
Sodium succinate prodrug
H+
DrugOH
O
O
O
Na+O-O
O
OH
Sodium succinate
DrugO
PO
O-Na+OH DrugOH P
O
O-Na+
OH
OH+
Phosphatase
Phosphate prodrug
DrugO
SO
O O-Na+ DrugOH
SulfataseS
O
O O-Na+
OH+
Sulfate prodrug
More stable: less prone to hydrolysis by water
Amine derivatives as prodrugs Amides not used due to high stability
Most common amine derivative used is a Mannich Base prodrug
WaterSNNH
CH3CH3
O
CH3
CH3
CO2HON
SNHNH2
O
CH3
CH3
CO2HON
Hetacillin Ampicillin
CH3 CH3
O
Acetone
+
CH3
OH
N(CH3)2OH
OOH OH
O
OH
O
NH2
-H2ON
+CH2
Iminium ion
H H
O
Formaldehyde
NH
Pyrrolidine
+
N
CH3
OH
N(CH3)2OH
OOH OH
O
OH
O
NH
Rolitetracycline - A prodrug of
tetracycline with increased
water solubility
Tetracycline
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
NNHSO2 N N OH
CO2H
Sulfasalazine - Azulfidine® - Pharmacia & UpjohnSulfonamide antibiotic and antiinflammatoryUsed to treat Ulcerative colitis, rheumatoid arthritis
NNHSO2 NH2
NH2 OH
CO2H
+
5-aminosalicylic acid
Sulfapyridine
Carbonyl prodrugs Aldehyde and ketone derivatives
Little clinical utility with one exception
Methenamine hippurate Hiprex® - Hoechst Marion Roussel
Urex ® - 3M Pharmaceuticals plus a number of combos– Used for prophylaxis or suppression/elimination of frequent UTI
NNN
N
Acidic urine pH
H H
O6 + 4 NH3
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
CH3
O
CH3O
OH
CH3OO
Series of oxidative
decarboxylation
Active form of the drugthat inhibits Prostaglandinbiosynthesis bycyclooxygenase
Non-steroidal antiinflammatory
Use: Arthritis
