Transcript Other ester prodrugs

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
H2 N
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