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Prodrugs
Medicinal Chemistry I
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Prodrugs
Are inactive compounds converted to the active
form in vivo.
 Useful for drugs with undesirable physicochemical
property.
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Undesirable Properties
• Physical Properties:
a) Poor aqueous solubility
b) Low lipophilicity
c) Chemical instability
d) Acid Sensitivity
e) Poor Membrane Permeability (poor absorption)
f) Toxicity (non-selective bioactivity)
g) Bad Taste
h) Short Duration of Action
i) Non-site specific
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Prodrugs activation mechanisms
• Variety of mechanisms by which prodrug can be
converted into active drug:
1. Metabolizing enzymes (phosphotase, esterases,
peptidase)
• Interpatient variable
2. Chemical activation (Hydrolysis, decarboxylation, light
activation)
• Stability issues
3. Mixture of both
• Two important points:
1. The prodrug should be effectively converted to the active form
once absorbed in the blood.
2. Cleavable groups are non toxic.
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Not all prodrugs are activated by metabolic
enzymes.
Photodynamic therapy involve the use of an
external light to activate prodrugs.
Prodrugs classification
• Can be classified into three categories:
1. Carrier-linked prodrugs
- Carrier-linked prodrugs are drugs that have been
attached through a metabolically labile linkage to
another molecule, the so-called promoiety, which is
not necessary for activity but may impart some
desirable property to the drug
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Prodrugs classification
2. Mutual prodrugs
- In this type, both the drug and the
carrier has activity
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Produrgs classification
3. Bioprecursor prodrugs
- contain no promoiety but rather rely on metabolism
to introduce the functionality necessary to create an
active species
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Carrier-linked prodrugs
Prodrugs functional groups
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Prodrugs functional groups - Esters
 The most common type of prodrug because of the ease with
which the ester can be hydrolyzed or formed.
 Esterase enzymes present in plasma and other tissues that are
capable of hydrolyzing a wide variety of ester linkages
 Can add lipophilicity or hydrophilicity to the drug
 Increasing lipophilicity of the compound may yield a number
of benefits, including increased absorption, decreased
dissolution in the aqueous environment of the stomach,
longer duration of action, and reducing bad taste
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Improve membrane permeability
• Problem: - Epinephrine is poorly absorbed through eye tissues
- Catechols are unstable
• Solution: The increased lipophilicity relative to epinephnine allows the
drug to move across the membrane of the eye easily and achieve higher
intraocular concentrations
• The steric bulk of pivalic acid slows down the hydrolysis
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Improve Membrane Permeability
 Ampicillin is poorly absorbed from the GI tract
(~30% absorbed)
WHY???
 The carboxylic acid functional group (COOH):
 Binds the drug to a receptor via ionic or
hydrogen bonding.
 An ionizable group may prevent drug from
crossing a fatty cell membrane.
Solution:
 Convert the acid function to an ester moiety.
 The less polar ester can cross fatty cell
membranes.
 The ester group will be hydrolyzed back to the
free acid by the esterase in the blood.
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Ampicillin activation In Vivo
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Masking bad taste
• Problem: Water soluble drugs when dissolve in the mouth
could lead to bad taste
- This cause low compliance (pediatric)
• Solution: A prodrug with reduced water solubility does not
dissolve to any appreciable extent in the mouth and,
therefore, does not interact with taste receptors.
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Prodrugs for stability
• Problem: propanolol undergo extensive first
pass metabolism (glucuronidation)
• Solution: adding ester group on the alcohol
will protect it from metabolism
Prodrugs for stability
Increasing hydrophilicity
• Increase the water solubility of drugs, making them more
suitable for parenteral or oral administration when high water
solubility is desirable
Clindamycin Phosphate
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Improve membrane permeability
Peptide carrier systems
Improve membrane permeability
Peptide carrier systems
Prodrug
Protein Carrier in BBB (Blood Brain Barrier)
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Drugs with amine moiety
• The amide derivative is not a suitable choice
in most of the case (WHY?)….Stable bond
toward hydrolysis compared to the ester
bond.
Drugs with amine moiety
Prodrug to increase lipophilicity
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Drugs with amine moiety
Prodrugs to increase water solubility
Prolong The Activity
Diazepam
Prodrug
O
•Sustained Action
•N-demethylation Metabolism
Hexobarbitone
Me
N
O
NH
O
Me
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Prodrugs to mask toxicity and side effects
Cyclophosphoramide for phosphoramide mustard
(anticancer agent)
NH
O
P
O
1. Cyt P450
2. Phosphoramidase
Cl
(liver)
H2N
Cl
P
HO
N
O
N
Cl
Cl
Cyclophosphoramide
Phosphoramide mustard
•
•
•
Non toxic
Orally active
Alkylating agent
Azo prodrugs from amine
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Prodrugs used to target drugs
Example:
Hexamine
N
N
N
N
•
•
•
•
Stable and inactive at pH>5
Stable at blood pH
Used for urinary infections where pH<5
Degrades at pH<5 to form formaldehyde (antibacterial agent)
Bioprecursor prodrugs
• Bioprecursor prodrugs mostly use either oxidative or reductive activation
reactions.
• The main activation pathways are:
1) Proton activation.
2) Hydrolytic activation
3) Elemination activation
4) Oxidative activation
5) Reductive activation
6) Nucleotide activation
7) Phosphorylation activation
8) Sulfation activation
9) Decarboxylation activation
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Reduce toxicity
Nabumetone
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Reduce toxicity
Idoxuridine phosphorylation
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Most other antiviral requires the same
activation mechanism
N
HO
N
N
N
N
PO
Vi ral
NH2 thymidi ne
kinase
Penciclovir
OH
N
N
N
N
NH2
P P PO
N
N
N
NH2
Cell kinases
OH
OH
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Proton Pump Inhibitor Activation
Omeprazole
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Bioluminescent
Red Tide
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