This document discusses prodrugs, which are pharmacologically inactive compounds that are metabolized into active drug forms inside the body. Prodrugs can improve drug properties like absorption, distribution, metabolism and excretion. They are designed to alter pharmacokinetics and deliver drugs in a targeted manner. Various functional groups like esters, amides and azo bonds are used to link a drug to a promoiety carrier that improves solubility and targeting. Upon metabolic conversion via hydrolysis, decarboxylation or other reactions, the active drug is released. Prodrugs provide benefits like reduced toxicity and side effects as well as site-specific drug delivery.

1. PRODRUGS
PRESENTED BY:
L.GOPI B.PHARM
AADHI BHAGAWAN COLLEGE OF
PHARMACY
RANTHAM
GUIDED BY:
M. RAJASEKARAN M.PHARM.,
ASST PROF OF DEPARTMENT OF
PHARMACEUTICAL CHEMISTRY
AADHI BHAGAWAN COLLEGE OF
PHARMACY
RANTHAM

2. Prodrugs
 Initial definition: A pharmacologically inactive chemical entity that
when metabolized or chemically transformed by a mammalian
system is converted into a pharmacologically active substance
 “Drug Latentiation” – included later
 Process of purposely designing and synthesizing a molecule that
specifically requires “bioactivation” to a pharmacologically active
substance
 Goal of prodrugs?
 Improve patient acceptability (decrease pain on injection)
 Alter and improve absorption
 Alter biodistribution
 Alter metabolism
 Alter elimination

3. Non-Prodrugs
 “Hard Drugs” - compounds that contain structural
characteristics required for activity but are not
susceptible to metabolism
 Increased efficiency by avoiding metabolism
 No toxic metabolites are formed
 HOWEVER, less readily eliminated due to lack of
metabolism
 “Soft Drugs” - These are the opposite of prodrugs.
These compounds are designed and synthesized as
ACTIVE compounds that readily undergo metabolic
inactivation to nontoxic products

4. Conversion of Prodrugs
 Metabolism (enzyme dependant)
 Chemical Methods (non-dependant)
 Hydrolysis
 Decarboxylation
 NOT patient dependant!
 Stability/Storage issues

5. Prodrugs
 Carrier-linked prodrugs – drugs that are attached
through a metabolically labile chemical linkage to
another molecule designated as the “promoiety”
 The “promoiety” alters the physical properites of the
drug to increase water or fat solubility or provide site-
directed delivery
 Advantages:
 Increased absorption
 Injection site pain relief
 Elimination of unpleasant taste
 Decreased toxicity
 Decreased metabolic inactivation
 Increased chemical stability
 Prolonged or shortened action

6. Chloramphenicol
N
H
Cl
O
O
O-Na+
O
O
ClOH
O2
N
N
H
Cl
O
H
O
ClOH
O2N
O-Na+
O
O
OH
Esterase
or Water
Chloramphenicol Succinate
Chloramphenicol
Sodium succinate
• Enzymatic and intramolecular spontaneous hydrolysis
• Increased water solubility, ester itself is inactive as an antibiotic
• Promoiety should be nontoxic and easily excreted
• Type of promoiety chosen is a function of properties desired

7. Mutual Prodrug
Actual alkylating species
CH3
OH
OH
NH
Cl
Cl
NH+Cl-
Cl
Nornitrogen mustard
Aziridine
Sodium phosphate
and
Carbon dioxide
CH3
OPO3Na2
ON
O
Cl
Cl Estermustine Sodium Phosphate
Emcyt® - Pharmacia & Upjohn
• Used for metastatic carcinoma of the prostate
• Promoiety also a drug!
• Prodrug is selectively taken up into estrogen receptor positive cells then
urethane linkage is hydroylzed
• 17-alphaestradiol slow prostate cell growth
• Nornitrogen mustard is a weak alkylating agent

8. Functional Groups in Prodrugs
• Carboxylic acids and Alcohols
Drug O
Promoiety
O
OH Promoiety
Promoiety O
Drug
O
Drug OH
O
Promoiety OH
O
OH Drug
or
+
+
• Types of esterase enzymes mediating the hydrolysis process
• Ester hydrolase, Lipases, Cholesterol esterases, Acetylcholinesterase,
Carboxypeptidase, Cholinesterase
• Bacterial microflora enzymes
• Wide number of choices of promoiety alcohols available
• Steric, electronic and hydrophobicity properties allow rate and extent of
hydrolysis to be controlled

9. O
CH3
O
O
O
O
OH
CH3
CH3
O
CH3
CH3
CH3
OH
CH3
CH3
OH
O
O
CH3
OH
CH3
OMe
CH3
O
NH(CH3
)2
+-SO4
Erthromycin estolate
Ilosone® - Eli Lilly
caps,tabs, suspension
Antibiotic used to treat
upper and lower respiratory
infections (URI or LRI),
Legionnaire's disease,
skin infections
• Erythromycin is a very bitter substance easily destroyed at acidic pH
• Propionate ester is to increase lipid solubility for improved absorption
• Ester must be hydrolyzed for antibacterial activity
• Lauryl sulfate salt – absorption not affected by food, less bitter after
taste and is acid stable
Functional Groups in Prodrugs

10. Esters Failure as Prodrugs
N
SN
H
O
O
CO2R2
H
R1
R3
R2 = ethyl, propyl, butyl, phenyl
Cephalosporin esters
Esterases
NO REACTION!
N
SN
H
O
O
CO2R2
H
CH3
CH3
R1
R2 = ethyl, propyl, butyl, phenyl
Penicillin esters

11. b-Lactam prodrug – Double esters
N
S N
SN
H
O
O
H
NH2
OMe
OMe
O
O
CH3
O
OCH3
O
CH3
CH3
N
S N
SN
H
O
O
H
NH2
OMe
OMe
O
O
O
CH3
H
CH3
OH
CH3
CH3
CO2 +
N
S N
SN
H
O
O
H
NH2
OMe
OMe
O
O
O
CH3
CH3
+
Active Drug
HO-Esterase
Esterase
H2O
Vantin® – Pharmacia & Upjohn
URI, UTI, Gonorrhea, skin
infections
Taking with food
increases absorption
Why?
Increase
absorption
Avoid acid
catalyzed
decomposition

12. 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+
OH Drug
OH P
O
O-Na+
OH
OH
+
Phosphatase
Phosphate prodrug
Drug
O
S
O
O
O-Na+
Drug
OH
Sulfatase
S
O
O
O-Na+
OH
+
Sulfate prodrug
More stable: less prone to hydrolysis by water

13. Amides not used due to high stability
Most common amine derivative used is a Mannich Base prodrug
WaterSN
NH
CH3
CH3
O
CH3
CH3
CO2HO
N
SN
HNH2
O
CH3
CH3
CO2
HO
N
Hetacillin Ampicillin
CH3
CH3
O
Acetone
+
CH3
O
H
N(CH3
)2OH
OOH O
H
O
OH
O
NH2
-H2O
N
+
CH2
Iminium
ion
H H
O
Formaldehyde
NH
Pyrrolidine
+
N
CH3
O
H
N(CH3
)2OH
OOH O
H
O
OH
O
N
H
Rolitetracycline - A prodrug of
tetracycline with increased
water solubility
Tetracycline

14. 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.

15. 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
N
NHSO2 N N OH
CO2H
Sulfasalazine - Azulfidine® - Pharmacia & Upjohn
Sulfonamide antibiotic and antiinflammatory
Used to treat Ulcerative colitis, rheumatoid arthritis
N
NHSO2 NH2
NH2 OH
CO2H
+
5-aminosalicylic acid
Sulfapyridine

16. 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
N
NN
N
Acidic urine pH
H H
O
6 + 4 NH3

17. 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
CH3O
O
Series of oxidative
decarboxylation
Active form of the drug
that inhibits Prostaglandin
biosynthesis by
cyclooxygenase
Non-steroidal
antiinflammatory
Use: Arthritis

18. Reduction example - Mitomycin C - Mutamycin® - Bristol Myers
Adenocarcinoma of the stomach and pancreas
N
O
O
NH2
CH3
O
NH2
O
NH
OMe
H
A quinone -
electron withdrawing
-H+
-CO2
-NH3
Electrophile
DNA
NH2
CH3
NHN
OH
OH
N
NH2
CH3
O
NH2
O
NH
H
+
NH2
CH3
O
NH2
O
NHN
OH
OH
H+
-OCH3
N
OH
OH
NH2
CH3
O
NH2
O
NH
OMe
H
A hydroquinone -
electron donating
Reduction
DNA
NH2
CH3
NHN
OH
OH
+
Further alkylation

19. Phosphorylation example –
O
N
H
O
O
I
OH
OPO
O
O
Viral Thymidine
Kinase
O
N
H
O
O
I
OH
OH
Iodoxuridine - Herplex®
Allergan - lipid soluble!
Opthalmic product for
Herpes simplex keratitis
Higher affininty for viral
kinases than mammalian
kinases but some toxicity
O
N
H
O
O
I
OH
OPO
O
O
POP-O
O
O
O
O
TWO mechanisms of action: 1. Inhibits DNA polymerase 2. Incorporated
into DNA affording incorrect base pairing and template activity
ATP
Not lipid soluble

20. Chemical Delivery Systems
 We have already seen 2 examples of this:
 Sulfasalazine – an azo compound
 Methenamine – An urinary antibacterial agent
 Requirements
 Prodrug reach the site of action in high concentrations
 Knowledge of high metabolism at site
 Other factors
 Extent of organ or site perfusion
 Information on the rate of prodrug conversion to the active form at
both target and non-target sites
 Rate of input/output of prodrug from the target site
 Limit side effects and increase effectiveness

21. Types of carriers that have been used
Proteins
Polysaccharides
Liposomes
Emulsions
Cellular carriers (erythrocytes and leukocytes)
Magnetic control targeting
Implanted mechanical pumps
What is the Basic Goal?
Protect a non-specific biological environment from a drug
Protect a drug from a non-specific biological environment
Especially evaluated for drugs with a narrow therapeutic
window especially anti-cancer agents

22. Chemical Delivery Systems
 The ideal situation:
 Prodrug readily transported to the site of action
 Prodrug is rapidly absorbed at the site
 Selective and rapid conversion to the active drug
 Kidney and Liver are easy targets due to high perfusion and high
metabolic rates
 Other tissue sites can be problematic for the same reasons
 Drug migrate slowly (site of action to a site of excretion)
 Ideal situation is VERY complex to achieve
 Example: Methenamine
 the lower the pH, the faster the rate of formaldehyde formed
 blood pH 7.4 therefore, little formaldehyde formed

23. Example: Cancer Chemotherapy
Tumor cells have a much higher growth fraction
This translates into higher enzymatic activity that can be exploited
Target a prodrug to these sites and exploit higher enzyme activity
Example: L-Dopa or Levodopa – Anti-Parkinsonism agent
Larodopa® – Roche and Dopar® - Procter & Gamble
Brain has a specific transport system for L-amino acids
Dopamine does not cross the blood brain barrier efficiently, is rapidly
metabolized by oxidative deamination, and can cause peripheral side effects
OH
OH
NH2
CO2
H
OH
OH
NH2
Decarboxylase
Dopamine