The document discusses prodrug design, highlighting that prodrugs are pharmacologically inactive compounds converted into active drugs via metabolic biotransformation, improving therapies by altering physicochemical properties, pharmacokinetics, and biopharmaceutical characteristics. Various types of prodrugs, including carrier-linked, bipartite, tripartite, mutual, and bioprecursors, are detailed, along with their activation mechanisms and applications to enhance drug solubility, absorption, toxicity reduction, and patient acceptability. Additionally, it outlines the rationale behind prodrug design in targeted therapies, particularly for cancer treatments using advanced strategies like antibody-directed and gene-directed enzyme prodrug therapies.

1. PRODRUG DESIGN
SUBMITTED BY,
Manimegalai.G
M.Pharm-I year
Advanced Medicinal Chemistry
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2. INTRODUCTION
• A Prodrug is pharmacologically inactive compound that is converted into
active drug by a metabolic biotransformation .
• Prodrug enhanced the usefulness of various therapeutic agents by altering
the physicochemical properties, pharmacokinetics and biopharmaceutical
properties.
• It might alter the tissue distribution , efficacy and toxicity of parent drug.
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4. REASONS FOR PRODRUG APPROACH
• Improved aqueous solubility
• Improved absorption and distribution
• Site specificity
• Improved stability of drugs
• For prolonged release
• To reduce toxicity
• In poor patient acceptability
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5. BASIC CONCEPT
• Prodrugs are pharmacologically inactive derivatives of active drugs that
are design to maximize the amount of active drug that reaches its site of
action, through manipulation of physicochemical , biopharmaceutical
and pharmacokinetic properties of drug.
• They are converted into active drug within the body through enzymatic
or non-enzymatic reaction.
Promoiety-Drug
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6. CARRIER LINKED PRODRUGS
• It is a complex that comprises an active drug which is temporarily
attached to some carrier with covalent linkage the carrier group can be
detached enzymatically.
• After administration to the body, the prodrug undergoes
biotransformation and converted to active compound.
a) Bipartite prodrug
b)Tripartite prodrug
c) Mutual prodrug
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7. BIPARTITE PRODRUG
• It is a prodrug composed of one carrier attached to the drug.( Drug+
Carrier)
• These are greatly modified lipophilicity due to the attached carrier . The
active released by hydrolytic cleavage either chemically or enzymatically.
For eg., Tolmetin – glycine prodrug (NSAIDs)
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8. TRIPARTITE PRODRUG
• In a tripartite prodrug, the carrier is not connected directly to the drug,
but rather to a linker which is attached to the drug.
• This allows for different kinds of functional to be incorporated for varying
stabilities and it also displaces the drug farther from the hydrolysis site,
which decrease the steric interference by the carrier.
• The drug – linker connection however, must be designed so that it cleaves
spontaneously after the carrier has been detached.
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10. MUTUAL PRODRUGS
• It consist of two pharmacologically active agents coupled together so that
each act as a promoiety for the other agent.
• It is a bipartite or tripartite prodrug in which the carrier is a synergistic
drug with the drug to which it is needed.
For eg., Benorilate (Mutual prodrug of aspirin and paracetamol)
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11. BIOPRECURSORS PRODRUG
• Bioprecursors results from the molecular modifications of the compound.
• There is no need of promoiety in bioprecursors. Carrier linked podrugs
rely largely hydrolysis reaction for their effectiveness, whereas
Bioprecursors prodrugs mostly utilize their oxidative or reductive
activation reaction.
a) Reductive Bioactivation
b)Oxidative activation
c) Oxidative deamination
d)N-oxidation
e) Azo reductive activation
f) Sulfoxide reduction
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12. REDUCTIVE BIOACTIVATION
• Omeprazole , effectively inhibits gastric secretion by inhibiting the gastric
H+ K+ ATPase. This enzyme is responsible for gastric acid secretion and
located in the secretory membranes of parietal cells.
• Invivo Omeprazole is transformed into the active inhibitor, a cyclic
sulfonamide, which forms disulfide bridge with thiol group of the enzyme
and thus inactivates enzyme
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14. OXIDATIVE ACTIVATION
• Bioprecursor prodrug is activated by O-dealkylation is the analgesic and
antipyretic agents Phenacetin , which is activity to its conversion by O-
dealkylation metabolism to Acetaminophen.
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15. OXIDATIVE DEAMINATION
• Cyclophosphamide is an alkylating agent it needs oxidative deamination
for active metabolite.
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16. N- OXIDATION
• Pralidoxime is an antidote for poisoning by organophosphorus
compound which is believed to be activated by N- oxidation.
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17. AZO REDUCTIVE ACTIVATION
• Sulfasalazine used in the treatment of inflammatory bowel disease is
reductively cleaved by anaerobic bacteria in the lower bowel to 5- amino
salicylic acid and sulfapyridine.
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18. SULFOXIDE REDUCTION
• The antiarthritis drug sulindac is an indene isostere of the drug
Indomethacin. Invivo it undergoes sulfoxide reduction to form an active
metabolite sulindac sulfide.
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19. PRODRUGS OF FUNCTIONAL GROUP
CARBOXYLIC ACID AND ALCOHOL
• Prodrugs of carboxylic acid & alcohol functionalities can be prepared
by conversion to esters. The esters can be easily hydrolysed by
esterase enzymes present in plasma and other tissues to give active
drug.
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20. AMINES
• Due to the high stability and lack of amidase enzyme necessary for
hydrolysis, the conversion of amines to amide as a prodrug is not been
used for most of the drugs.
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21. AZO LINKAGE
• Prodrugs of amines are occasionally prepared by incorporating them into
an azo linkage. By the action of azo reductase the amino compounds are
released.
For eg.,
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22. CARBONYL GROUP
For eg., Hexamine releases Formaldehyde in the Urine(acidic pH) which act
as an antibacterial agent.
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23. PRODRUGS TO IMPROVE PATIENT
ACCEPTABILITY
• Painful injections and unpleasant taste or odour are the most common
reasons for the lack of patient acceptance of a drug.
For eg., Ethyl Mercaptan is a foul smelling liquid used in the treatment of
leprosy. This is converted to phthalate ester, a diethyl dithioisophthalate that
has higher boiling point and is odourless.
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24. PRODRUG FOR IMPROVED ABSORPTION AND
DISTRIBUTION
• The skin is designed to maintain the body fluids and prevent absorption
of xenobiotics into the general circulation. Consequently , drugs applied
to the skin are poorly absorbed.
• Even steroids have low dermal permeability if they contain OH groups
that can interact with the skin or binding site in the keratin.
• Corticosteroids for the topical treatment of inflammatory , allergic and
pruritis skin conditions can be made more suitable for topical absorption
by esterification.
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25. • Fluocinonide is a prodrug of Flucinolone acetonide used for inflammtory
and pruritic manifestation . Once absorbed through the skin an esterase
release the drug.
Fluocinolone acetonide R =H (active)
Fluocinonide R= COCH3 (prodrug)
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26. PRODRUG FOR SITE SPECIFICITY
• Blood Brain Barrier a unique lipid like protective barrier that prevents
hydrophilic compounds from entering the brain unless they are actively
transported.
• An increasing the brain concentration of the inhibitory neurotransmitter
GABA results in anticonvulsant activity.
• However, GABA is too polar to cross the BBB so it is not an effective
anticonvulsant drug.
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27. • Progabide is an effective lipophilic analog of GABA that crosses the BBB,
releases GABA inside the brain and exhibit anticonvulsant activity.
GABA (unable to cross BBB)
Progabide (prodrug)
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28. PRODRUG FOR PROLONG ACTIVITY
• The prodrug by its improved characteristics get closer to the receptor site
for a longer period of time and conversion to the parent drug takes place
at the site of action.
• It reduces the number and frequency of dose
• It eliminates night time administration of drugs
• Minimize patient non compliance.
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29. • Haloperidol is a potent tranquilizer and its peak plasma observed
between 2-6 hrs after administration .The ester prodrug haloperidol
decanoate is injected i.m. as a solution in sesame oil and its antipsychotic
activity last for about 1 month.
Haloperidol decanoate (prodrug) Haloperidol (active)
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30. DRUG SOLUBILITY
• Hydrophilic or water soluble drugs are needed when parenteral or
ophthalmic formulation .
• Drug with hydroxyl functional group can be converted to their
hydrophilic form through the use of half ester such as hemi- glutarate or
hemi phthalate , the other half of this acid carries sodium, potassium or
amine salts and render this moiety more soluble.
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31. methyl prednisolone methyl presdnisolone
succinate ester
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32. RATIONALE OF PRODRUG DESIGN
• The prodrug design includes an infixed position that can be altered to improve
in membrane permeability, solubility and ADME properties.
• Different prodrugs used for cancer therapies and other related therapies
include,
• Antibody directed enzyme prodrug therapy
• Gene directed enzyme prodrug therapy
• Polymer directed enzyme prodrug therapy
• Virus directed enzyme prodrug therapy
• Lectin directed enzyme prodrug therapy
• Clostridiol directed enzyme prodrug therapy
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33. • ANTIBODY DIRECTED ENZYME PRODRUG THERAPY
In the targeted therapy , the antibody enzyme conjugate will help in
selective binding of enzyme to the tumor cell and then the prodrug
converts into the active drug by the targeted enzyme , thus only affecting
the tumor and leaving back the normal cells.
• GENE DIRECTED ENZYME PRODRUG THERAPY
It is a suicide gene therapy in which the enzyme required for prodrug
conversion is produced within the target cell , using a gene delivered to it
by gene therapy
• VIRUS DIRECTED ENZYME PRODRUG THERAPY
It is an emerging strategy against cancer to the use of virus . It can be
potentially used to enhance the therapeutic potential of oncolytic virus.
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34. • POLYMER DIRECTED ENZYME ACTIVATED PRODRUG
THERAPY
It is a novel two step antitumor approach using a combination of a
polymeric prodrug and polymeric enzyme conjugated to generate cytotoxic
drug selectivey at the tumor site.
• LECTIN DIRECTED ENZYME ACTIVATED PRODRUG
THERAPY
It is designed to exploit endogenous carbohydrate - lectin binding by
combining it with biocatalysis through the construction of novel
glycosylated enzymes and prodrugs.
• CLOSTRIDIA - DIRECTED ENZYME PRODRUG
THERAPY
The use of clostridia to convert prodrugs into active drug agents. It
expoits the tumor using anaerobic bacteria resident in the tumor to convert
the prodrug to the active form
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