This power point presentation deals with the definition of prodrug design its objectives, requirements, rationale and the practical considerations ..

1. PREPARED BY
KESHARI KUMAR SRIWASTAWA
M.PHARM (PHARMACOLOGY),1ST YEAR

2. WHAT IS A PRODRUG?
A prodrug is a mediation or compound that, after administration,
is metabolized (i.e.,converted within the body) into
a pharmacologically active drug. Instead of administering a drug
directly, a corresponding prodrug can be used to improve how the
drug is absorbed, distributed, metabolized, and excreted (ADME).
(OR)
Prodrugs are bioreversible derivatives of drug molecules that must
undergo an enzymatic and/or chemical transformation in vivo to
release the active parent drug, which can then exert its desired
pharmacological effect.
PRODRUG
(INACTIVE)
ENZYMES DRUG
(ACTIVE)

3. WHAT IS PRODRUG DESIGN?
Prodrug design is a widely known molecular
modification strategy that aims to optimize the
physicochemical and pharmacological properties
of drugs to improve their solubility and
pharmacokinetic features and decrease their
toxicity.

4. RATIONALE OF PRODRUG DESIGN
• A large number of the new molecular entities with promising therapeutic
profiles are dropped from the screening stage because of their inferior
physicochemical and biopharmaceutical properties.
• These undesired properties result in poor absorption, extensive
metabolism, and low bioavailability because of physical, biological, or
metabolic barriers. If the chemical structure of the drug or lead compound
can be modified to overcome these barriers and then revert to the
pharmacologically active form, the drug can be delivered efficiently.
• The development of prodrugs is presently well established as a strategy for
improving the physicochemical, biopharmaceutical or pharmacokinetic
properties of pharmacologically potent compounds and thereby
overcoming barriers to a drug's developability and usefulness.
• About 5–7% of the drugs approved worldwide can be classified as
prodrugs, and the implementation of a prodrug approach in the early
stages of drug discovery is a growing trend.

5. • Clinically, the majority of prodrugs are used with the aim of enhancing
drug permeation by increasing drug lipophilicity and more recently to
improve drug water solubility.
• Site-selective drug delivery with reduced side effects, prevention of pre-
systemic drug metabolism and the circumvention of efflux-limited drug
absorption/distribution have not yet received enough attention in
prodrug research, despite great possibilities.
• The rationale for the design of prodrugs is to achieve favorable
physicochemical characteristics (e.g., chemical stability, solubility, taste,
or odor), biopharmaceutical properties (e.g., oral absorption, first-pass
metabolism, permeability across biological membranes such as the
blood-brain barrier, or reduced toxicity), or pharmacodynamic
properties (e.g., reduced pain or irritation).

6. BENEFITS OF PRODRUG DESIGN
• Decrease presystemic metabolism
• Improves absorption by nonoral routes
• Improve plasma concentration-time profile
• Provide organ/tissue-selective delivery of active agent
• Increased bioavailability with ester prodrugs
• Increased permeability with hydroxyl amine prodrugs
• Enhanced solubility with prodrug salts
• Enhanced stability with PEGylated prodrugs
• Enhanced absorption with prodrugs targeted at intestinal
transporters, and improved cancer therapy with gene- and
receptor-targeted prodrugs.

7. IDEAL REQUIREMENTS OF
PRODRUG
• Prodrugs should be less active or inactive when compared to
the parent compound .
• Prodrugs should not posses intrinsic pharmacological activity.
• The carrier molecule released in vivo must be intoxic
• The linkage between drug and carrier must be cleared in vivo
• Prodrugs should be stable at different pH
• Prodrugs should have good aqueous solubility
• Prodrugs should possess hydrolysis resistance during
absorption
• Prodrugs should have good permeability through the cells

8. PRACTICAL CONSIDERATIONS OF
PRODRUG DESIGN
1. Ideally, the design of an appropriate prodrug structure should be considered at
the early stages of preclinical development, bearing in mind that prodrugs might
alter the tissue distribution, efficacy and the toxicity of the parent drug.
2. Several important factors should be carefully examined when designing a
prodrug structure, including
 Parent drug : Which functional groups are amenable to chemical
prodrug derivatization.
 Promoiety: This should ideally be safe and rapidly excreted from the body. The
Prodrug (ADME) and pharmacokinetic properties need to be
comprehensively understood.
choice of promoiety should be considered with respect to the
disease state, dose and the duration of therapy.
 Parent and: The absorption, distribution, metabolism, excretion

9. FUNCTIONAL GROUPS AMENABLE
TO PRODRUG DESIGN
1. Esters as prodrugs of carboxyl, hydroxyl and thiol
functionalities
2. Carbonates and carbamates as prodrugs of carboxyl,
hydroxyl or amine functionalities
3. Amides as prodrugs of carboxylic acids and amines.
4. Oximes as derivatives of ketones, amidines and guanidines
5. Phosphates as prodrugs

10. • Esters are the most common prodrugs used, and it is estimated that
approximately 49% of all marketed prodrugs are activated by enzymatic
hydrolysis.
• Ester prodrugs are most often used to enhance the lipophilicity, and thus
the passive membrane permeability, of water soluble drugs by masking
charged groups such as carboxylic acids and phosphates.
• The synthesis of an ester prodrug is often straightforward. Once in the
body, the ester bond is readily hydrolysed by ubiquitous esterases found in
the blood, liver and other organs and tissues, including carboxyl esterases,
acetylcholinesterases, butyrylcholinesterases, paraoxonases and
arylesterases.
1. ESTERS AS PRODRUGS OF CARBOXYL,
HYDROXYL AND THIOL FUNCTIONALITIES
• For example Palmarumycin is a lipophilic drug with poor aqueous
solubility and shows poor anticancer activity in vivo. The glycyl-ester
derivative of palmarumycin is found to have seven times increased aqueous
solubility than that of parent drug.

11.  Carbonates and carbamates differ from esters by the
presence of an oxygen or nitrogen on both sides of the
carbonyl carbon.
 They are often enzymatically more stable than the
alcohols, and carbamates are carboxylic acid and amine
derivatives.
 The bioconversion of many carbonate and
CARBONATES AND CARBAMATES AS PRODRUGS OF
CARBOXYL, HYDROXYL OR AMINE FUNCTIONALITIES
2
corresponding esters but are more susceptible to
hydrolysis than amides.
 Carbonates are derivatives of carboxylic acids and
carbamate prodrugs requires esterases for the formation
of the parent drug

12.  Carbamates generally exhibits very good chemical and proteolytic
stability
 Carbamates easily permeate through cell membranes and also has the
capability to alter intermolecular and intramolecular interactions
within the receptor or enzyme
 For eg. Histone deacetylases are responsible for gene expression and
exhibit anti-tumor activity. One of the histone deacetylases inhibitor is
a benzamide compound CI-994 .
The poor aqueous solubility of this compound is overcomed by
addition of two glucuronide prodrugs. In one compound they have
linked glucuronide moiety with the aid of spacer and in another
compound they have directly linked the glucuronide moiety with the
carbamate group of parent drug . The aqueous solubility of parent
compound CI-994 was found to be 0.08 mg/mL and both the prodrugs
showed aqueous solubility more than 1 mg

13. • Amides are derivatives of amine and carboxyl functionalities of a molecule.
• In prodrug design, amides have been used only to a limited extent owing to
their relatively high enzymatic stability in vivo.
• An amide bond is usually hydrolyzed by ubiquitous carboxylesterases,
peptidases or proteases.
• Amides are often designed for enhanced oral absorption by synthesizing
substrates of specific intestinal uptake transporters.
• The amide prodrugs are also used for increasing aqueous solubility of parent
drug and its bioavailability..
• For eg, DW2282 (26) is chemically (S)-1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-
indol-6-sulphonyl]-4-phenyl-imidazolidin-2-one, which is an anticancer drug
with low water solubility (0.024 mg/mL) and higher gastrointestinal toxic
effects. Many amino acid prodrugs were synthesized almost all of them
attained higher water solubility as compared to the parent drug. One of the
compound have shown very good aqueous solubility (0.865 mg/mL) and
bioavailability by oral route
3. AMIDES AS PRODRUGS OF CARBOXYLIC ACIDS
AND AMINES

14. 4. OXIMES AS DERIVATIVES OF KETONES,
AMIDINES AND GUANIDINES
• Oximes (for example, ketoximes, amidoximes and
guanidoximes) are derivatives of ketones, amidines and
guanidines, thus providing an opportunity to modify
molecules that lack hydroxyl, amine or carboxyl
functionalities.
• Oximes are hydrolyzed by the versatile microsomal
cytochrome P450 (CYP450) enzymes, better known as
xenobiotic metabolizing enzymes.
• Oximes, especially strongly basic amidines and guanidoximes,
can be used to enhance the membrane permeability and
absorption of a parent drug.

15. 5. PHOSPHATES AS PRODRUGS
• The phosphate prodrugs have been proven to increase the
aqueous solubility and bioavailability of the parent drug.
• Phosphate prodrugs get converted to its parent drug by the
action of intestinal alkaline phosphatase enzyme.
• For eg. A prodrug of benzimidazole derivative α-6-chloro-2-
(methylthio)-5-(napthalen-1-yloxy)-1H- benzo[d] imidazole.
The prodrug synthesized by linking disodium phosphate and
found be 50,000-folds higher water soluble than the parent
drug.

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