Principles of drug discovery, Mpharm ( Pharmacology) , 1st year, 1st semester

1. Principles of Drug Discovery
Que : Discuss Rationale and Practical
consideration of prodrug design. (15M)
Name:-Chetana Pandurang Dakhare
Roll No. 02, (2nd semester)
M.Pharm (Pharmacology)

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).
• PRODRUG ENZYMES DRUG
(INACTIVE) (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.

5. • The development of prodrugs is presently well
established as a strategy for improving the
physicochemical, biopharmaceutical or pharmacokinetic
properties of pharmacologically potent compounds and
there by overcoming barriers to a drug's develop ability
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.

6. • 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.

7. • 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).

8. BENEFITS OF PRODRUG DESIGN
• Decrease presystemic metabolism
• Improves absorption by non-oral 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 absorption with prodrugs targeted at intestinal
transporters, and improved cancer therapy with gene-
and receptor-targeted prodrugs.

9. 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

10. 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 amendable to
chemical prodrug derivatization.

11. • Promoiety: This should ideally be safe and rapidly
excreted from the body.
• The choice of promoiety should be considered with
respect to the disease state, dose and the duration of
therapy.
• Parent and Prodrug : The absorption, distribution,
metabolism, excretion (ADME) and pharmacokinetic
properties need to be comprehensively understood.

12. 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

13. ESTERS AS PRODRUGS OF CARBOXYL,
HYDROXYL AND THIOL FUNCTIONALITIES
• 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.

15. CARBONATES AND CARBAMATES AS PRODRUGS
OF CARBOXYL, HYDROXYL OR AMINE
FUNCTIONALITIES
• 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
corresponding esters but are more susceptible to
hydrolysis than amides.
• The bioconversion of many carbonate and carbamate
prodrugs requires esterases for the formation
of the parent drug

16. • 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
• 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.

17. AMIDES AS PRODRUGS OF CARBOXYLIC ACIDS
AND AMINES
• 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..

18. 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, especially strongly basic amidines and
guanidoximes, can be used to enhance the membrane
permeability and absorption of a parent drug.

20. 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.

21. THANK YOU