THE PRODRUG DESIGNING FOR NEW SELECTION AND FORMULATION OF DRUG COMPATIBLE WITH API I.E. ACTIVE PHARMACUTICAL INGREDIENT, AND ITS EFFECT WHICH SHOULD BE 0. THE DRUG COMBINED WITH API AND AVILABLE IN MARKET AND DRUGS NEED TO BE COMBINE ARE ALSO DISCUSSED WITH ITS STRUCTURE AND SAR, AND COVERED AS PER THE SYLLABUS OF PCI.

1. Presented by
Shikha D. Popali
Harshpal Singh Wahi
M. Pharmacy 1st semester
(Pharmaceutical chemistry)
Gurunanak college of pharmacy,
Nagpur

2. Overview
 Introduction
 What is prodrug & prodrug design?
 Objectives of prodrug design
 Basic concept of prodrugs
 Classification of prodrugs
 Prodrugs of functional group
 Why use prodrugs?
 Applications of prodrugs
 Examples
 Recent search
 Conclusion
 References
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3.  In 1958, Albert introduced the prodrug term for the first time in his book
„selective toxicity‟. This term includes any inert compound that undergoes
in vivo biotransformation.
 Methenamine was discovered in 1899 by Schering as inactive prodrug that
delivers the antibacterial formaldehyde. It is useful in the treatment of
urinary tract infection, when transported to urinary bladder it becomes
acidified to provide a medium in which formaldehyde is generated .
Methenamine prodrug activation at acidic ph.
Introduction
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4. What is prodrug & prodrug design?
 Prodrug is a pharmacological substance
administered in an inactive form.
 Once administered, the prodrug is metabolized in
vivo into an active drug within the body through
metabolic process, such as hydrolysis of an ester
form of the drug.
 Sometimes drugs are designed to make use of
metabolic processes in order to generate their
active form.
 This is done in order to improve some selected
property of the molecule, such as water solubility
or ability to cross a membrane, temporarily.
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5. Objectives of prodrug design
The main objectives of a prodrug designing are
• To bring active drugs to their respective active sites.
• To provide the desired pharmacological effects while minimizing
adverse metabolic and/or toxicological events.
• To improve the clinical and therapeutic effectiveness of those drugs
which suffer from some undesirable properties that otherwise hinder
their clinical usefulness.
• To avoid the practice of clinically Coad ministering two drugs in order
to enhance pharmacological activity or prevent clinical side effects.
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6. Basic concept of prodrugs
• The drug – promoiety is the prodrug that is typically pharmacologically
inactive.
• Limitation of a parent drug that prevents optimal (bio)pharmaceutical or
pharmacokinetic performance.
• The drug and promoiety are covalently linked via bio-reversible groups that
are chemically or enzymatically labile.
Promoiety
A functional group used
To modify the structure
Of pharmacologically
Active agents to improve
Physicochemical,
Biopharmaceutical or
Pharmacokinetic properties.
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7. Classification of prodrugs
A. Carrier-linked prodrugs:
 Simple prodrug that contains an active drug linked with a carrier group
that is removed enzymatically.
 The carrier group must be non-toxic and biologically inactive when
detached from drug.
 Carrier type Prodrug: formulation and drug release
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8.  Carrier- linked prodrug may further be classified into:
1) Double prodrugs pro-prodrugs or cascade-latentiated prodrug
Where a prodrug is futherderivatized in a fashion such that only
enzymatic conversion to prodrug is possible before the latter can cleave to
release the active drug.
2) Macromolecular prodrugs
Where macromolecules like polysaccharides, dextrans, cyclodextrins,
proteins, peptides and polymers are used as carriers.
3) Site- specific prodrugs
where a carrier acts as a transporter of the active drug to a specific
targeted site.
4) Mutual prodrug
where the carrier used is another biologically active drug instead of
some inert molecule.
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9. B. Bioprecursors:
 A compound that is metabolized by molecular modification into a new
compound that may itself be active or further metabolized to an active
metabolite.
 This prodrug does not contain carriers but ready up on metabolism to
induce the necessary functionally active species.
 Bioprecursor prodrugs rely on oxidative or reductive activation reactions
unlike the hydrolytic activation of carrier-linked prodrugs.
 They metabolized into a new compound that may itself be active or
further metabolized to an active metabolite (e.g. Amine to aldehyde to
carboxylic acid, Inactive prontosil to sulphanilamide).
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11. Prodrugs of functional group
 Various types of functional groups are present in different therapeutic
agents. These functional groups react with other functional groups of non
toxic promoiety to form prodrugs.
 1) Ester
Groups like -COOH, -OH can easily undergo esterification reaction.
Bioavailability of drug can be improved by ester formation. Enzyme
esterase which is present widely in vivo can easily break up the linkage at
target organ so that targeted delivery is achieved e.g. Thioester of
Erythromycin, palmitate ester of Clindamycin.
Prodrug Active Form of Drug
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12.  2) Amides
The utility of the N-(acyloxy alkoxy carbonyl) derivative is limited
due to the resistance to undergo enzymatic cleave in vivo. However, certain
activated amides are chemically labile and also certain amides formed with
amino acids may undergo enzymatic cleavage. For example the γ-glutamyl
derivatives of dopamine, L-Dopa, N-glycyl derivative.
N-glycyl derivative
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13.  3) Prodrugs of amides, imides and urides
• e.g.N-hydroxymethylation
The N-hydroxyl methyl derivatives of amides or imide type
compounds are more water soluble than the parent compounds. By
replacing a proton bind to nitrogen atom by a hydroxyl methyl group, intra
or intermolecular hydrogen bonding in such molecules may be increased
resulting in a decrease in melting point and increase in water solubility
The mechanism for the decomposition of N-hydroxyl methyl derivatives.
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14.  4) Ring formation derivative
Thiamine quaternary ammonium compounds like Hydantoin, Barbituric
acid etc. can undergo ring opening and show in vivo pharmacological properties.
 5) Glycol amide esters
These are bioavailable products of carboxylic group e.g. Benzoic acid
esters.
 6) Carbamates
They exhibit restricted distribution in the body. Carbamates do not have
any specific enzyme for hydrolysis. However, enzymes such as esterase can
hydrolyze carbamates e.g. co-carboxy methyl phenyl ester of Amphetamine.
Other approaches used in the formation of prodrug are phosphamides,
glycosides, ethers, and ketals.
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15. Why use prodrugs?
 Improve membrane permeability
 Improve absorption and distribution
 Improve solubility
 Alter metabolism
 Alter toxicity
 Alter elimination
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16. Application of prodrugs
 Pharmaceutical applications
 Improvement of taste
 Improvement of odour
 Reduction of irritation
 Reduction of pain on injection
 Enhancement of drug solubility and dissolution rate
 Enhancement of chemical stability of drug
 Pharmacokinetic applications
 Enhancement of provability
 Prevention of pre-systemic metabolism
 Prolongation of duration of action
 Reduction of toxicity
 Site specific drug-delivery
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17. E.g.
A. Esters
 Esters are the most commonly employed prodrugs.
 Numerous catalytic esterases are present in vivo to hydrolyze simple
esters.
Prodrug Active Form of Drug
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18. B.Enalapril
 The monoethyl ester of enalaprilat
 Enalaprilate was first discovered as an inhibitor of angiotensin converting
enzyme (ACE) and used to treat hypertension.
 Due to its high polarity, it was not orally bioavailable, and thus needed to be
administered by injection.
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19. Recent search
 Table 1. Prodrugs launched in the USA, 2013–2015
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20. Conclusion
 Prodrugs are inactive compounds which are converted to active drugs in the
body.
 Prodrugs were design to improve pharmacokinetic and drug delivery
properties.
 Esters are commonly used as prodrugs to make a drug less polar.
 The nature of the ester can be altered to vary the rate of hydrolysis.
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21. References
1. Alagarsamy, V. (2010). Textbook of medicinal chemistry (vol. 1, pp. 71-79).
New Delhi: reed/elsevier.
2. Testa, b., & Mayer, J. (2003). <I>hydrolysis in drug and prodrug
metabolism: chemistry, biochemistry, and enzymology</i>. Zurich: VHCA.
3. Drug metabolism. (N.D.). Retrieved November 18, 2014, from
http://www.Merckmanuals.Com/home/drugs/administration and kinetics of
drugs/drug metabolism.html.
4. Supriya shirke*, Sheetal Shewale and Manik Satpute (2015), Department
of Pharmaceutics, SCOP Satara, Maharashtra, India. Prodrug design: an
overview international journal of pharmaceutical, chemical and biological
sciences, IJPCBS 2015, 5(1), 232-241(pp. 233-236).
5. Prodrug design available from:
file:///I:/prodrug/prodrug%20concept%20PPT.htm.
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23. THANKS TO
ALL OF U
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