Basic concepts of prodrugs, Applications of prodrugs for B Pharm Sem VI (PCI)

1. by
Prof. Jayshree Patil
Department of Pharmaceutical Chemistry,
AIKTC School of Pharmacy, New Panvel
PRODRUG
for Sem VI (PCI)

2. ➢ Basic concepts
➢ Application of prodrugs design.

3. ENZYME ACTIVATION OF DRUGS
The term prodrug, which was used initially by Albert, is a pharmacologically inactive compound
(or at least 1000 times less potent than the parent drug) that is converted into an active drug by a
metabolic biotransformation.
A prodrug can also be activated by a nonenzymatic process such as hydrolysis, but in this case,
the compounds generally are inherently unstable and may cause stability problems, for example,
during storage.
The prodrug to drug conversion can occur before, during, or after absorption or at a specific site
in the body, especially if the activating enzyme is more abundant at the target site than anywhere
else.
In the ideal case, a prodrug is converted to the drug as soon as the desired goal for designing the
prodrug has been achieved. In 2006, about 16% of small-molecule drugs were prodrugs.
Prodrugs are inactive compounds that require a metabolic conversion to the active form, whereas
a soft drug is pharmacologically active and uses metabolism as a means of promoting
deactivation and excretion. However, it is possible to design a pro-soft drug, a modified soft drug
that requires metabolic activation for conversion to the active soft drug.

4. Utility of Prodrugs
Prodrug design is a lead modification approach that is used to correct a flaw in a viable drug
candidate. Typically, it is considered as an option after lead optimization has been carried out and
when the desired drug candidate has failed in pharmacokinetic/ preclinical studies. However, it
has been argued that a prodrug approach should be considered in early stages of lead optimization
as well, particularly when there are pharmacokinetic defects in the molecule, such as poor
absorption, very short or very long half-life, high first-pass effect, or off-target inhibition.
Below are briefly discussed numerous reasons why you may want to utilize a prodrug strategy in
drug design.
Aqueous Solubility
Problem: Consider an injectable drug that is so insoluble in water that it
would need to be taken up in more than a liter of saline to administer the
appropriate dose!
Or what if each dose of your ophthalmic drug required a liter of saline for
dissolution, but it was to be administered as eye drops? These drugs could be
safe, effective, and potent, but they would not be viable for their applications.
Solutions: In these cases, a water solubilizing group, which is metabolically released after drug
administration, could be attached to the drugs.

5. Absorption and Distribution
If the desired drug is not absorbed and transported to the target site in
sufficient concentration, it can be made more water soluble or lipid soluble
depending on the desired site of action. Once absorption has occurred or
when the drug is at the appropriate site of action, the water- or lipid-soluble
group is removed enzymatically.
Site Specificity
Specificity for a particular organ or tissue can be made if there are high
concentrations of or uniqueness of enzymes present at that site that can
cleave the appropriate appendages from the prodrug and unmask the drug.
Alternatively, something that directs the drug to a particular type of tissue,
which is released after the drug reaches the target tissue, could be attached
to the drug.
Instability
A drug may be rapidly metabolized and rendered inactive before it reaches
the site of action. The structure may be modified to block that metabolism
until the drug is at the desired site.

6. Prolonged Release
It may be desirable to have a steady low concentration of a drug released over
a long period of time. The drug may be altered so that it is metabolically
converted to the active form slowly.
Toxicity
A drug may be toxic in its active form and would have a greater therapeutic
index if it were administered in a nontoxic inactive form that was converted
into the active form only at the site of action.
Poor Patient Acceptability
An active drug may have an unpleasant taste or odor, produce gastric irritation,
or cause pain when administered (for example, when injected). The structure
of the drug could be modified to alleviate these problems, but once
administered, the prodrug would be metabolized to the active drug.

7. Formulation Problems
If the drug is a volatile liquid, it would be more
desirable to have it in a solid form so that it
could be formulated as a tablet.
An inactive solid derivative could be prepared,
which would be converted in the body to the
active drug.

8. Types of Prodrugs
There are several classifications of prodrugs. Some prodrugs are not designed as such; the
biotransformations are fortuitous, and it is discovered only after isolation and testing of the
metabolites that activation of the drug had occurred.
In most cases, a specific modification in a drug has been made on the basis of known
metabolic transformations. It is expected that, after administration, the prodrug will be
appropriately metabolized to the active form. This has been termed drug latentiation to signify
the rational design approach rather than serendipity. The term drug latentiation has been
refined even further by Wermuth into two classes, which he called carrier-linked prodrugs
and bioprecursors.

9. A carrier-linked prodrug is a compound that contains an active drug linked to a carrier group
that can be removed enzymatically, such as an ester, which is hydrolyzed to an active
carboxylic acid-containing drug.
The bond to the carrier group must be labile enough to allow the active drug to be released
efficiently in vivo, and the carrier group must be nontoxic and biologically inactive when
detached from the drug.
Carrier linked prodrugs can be subdivided even further into
➢ bipartite,
➢ tripartite, and
➢ mutual prodrugs.
A bipartite prodrug is a prodrug composed of one carrier attached to the drug.
When a carrier is connected to a linker that is connected to the drug, it is called a tripartite
prodrug.
A mutual prodrug (also known as a codrug) consists of two, usually synergistic, drugs attached
to each other (one drug is the carrier for the other, and vice versa).

10. A bioprecursor prodrug is a compound that is metabolized by molecular modification into a
new compound, which is the active principle or which can be metabolized further to the active
drug.
For example, if the drug contains a carboxylic acid group, the bioprecursor may be a primary
amine, which is metabolized by oxidation to the aldehyde and then further metabolized to the
carboxylic acid drug.
Unlike the carrier-linked prodrug, which is the active drug linked to a carrier, a bioprecursor
contains a different structure that cannot be converted into the active drug by simple cleavage
of a group from the prodrug.

11. The concept of prodrugs can be analogized to the use of protecting groups in organic synthesis.
If, for example, you wanted to carry out a reaction on a compound that contained a carboxylic
acid group, it may be necessary first to protect the carboxylic acid as, say, an ester, so that the
acidic proton of the carboxylic acid did not interfere with the desired reaction.
After the desired synthetic transformation was completed, the carboxylic acid analog could be
unmasked by deprotection, i.e., hydrolysis of the ester.
Protecting Group Analogy for a prodrug
This is analogous to a carrier-linked prodrug; an ester functionality can be used to make the
properties of the drug more desirable until it reaches the appropriate biological site where it is
“deprotected”.

12. Another type of protecting group in organic synthesis is one that has no resemblance to the
desired functional group.
For example, a terminal alkene can be oxidized with ozone to an aldehyde,and the aldehyde
can be oxidized to a carboxylic acid with hydrogen peroxide.
As in the case of a bioprecursor prodrug a drastic structural change is required to unmask the
desired group.
Oxidation is a common metabolic biotransformation for bioprecursor prodrugs.
Approximately 49% of marketed prodrugs are activated by hydrolysis, and 23% are
bioprecursor prodrugs.

13. Targeting drugs

14. One of the major goals in drug design is to find ways of targeting drugs to the exact locations in the
body where they are most needed.
Here, we discuss other tactics related to the targeting of drugs.
Strategies designed to target drugs to particular cells or
tissues are likely to lead to safer drugs with fewer side effects.
Drugs can be linked to amino acids or nucleic acid bases to target
them against fast-growing and rapidly-dividing cells.
Drugs can be targeted to the gastrointestinal tract by making them
ionized or highly polar such that they cannot cross the gut wall.
The CNS side effects of peripherally acting drugs can be
eliminated by making the drugs more polar so that they do not
cross the blood–brain barrier.
Drugs with toxic side effects can sometimes be made less toxic by
varying the nature or position of substituents, or by preventing
their metabolism to a toxic metabolite.

15. Prodrugs to improve
membrane permeability

16. Esters as prodrugs
Prodrugs have proved very useful in temporarily masking an ‘awkward’ functional group
which is important to target binding but which hinders the drug from crossing the cell
membranes of the gut wall.
For example, a carboxylic acid functional group may have an important role to play in binding
a drug to its binding site via ionic or hydrogen bonding. However, the very fact that it is an
ionizable group may prevent it from crossing a fatty cell membrane.
The answer is to protect the acid function as an ester. The less
polar ester can cross fatty cell membranes and, once it is in the
bloodstream, it is hydrolysed back to the free acid by esterases
in the blood.
Examples of ester prodrugs used to aid membrane permeability
include enalapril , which is the prodrug for the antihypertensive
agent enalaprilate
Enalapril R = Et
Enalaprilate R = H

17. N-Methylated prodrugs
N -Demethylation is a common metabolic reaction in the liver, so polar amines can be N -
methylated to reduce polarity and improve membrane permeability. Several hypnotics and
anti-epileptics take advantage of this reaction,
for example hexobarbitone
N-Demethylation of hexobarbitone

18. Trojan horse approach for transport proteins
Another way round the problem of membrane permeability is to design a prodrug which can
take advantage of transport proteins in the cell membrane, such as the ones responsible for
carrying amino acids into a cell.
A well-known example of such a prodrug is levodopa. Levodopa is a prodrug for the
neurotransmitter dopamine and has been used in the treatment of Parkinson’s disease—a
condition due primarily to a deficiency of that neurotransmitter in the brain.
Dopamine itself cannot be used as it is too polar to cross the blood–brain barrier.
Levodopa is even more polar and seems an unlikely prodrug, but it is also an amino acid, and
so it is recognized by the transport proteins for amino acids which carry it across the cell
membrane. Once in the brain, a decarboxylase enzyme removes the acid group and generates
dopamine.

19. Prodrugs to prolong drug
activity

20. Sometimes prodrugs are designed to be converted slowly to the active drug, thus prolonging a
drug’s activity.
For example, 6-mercaptopurine suppresses the body’s immune response and is, therefore,
useful in protecting donor grafts. Unfortunately, the drug tends to be eliminated from the body
too quickly. The prodrug azathioprine has the advantage that it is slowly converted to 6-
mercaptopurine by being attacked by glutathione, allowing a more sustained activity.
The rate of conversion can be altered, depending on the electron- withdrawing ability of the
heterocyclic group. The greater the electron-withdrawing power, the faster the breakdown. The
NO2 group is therefore present to ensure an efficient conversion to 6-mercaptopurine, as it is
strongly electron-withdrawing on the heterocyclic ring.
Azathioprine acts as a prodrug for 6-mercaptopurine (GS = glutathione).

21. Another approach to maintaining a sustained level of drug over long periods is to deliberately
associate a very lipophilic group to the drug. This means that most of the drug is stored in fat
tissue from where it is steadily and slowly released into the bloodstream.
The antimalarial agent cycloguanil pamoate is one such agent. The active drug is bound
ionically to an anion containing a large lipophilic group and is only released into the blood
supply following slow dissociation of the ion complex.
Cycloguanil pamoate

22. Prodrugs masking drug toxicity and side effects
Prodrugs can be used to mask the side effects and toxicity of drugs.
For example, salicylic acid is a good painkiller, but causes gastric bleeding because of the
free phenolic group. This is overcome by masking the phenol as an ester ( aspirin ). The
ester is later hydrolyzed to free the active drug.
Aspirin (R = COCH3 ) and
Salicylic acid (R = H).

23. Prodrugs to lower water solubility
Some drugs have a revolting taste! One way to avoid this problem is to
reduce their water solubility to prevent them dissolving on the tongue.
For example, the bitter taste of the antibiotic chloramphenicol can be
avoided by using the palmitate ester. This is more hydrophobic because
of the masked alcohol and the long chain fatty group that is present. It
does not dissolve easily on the tongue and is quickly hydrolysed once
swallowed.
Chloramphenicol (R = H) And
Chloramphenicol Prodrugs;
Chloramphenicol Palmitate (R = CO(CH2 )14CH3);

24. Prodrugs to improve water solubility
Prodrugs have been used to increase the water solubility of drugs.
This is particularly useful for drugs which are given intravenously,
as it means that higher concentrations and smaller volumes can be
used.
For example, the succinate ester of chloramphenicol increases
the latter’s water solubility because of the extra carboxylic acid
that is present. Once the ester is hydrolysed, chloramphenicol is
released along with succinic acid, which is naturally present in the
body.
Chloramphenicol Succinate
(R = CO(CH2)2CO2H).
Prodrugs designed to increase water solubility have proved useful
in preventing the pain associated with some injections, which is
caused by the poor solubility of the drug at the site of injection.
For example, the antibacterial agent clindamycin is painful when
injected, but this is avoided by using a phosphate ester prodrug
which has much better solubility because of the ionic phosphate
group
Clindamycin
phosphate

25. Prodrugs used in the targeting of drugs
Methenamine is a stable, inactive compound when the pH is more than 5. At a more acidic
pH, however, the compound degrades spontaneously to generate formaldehyde , which has
antibacterial properties.
This is useful in the treatment of urinary tract infections.
Methenamine
The normal pH of blood is slightly alkaline (7.4) and so
methenamine passes round the body unchanged. However, once
it is excreted into the infected urinary tract, it encounters urine
which is acidic as a result of certain bacterial infections.
Consequently, methenamine degrades to generate formaldehyde
just where it is needed.

26. Prodrugs to increase chemical stability
The antibacterial agent ampicillin decomposes in concentrated aqueous solution as a result of
intramolecular attack of the side chain amino group on the lactam ring. Hetacillin is a prodrug
which locks up the off ending nitrogen in a ring and prevents this reaction.
Once the prodrug has been administered, hetacillin slowly decomposes to release ampicillin
and acetone.

27. Prodrugs activated by external influence (sleeping agents)
Conventional prodrugs are inactive compounds which are normally metabolized in the body to
the active form.
A variation of the prodrug approach is the concept of a ‘sleeping agent’. This is an inactive
compound which is only converted to the active drug by some form of external influence.
The best example of this approach is the use of
photosensitizing agents (such as porphyrins or chlorins in
cancer treatment)—a strategy known as photodynamic
therapy .
Given intravenously, these agents accumulate within cells and
have some selectivity for tumour cells. By themselves, the
agents have little effect, but if the cancer cells are irradiated
with light, the porphyrins are converted to an excited state
and react with molecular oxygen to produce highly toxic
singlet oxygen.

28. References:
1. An Introduction to Medicinal Chemistry by Graham Patrick
2. The Organic Chemistry of Drug Design and Drug Action by Richard B.
Silverman