Drug Design Final Assignment

Pro Drugs In Drug Design & Development

What Are Pro-Drugs?

 Prodrugs are molecules with little or no pharmacological activity that are

converted to the active parent drug in vivo by enzymatic or chemical
reactions or by a combination of the two. They are bio-reversible
derivatives of active drug molecules that will elicit its desired
pharmacological effect in the body once it is transformed to the active
parent drug.
 Designing prodrugs has the potential to enable a suitable drug candidate
with the optimal ADME properties and pharmacological potency to be
selected for development faster and with less overall costs.

Prodrug concept

History of pro-drug
Classification of Pro-Drug

The conventional method used to classify prodrugs is based on derivatization

and the type of carriers attached to the drug. This method classifies prodrugs
into two sub-major classes:

1. Carrier-linked prodrugs: in which the promoiety is covalently linked to

the active drug but it can be easily cleaved by enzymes or non-
enzymatically to provide the parent drug. Ideally, the group removed is
pharmacologically inactive, nontoxic, and non-immunogenic, while the
prompoiety must be liable to change for in vivo efficient activation.
 Carrier-linked prodrugs can be further subdivided into:

a) bipartite which is composed of one carrier attached directly to

the drug. The active drug is release by hydrolytic cleavage either
chemically or enzymatically. Example: Tolmetin – Glycine prodrug

b) tripartite which connect a group between the drug and a

promoiety
c) mutual prodrugs, which are consisting of two drugs linked
together.

2. Bio-precursors: result from a molecular modification of the active

principle. The modification generates a new compound that is capable of
being a substrate of the metabolic enzymes, with the metabolite being
the expected active compound. For example, if the drug contains a
carboxylic acid group, the bio-precursor may be an alcohol that is
metabolized by oxidation to the aldehyde and then to the carboxylic acid
drug.
Functional Group Derivative in Pro-Drug
1. COOH - carboxylic acid
2. NH2 - amine
3. OH – alcohol

Application of Pro-Drugs
A. Pharmaceutical applications

1- Masking odor: the odor of a compound is due to its vapor pressure.

Compounds with low boiling point will have a strong odor, for examples,
ethyl mercaptan have a foul smell and is liquid at a boiling point 35 °C it
is useful in the treatment of leprosy, its foul smell is removed by
converting it to its phthalate ester, diethyl iso-phthalate, which has
higher boiling point and odorless. The prodrug is administered by
rubbing on the skin, after absorption the ester is metabolized to parent
drug by thio-esterase.

2- Masking taste: the undesirable taste arises due to the adequate

solubility and interaction of drug which can be solved by lowering the
solubility of the drug or the pro-drug in the saliva, for example,
chloramphenicol is an extremely bitter drug that has been derivatized to
chloramphenicol palmitate which is a sparingly soluble ester. It
possesses low aqueous solubility which makes it tasteless and later
undergoes in vivo hydrolysis to active chloramphenicol by the action of
pancreatic lipase.

3- Reduction of G.I irritation: several drugs cause irritation and damage to

the gastric mucosa through direct contact, increased stimulation of acid
secretion or through interference with protective mucosal layer.

Drug Pro-drug
 Salicylic acid Salsalate, aspirin
Diethyl stilbesterol fosfestrol
Kanamycin Kanamycin pamoate
phenylbutazone N-methyl piperazine salt
Nicotinic acid Nicotinic acid hydrazide

4- Change of physical form of the drug: some drugs which are in liquid
form are unsuitable for formulation as a tablet especially if their dose is
high. The method of converting such a liquid drug into solid pro-drug
involved formation of symmetrical molecules having a higher tendency
to crystallize. For example, 1,3-diester derivative of ethyl mercaptan.

5- Minimizing pain at site of injection: pain caused by intramuscular

injection is mainly due to the weakly acidic nature or poor aqueous
solubility of drugs. For example, intramuscular injection of antibiotic like
clindamycin and anti-convulsant drug like phenytoin was found painful
due to the poor aqueous solubility and could overcome by making
phosphate, ester pro-drugs.

B. Pharmacokinetic applications

1- Enhancement of bioavailability: passive diffusion is the most common

pathway for transportation of a drug from site of administration to
systemic circulation through a lipoidal membrane. Therefore, the
 improvement in the lipophilic character serves as a tool for enhancing
the bioavailability. There are two reasons that can be attributed to the
enhanced oral bioavailability of lipophilic compound. First one is that
the lipophilic form of a drug has enhanced membrane/water partition
coefficient as compared to the hydrophilic form thus favoring passive
diffusion. For example, bacampicillin prodrugs of ampicillin is more
lipophilic, it is better absorbed and rapidly hydrolyzed to the parent
drug in blood. Second reason is that the lipophilic prodrugs have poor
solubility in gastric fluids and thus greater stability and absorption for
example the ester of erythromycin.
2- Reduction of stability problem: most of the drugs may be rapidly
metabolized and rendered inactive before it reaches the site of action.
The structure may be modified to block the metabolism until the drug is
at the desired site. Some pro-drugs protect the drug from first-pass
effect, for example, propranolol, it is widely used anti-hypertensive drug
but its bioavailability is very low because of first-pass metabolism. The
hemisuccinate ester of propranolol was prepared to block glucuronide
formation, therefore the oral administration of propranolol
hemisuccinate elevated plasma levels of propranolol for about 8 times.

3- Reduction of toxicity: an important objective of drug design is to

develop a moiety with high activity and low toxicity. For example,
NSAIDs local side effects like gastric distress can be overcame by pro-
drug design. A second example is the bio-precursor sulindac, as it is a
sulphoxide, it doesn’t cause any gastric irritation and it is absorbed
 better. A third example is the prodrug of ibuterol is diisobutyrate ester
of terbutaline in glaucoma, the pro-drug is 100 times more potent and
has a longer duration of action and is free from both local and systemic
toxicity.

Designing Pro-Drugs
The design of a prodrug structure should always be considered at the early
stages of preclinical development, keeping in mind that prodrugs may alter the
tissue distribution, metabolism, efficacy, and even toxicity of the parent drug.

There are several factors that should be carefully considered when designing
prodrug structures:
• What is the limitation of the parent drug that needs prodrug
intervention?
• Which functional groups on the parent drug are suitable for chemical
modification?
• Can the prodrug be readily synthesized?
• Chemical modification must be reversible and allow the parent drug to
be released by an in vivo chemical or enzymatic reaction at the rate that
is greater than the elimination rate of the prodrug or parent drug.
• The promoiety should ideally be safe and rapidly excreted from the
body. The selection of promoiety should be considered with respect to
the disease, the dose, and the duration of therapy.
• The absorption, distribution, metabolism, and excretion properties of
both the parent drug and prodrug need to be comprehensively
understood.
• Can bioavailability in humans be predicted, with a high degree of
certainty, using preclinical animal models?
• Is the final prodrug formulation sufficiently chemically and physically
stable with a reasonable shelf life?

Some steps must be followed in designing prodrugs

1- Identification of the drug delivery problem
2- Identification of desired physiochemical properties
 3- Selection of transport moiety which will give the prodrug desired
transport properties be readily cleaved in the desired biological
compartment

How are pro-drugs metabolized?

Most drugs must pass through the liver, which is the primary site for drug
metabolism. Once in the liver, enzymes convert prodrugs to active
metabolites or convert active drugs to inactive forms. The liver’s primary
mechanism for metabolizing drugs is via a specific group of cytochrome P-450
enzymes. The level of these cytochrome P-450 enzymes controls the rate at
which many drugs are metabolized. The capacity of the enzymes to
metabolize is limited, so they can become overloaded when blood levels of a
drug are high

Characteristic of Pro-Drugs

There are a few characteristics for a pro-drug to be improved for site-specific

drug delivery which are:
1- The pro-drug must be reliability transported to the site of the action
2- The pro-drug must be selectively cleaved to the active drug utilizing
special enzymatic profile of the site.
3- Once the pro-drug is selectively generated at the site of action the tissue
must retain the active drug without further degradation.

Major Limitations to Drug’s Usefulness That May Be Overcome by

Prodrugs

Formulation and  Insufficient aqueous solubility

administration  Insufficient shelf life for liquid and solid dosage
forms
 Irritation or pain after local administration
 Unpleasant taste or odor

Absorption  Insufficient dissolution rate due to low aqueous

solubility
 Poor membrane permeability and low oral or
topical bioavailability due to poor lipophilicity
 Insufficient stability during first-pass
 metabolism or in acidic gastric juices
 Insufficient availability due to efflux mechanisms

Distribution  Lack of site specificity (e.g., poor brain or tumor

targeting)
 Excessively strong protein binding in plasma or
disposition in lipophilic compartments of body

Metabolism and excretion  Lack or need of site-specific bioactivation

 Short duration of action

Toxicity  Lack of site specificity

 Lack or need of site-specific bioactivation
 Irritation or pain after local administration
 Need to temporarily mask a reactive, inherently
active, functional group

Life cycle management  Development of a prodrug with improved

properties that may represent a life cycle
management opportunity for an existing drug

Pro-Drugs & Drugs

Pro-drug Active drug Notes

Enalapril enalaprilat Enalaprilat is poorly absorbed from the g.i
tract when administered
Enalapril is extensively hydrolyzed in the
liver to enalaprilat
levodopa dopamine Unlike dopamine, levodopa can cross the
blood brain barrier.

Levodopa is converted to dopamine in

both the periphery and CNS.
carbimazole thiamazole Carbimazole is rapidly and almost
completely metabolized to thiamazole
Fosphenytoin sodium Phenytoin Fosphenytoin is a water-soluble prodrug
that was developed to overcome the
problems that were associated with giving
phenytoin parenterally.
Fosphenytoin is rapidly metabolized to
phenytoin by endogenous phosphatases in
the body.

Oxcarbazepine monohydroxy Oxcarbazepine is structurally related to

derivative carbamazepine.
Oxcarbazepine differs from
carbamazepine in its lack of auto induction
and less potential for drug interactions.
Oxcarbazepine is rapidly metabolized to its
pharmacologically active metabolite,
MHD, by cytosolic enzymes in the liver.

Clopidogrel Thiol derivative Clopidogrel is a prodrug which is

metabolized by cytochrome P450 enzymes
to form the active thiol derivative.
The thiol derivative prevents the binding
of ADP to its platelet receptor, which in
turn blocks the ADP-mediated activation
of the glycoprotein GPIIb/IIIa complex and
thus inhibiting platelet aggregation.

Dabigatran Etexilate Dabigatran Dabigatran etexilate is converted to the

active drug dabigatran by esterase-
catalyzed hydrolysis.
Dabigatran etexilate was developed as
dabigatran is highly polar and charged,
thus resulting in poor gastrointestinal
absorption, whereas dabigatran etexilate
is highly lipophilic and rapidly absorbed
from the gastrointestinal tract.
Dabigatran is a direct thrombin inhibitor.
Fenofibrate Fenofibric acid Fenofibrate is rapidly hydrolyzed to
fenofibric acid.

Valganciclovir Ganciclovir Oral bioavailability is improved with

valganciclovir.
 Valganciclovir is rapidly converted to
ganciclovir by hepatic and intestinal
esterases.

Valaciclovir Aciclovir Oral bioavailability is improved with

valaciclovir.
Valaciclovir is rapidly converted to
aciclovir and valine.
Famciclovir Penciclovir Oral bioavailability is improved with
famciclovir
Famciclovir is rapidly converted to
penciclovir.

Oseltamivir Oseltamivir Oral bioavailability is improved with

phosphate carboxylate oseltamivir phosphate.
Oseltamivir phosphate is rapidly converted
to oseltamivir carboxylate by hepatic
esterases primarily.
Adefovir dipivoxil adefovir Oral bioavailability is improved with
adefovir dipivoxil
Adefovir dipivoxil is rapidly converted to
adefovir.
Latanoprost Latanoprost acid Latanoprost the prodrug is better
absorbed through the cornea than
latanoprost acid where latanoprost is
converted by hydrolysis to latanoprost
acid, the active drug.

Conclusion
In conclusion, pro-drug design is a part of the general drug discovery process,
in which a unique combination of therapeutically active substances is observed
to have desirable pharmacological effects. In drug research the prodrug
concept has found many useful applications, especially in the target releasing
field, but other problems such as a poor water solubility, incorrect absorption
rate, early metabolic destruction or unwanted side effects continue
to be topics to consider for the successful development of a pro-drug.

References:
1- Textbook of drug design and discovery, Fifth Edition
2- The expanding role of prodrugs in contemporary drug design and
development
https://www.readcube.com/articles/10.1038/nrd.2018.46
3- Textbook Pro-drug design – a new era
4- https://pubmed.ncbi.nlm.nih.gov/20858214/
5- https://www.researchgate.net/publication/
5633050_Prodrugs_Design_and_clinical_applications
6- https://www.researchgate.net/publication/
309545474_Prodrug_approach_An_overview_of_recent_cases
7- https://www.merckmanuals.com/home/drugs/administration-and-
kinetics-of-drugs/drug-metabolism
8- https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-
2125.1989.tb03535.x