Medicinal chemistry

(PCHE 0301)
Unit 3
Prodrugs and drug Latentiation

Fall 2023-24

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 Learning Objectives
After the completion of the unit students should be able to:
1. Define pro-drugs and drug latentiation.
2. Describe how the prodrugs are made
3. Explain the utility of prodrugs in clinical practice
4. Classify prodrugs
/ redict
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5. Comprehend the metabolism of prodrugs in vivo to generate
the active moeity.
6. Identify few examples of prodrugs commonly used in
pharmaceutical care.

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 Overview of Lecture-1
• Definition of prodrugs
• How prodrugs are made
• Utility of prodrugs
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Soft drugs and hard drugs
 inactive drug
active
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after metabolism

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Prodrugs and drug Latentiation
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 Bioconversion

• Sometimes drugs are designed to make use of

metabolic processes in order to generate their active
form.

• Why prepare prodrugs:

To improve some selected property of the molecule,
such as water solubility or ability to cross a membrane,
 temporarily.

• Prodrug refers to a pharmacological inactive

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compound that is transformed by the body
into an active substance by either chemical or
metabolic
L
means. (Albert 1958)
other ↳
enzymes
↳ Father ofProdungs
name

• Drug latentiation refers to drug that is

specifically designed to require bio-activation (
bio-conversion
Harper 1959)
Bioconversion:
A process in which the pharmacologically active drug is
released or formed in vivo.
How prodrugs are made
 Utility of Prodrugs
1. Aqueous Solubility - to increase water solubility so it
can be injected in a small volume (prepare salt, phosphate
prodrugs)
2. Absorption and Distribution - to increase lipid
solubility to penetrate membranes for better absorption
(prepare ester prodrugs)
3. Site Specificity - to target a particular organ or tissue if
a high concentration of certain enzymes is at a particular
site or append something that directs the drug to a
particular site---often tried to limit the toxicity of
anticancer drugs.
4. Instability - to prevent rapid metabolism; avoid first-
 pass effect.

• 5. Prolonged Release - to attain a slow, steady

release of the drug
• 6. Toxicity - to make less toxic until it reaches the
site of action
• 7. Poor Patient Acceptability - to remove an
unpleasant taste or odor; gastric irritation
• 8. Formulation Problems - to convert a drug that is
a gas or volatile liquid into a solid
 Monoesterification with Ethanol

Enalapri
Enalaprilat l

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Bioactivation of enalapril to
enalaprilat
• One example is the monoethyl ester of enalaprilat, which is called enalapril.

• Enalaprilat (upper left) was first discovered as an inhibitor of angiotensin converting

enzyme (ACE) and used to treat hypertension.
• Due to its high polarity (Bcoz of two COOH’s), it was not orally bioavailable, and thus
needed to be administered by injection.
• The monoEthyl ester, enalapril (upper right) is orally bioavailable.
 Free p
↓ xy o

Jester increase bioavailability

• Another example is the anti-viral agent Oseltamavir

(Tamiflu®) shown above.
• Notice that the oral bioavailability is improved by
employing the ethyl ester of the carboxylic acid
Soft drug: They are active drugs that are designed to undergo a
predictable and controllable deactivation or metabolism in vivo after
achieving their therapeutic effect to non-toxic, inactive compounds .
Prodrugs and soft drugs are opposite:
• A prodrug is Inactive - requires metabolism to give active form
• A soft drug is Active - uses metabolism to promote excretion
• Hard drug ( non metabolizable ie resistant to metabolism, highly
lipid/water soluble, long t1/2, cocaine, heroine)
 Overview of Lecture-2
• Classification of prodrugs
• Carrier linked prodrug
• Bipartate
• Tripartate
• Mutual prodrugs

• Bioprecursor prodrug
• Preparation of Prodrugs of functional groups
 Prodrugs are of two types

1. Carrier linked prodrug

2. Bioprecursor prodrug
 Carrier-linked Prodrugs
● They have attachment of a metabolically liable linkage to
another molecule –called pro-moiety.

– Pro-moiety is not necessary for activity but may impart

some desirable property to the drug such as increased
lipid or water solubility or site directed delivery.

E.g. Antibiotic chloramphenicol is less water soluble

and converted to more water-soluble succinate salt so
that it is used to prepare less painful as injection
Increased water solubility, ester itself is inactive as an
antibiotic

Promoiety is nontoxic and easily excreted.

Type of promoiety chosen is a function of properties

desired
 Mutual Prodrug

• Used for metastatic carcinoma of the prostate

• Promoiety is also a drug!
• Prodrug is selectively taken up into estrogen receptor positive
cells then urethane linkage is hydroylzed
•Nornitrogen mustard is a weak alkylating agent
 Preparation of Prodrugs of functional
groups
• Modification of Carboxylic acids and
alcohols into esters:

Thereby converting into more lipophilic molecules.

• These esters are metabolized by
– Esterase,
– Hydrolase,
– Lipase,
– Carboxypeptidase etc
in the body to release the active metabolites.
Most common (biologically labile) functional groups
utilized in prodrug design are shown above.
 Examples of prodrug design
Hetacillin , an ampicillin prodrug has better oral
absorption profile and after metabolism it gives
ampicillin and acetone
 Problem: CP is bitter. Water soluble drugs when dissolve in mouth could
lead to bad taste.

Solution: To overcome the bitter taste, CP is conjugated with palmitic acid

via esterification to make it water-insoluble and tasteless (masking the
taste).
Other examples are:
-Clindamycin palmitate
-Erthromycin estolate (Alkyl ester)

• Chloramphenicol palmitate produce

chloramphenicol and palmitic acid after
metabolism
 Amine derivatives as prodrugs
• Amides are not used as prodrugs due to high stability
• Most common amine derivative used is a N-Mannich Base prodrug

Rolitetracycline- A N-Mannich base prodrug

of
Tetracycline with improved
BIOAVAILABILITY
• Carbonyl Compound: Aldehydes and ketone
functional groups not much involved in prodrug
design.
• Eg. Methenamine or Hexamine.

• The enteric coated drug after absorption undergoes

chemical hydrolysis into formaldehyde and
ammonia in acidic urinary pH and exerts urinary
antiseptic property.
 Azo Prodrugs
Azo linkage: reduction takes
place in gut by azo reductase
enzyme to yield amino
•Bacterial reductases reductive cleavage compounds e.g Prontosil,
Sulfaslazine
• Release of 2 amine compounds
• Occurs in colon discourages small intestine systemic absorption
• Concentrates the drug at the desired site of action
 Bio-precursor prodrug
• They do not contain a carrier or pro-moiety but
rather contain a latent functionality that is
metabolically or chemically transformed into an
active drug. E.g.
• Sulindac is converted into active sulfide to have anti-
inflammatory activty
• Mitomycin C undergoes reductive activation
• Idoxuridine phosphorylated to the triphosphate
inhibit DNA polymerase enzyme in virus.
Oxidation of Sulfide:
methylsulfoxide group in the anti-inflammatory agent,
Sulindac is metabolized to active sulfide analogue by
reductive metabolism
 The keto group in Nebumetone is oxidized to active (6-
methoxy- naphthalene-2-yl)acetic acid and acetic acid

• Nebumetone is converted into active form and

inhibits cyclooxygenase.
Prodrug for improved aqueous
solubility

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 L Dopa Anti-Parkinsonism agent

– Brain has a specific transport system for L-amino

acids
– Dopamine does not cross the blood brain barrier
efficiently, is rapidly metabolized by oxidative
deamination, and can cause peripheral side effects