HARD DRUGS AND SOFT DRUGS
DRUG LATENTIATION
(PRODRUGS AND BIOPRECURSOR
PRODRUGS)
BY
Dr.K.G.LALITHA
PROFESSOR
DEPT OF PHARMACEUTICAL CHEMISTRY
JAZAN UNIVERSITY,KSA
Subject: Drug Discovery and Development
1 Lecture notes – 3rd year, 6th semester, Pharm.D
Chemical approach for optimizing the drug
therapeutics are
DESIGN OF HARD AND SOFT
DRUGS
DESIGN OF PRODRUGS
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HARD DRUG
A Hard drug is one which is resistant to
biotransformation and therefore, has a long
biological half-life
Such a drug will be eliminated by the body through
excretion in unchanged form only
Design of hard drugs involve metabolic
stabilization of the existing drug by replacing
functional groups susceptible to biotransformation
with the stable functional groups
Disadvantages of hard drugs are too long half-lives
and a potential risk of accumulation
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Tolbutamide; t1/2 = 6 hrs
Chlorpropamide – is an example of hard drug,
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it is metabolized very slowly; t1/2 = 33 hrs
SOFT DRUG
A soft drug is a biologically active compound that is
biotransformed in vivo in a rapid and predictable
manner into non-toxic moieties
They have a very short duration of action
Natural endogenous agents like Insulin and Adrenaline
are examples of soft drugs
Design of synthetic soft drugs involves introduction of
a group or a bond susceptible to rapid metabolic action
Example, replacement of alkyl side chain of the drug
with an ester group that can be readily hydrolyzed in
vivo
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VINYLOGY PRINCIPLE
The vinylogy principle was first formulated by
Claisen in 1926, who observed for
formylacetone acidic properties similar to that
of acetic acid.
The vinyl group plays the role of an electron-
conducting channel between the carbonyl and
the hydroxyl group. The same effect explains
the acidity of Ascorbic acid
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Today the vinylogy principle is explained by
the mesomeric effect and it applies to all
conjugated systems: imine and ethynyl groups,
phenyl rings, and aromatic heterocycles
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APPLICATIONS OF VINYLOGY
PRINCIPLE
Preparation of vinylogues usually leads to
compounds which are more sensitive to metabolic
degradation and more toxic (reactivity of the
conjugated double bond) than the parent drug,
without being more active.
In preparing the vinylogues of acetylcholine,
Tenconi and Barzaghi succeeded in separating the
nicotinic from the muscarinic activity
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Pethidine and Phenylbutazone vinylogues were designed
which has a shorter duration of action than the parent dru
may be due to the easier metabolic degradation of the
tyryl double bond
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PRODRUGS
Prodrugs are compounds which are inactive,
but converted in the body to active drug by
metabolism
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Prodrugs are classified into three types
1) Carrier linked prodrugs
2) Mutual prodrugs,
3) Bioprecursor prodrugs.
Carrier Linked Prodrugs
A carrier (promoiety, which is not necessary
for activity) is covalently linked with an active
drug to impart some desirable property to the
drug such as water or lipid solubility.
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Ex. Chloramphenicol has low water solubility,
so the succinate ester (Chloramphenicol
succinate) is prepared to increase the water
solubility for parenteral administration
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Mutual Prodrugs
Both the active drug and carrier has the
pharmacological activity.
Ex. Estramustine (anticancer, prostate cancer)
is composed of estradiol linked to normustard
(anticancer) through a carbamate linkage
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Bioprecursor prodrugs
Contains no carrier. The inactive prodrug converted to
active drug.
Ex. Sulindac (non steroidal anti-inflammatory agent) is
inactive drug. On oral administration it is absorbed in
small intestine and reduced to the active drug (sulfide).
Sulfide is not administered orally, because it irritates the
GIT.
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Advantage of prodrugs
Increased absorption.
Eliminate the pain at the site of injection
Elimination of unpleasant taste.
Decreased toxicity
Decreased metabolic inactivation
Increased chemical stability
Prolonged or shortened the duration of
action.
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REFERENCE
Graham L.Patrick, An Introduction to
Medicinal Chemistry, Fourth Edition,
Oxford University Press, New York, 2009,
252 - 267
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