Prodrug

medicinal chemistry

1. Seminar Presentation
on
Prodrug Concept

2. The Prodrug Concept
The prodrug concept was first proposed by Albert in 1958.
 Albert and his co-workers described prodrugs as
pharmacologically inactive chemical derivatives that
could be used to alter the physicochemical properties of
drugs, in a temporary manner, to increase their usefulness
and/or to decrease associated toxicity.
They have also been called ‘latentiated drugs’, ‘bioreversible
derivatives’, and ‘congeners’.
Ideally, the prodrug is converted to the original drug as soon as
the derivative reaches the site of action, followed by rapid
elimination of the released derivatizing group without causing
side effects in the process.

6. Applications Of Prodrug
Prodrugs are converted into the active drug within the body
through enzymatic or non-enzymatic reactions. The various
applications of prodrug approach are;
1. Improved physicochemical properties (e.g., better solubility in
the intended formulation)
2. Enhanced delivery characteristics and/or therapeutic value of
the drug
3. To improve drug penetration through biological membranes
4. To increase site specificity of the drug
5. To improve the drug’s stability and solubility
6. To increase duration of pharmacological activity
7. To decrease the drug’s toxicity and adverse effects
8. To improve patient acceptance.

7. Ideal Requirements of Prodrugs
1. The prodrug is inactive or less active than the parent compound
2. The linkage between the drug and the carrier must be cleaved in
vivo
3. The carrier molecule released in vivo must be non-toxic
4. The metabolic fragments of carrier molecule, apart from the
drug should be non-toxic

8. Classification of Prodrugs
1. Carboxylic acids and alcohols.
Prodrugs of carboxylic acid and alcohol functionalities can be
prepared by conversion to an ester.
The ester can be easily hydrolysed by esterase enzymes present
in plasma and other tissues to give active drug.
Enzymes: ester hydrolase, lipase, cholesterol esterase,
acetylcholinesterase, carboxypeptidase

9. Carboxylic acids and alcohols (continued)...
Ex: Pivampicillin, talampicillin and bacampicillin are prodrugs
of ampicillin.
The absorption of these prodrugs is nearly complete (98-99%)
whereas that of ampicillin is < 50%.
Enalapril, the most widely prescribed ACE inhibitor, is the ethyl
ester prodrug of the active diacid, enalaprilat.
Enalaprilat is poorly absorbed from the gastrointestinal tract (<
10%), but absorption of the prodrug enalapril is greatly improved
(60%).

10. 2. Amines.
Due to high chemical stability of amide linkage and lack of
amidase enzymes, amines are not derivatised to amide prodrugs.
A more common approach has been to utilize mannich bases as a
prodrug form of the amines.

11. 3. Azo Linkage
Amines are derivatised to azolinkage prodrugs.
Ex: Prontosil

12. 4. Carbonyl compounds
Carbonyl compounds such as aldehydes and ketones are
converted to prodrugs.
These have generally involved derivatives in which the sp2
hybridized carbonyl carbon is converted to an sp3 hybridised
carbon attached to two heteroatoms such as oxygen, nitrogen, or
sulfur.
Ex: Methenamine releases HCHO in the urine, which acts as an
antibacterial agent.

13. Developments of Prodrugs
1. To improve patient acceptance:
Clindamycin has bitter taste. It was found that by increasing the
chain-length of 2-acylesters of clindamycin, the taste improved
from bitter to non-bitter taste (phosphate ester).
2. To reduce gastric irritation:
Several drugs (NSAIDS, nicotinic acid, kanamycin,
diethylstilboestrol) cause irritation and damage to gastric
mucosa.
These problems of drugs can be overcome by changing to
prodrugs.
Ex. : Salicylic acid to aspirin, nicotinic acid to nicotinic acid
hydrazide

14. Developments of Prodrugs (continued)…
3. To improve chemical stability:
Several drugs may decompose during their shelf life or in the GIT
when used orally.
The prodrug approach of such drugs is a good technique to
improve stability.
Ex. : Azacytidine in aqueous solution is readily hydrolyzed but its
bisulphite prodrug is stable.
4. Prodrugs for increased water solubility:
Prednisolone and methylprednisolone are poorly water-soluble
corticosteroid drugs.
Prednisolone phosphate is a water-soluble prodrug of
prednisolone that is activated in vivo by phosphatases.

15. Developments of Prodrugs (continued)…
5. To decrease drug’s toxicity and adverse effects:
Dipivaloylepinephrine prodrug instead of epinephrine to treat
glaucoma.
Esterification of aspirin greatly suppresses gastric uterogenic
activity.
6. To improve membrane transport:
Barbiturates are weakly acidic in nature and are converted to the
corresponding sodium salt. The sodium salt is extensively
employed for intravenous anaesthetic properties.
Dopamine used for the treatment of Parkinson’s disease can be
improved by administering its prodrug Levo-DOPA.

16. Developments of Prodrugs (continued)…
7. Prolonged Activity:
Nordazepam, an anxiolytic loses activity too quickly due to
metabolism and excretion.
A prodrug introduced to improve the retention characteristics is
(diazepum).
8. Tissue specific prodrug design:
The site-specific drug delivery can be achieved by the tissue
activation, which is the result of an enzyme unique to the tissue
or present in higher concentration.
Dexamethasone is absorbed efficiently in intestinal tract and as
such do not reach colon area for treatment.
when prodrugs dexamethasone-21-β-glucoside were used they
were absorbed in colon more efficiently compared to their parent
drugs.