Prodrugs
© Oldřich Farsa 2011
Prodrugs
● inactive compounds that yield an active compound in the body
● this conversion is frequently carried out by enzyme-controlled
methabolic reactions and less frequently by non-enzymatic
chemical reactions within the body
● prodrugs are used as a way to:
● increase lipid or water solubility
● improve the taste of a drug to make it more patient
compatible
● alleviate pain when the drug is administered parenterally by
injection
● reduce toxicity
● increase chemical stability
● change the length of the time of duration of action
● deliver the drug to a specific site in the body
Bioprecursor prodrugs are compounds that already contain the embryo of the active species
within their srtucture. They rely on metabolism to produce the active compound.
N
N
S
NH2
OO
NH2
NH2
NH2
S
NH2
O O
NH2
NH2
NH2
4-(2,4-diaminophenylazo)benzenesulphonamide
metabolic reduction
+
4-aminobenzenesuphonamide
sulphanilamide
1,2,4-triaminobenzene
Prontosil(s)
Prontosil album
(antimicrobial)
1935 Jacques and
Therése Tréfoule:
sulphanilamide is the
active compound
Prontosil rubrum (inactive)
●prepared 1932 by Mietsch and
Klarer
●Gerhard Domagk: active against
streptococci
Carrier prodrugs differ from bioprecursor prodrugs in that they are formed by combining an
active drug with a carrier species to form a compound with the desired chemical and
biological characteristics.
O S
N
O
O NH2
O
O
HH
O
N
H
O
N
O
CH3
O
CH3
CH3
O
O S
N
OH
O NH2
O
O
HH
O
N
H
O
N
O
CH3
H2O
- CH3CHO
- CH3COOH
cefuroxim axetil
Zinnat ®
●
higher lipohilicity ⇒ improved
permeation through GIT mucosa
cefuroxim
An example: cefalosporine antibiotics
An example of a bioprecursor prodrug activated by oxidation:
antineoplastic cyclophosphamide
N
Cl
Cl
P
O
N
H O
NH
Cl
P
O
N
H O +
H
Cl
O
N
Cl Cl
PNH2 O
OH
phosphoramide mustard
(active antineoplastic)
cyclophosphamide
(inactive)
liver
CYP-
450
inactive
desmethylated
product
N
N
N
H
N
S
NNCH3
NO2
N
N
N
H
N
SH
NN
CH3
NO2
metabolism
+
Antineoplastics: azathioprin – an example of a bioprecursor prodrug
azathioprin
6-mercaptopurine
chloramphenicol sodium succinate
Chloramphenicoli natrii succinas PhEur
Chloramphenicol®
ICN plv. inj. sol.
●
injection administration
chloramphenicol palmitate
Chloramphenicoli palmitas PhEur
nearly insoluble in water, bitter taste
suppressed
●esters are hydrolyzed to parent chloramphenicol by esterases
O
NH
O
N
+
O
OO
Cl Cl
R
1
R
2
O
O
O
Na
+ H
CH3
O
H
O
O
O
Na
+
H
R1
R2
nebo
Examples of carrier produgs: chloramphenicol prodrugs optimized for a particular route of
administration