Biomedical Engineering Reference
In-Depth Information
Evaluation of
N
-Mannich bases as potential prodrugs for NH-acidic drugs offers considerable room
for the design of appropriate characteristics with respect to lipophilicity, aqueous solubility, and bio-
logical half-life (
t
1/2
). This is achieved by proper selection of p
K
a
and substituent pattern (R
1
and R
2
in
Figure 9.4b) of the attached amino moiety as the rate of biotransformation is controlled by both the
p
K
a
and the sterical hindrance caused by substituents connected to the amino moiety.
Nonenzymatic catalyzed bioconversion of prodrugs has the advantage that physicochemical
properties such as pH in the bloodstream is predictable and show low interindividual variability
leading to predictable and reliable conversion of the prodrug
in vivo
.
On the other hand, it should be noted that such prodrugs possess an inherent drawback in that
incorporation of a chemically labile function may lead to formulation stability problems and,
consequently, to reduced shelf-life. An elegant solution to this problem is the double-prodrug
concept where an enzymatic-mediated transformation is combined with a subsequent spontane-
ous reaction releasing the active parent drug.
An example of this is the protection by acylation of very labile
N
-hydroxyalkyl derivatives of
NH-acidic drugs with p
K
a
values below approximately 11 (
t
1/2
< 1 min at 37°C and pH 7.4) as illus-
trated in Figure 9.6. After enzymatic cleavage of the ester function the highly unstable
N
-hydroxyalkyl
intermediate is rapidly converted into the parent HN-acidic drug molecule.
O
O
+
DRUG
C
NH
CH
2
OH
DRUG
C
NH
2
CH
2
O
(a)
O
O
+
DRUG
C
NH
CH
2
NR
1
R
2
DRUG
C
NH
2
CH
2
O
+
HNR
1
R
2
(b)
FIGURE 9.4
Schematic examples of prodrugs designed to undergo spontaneous nonenzymatic transformation.
CH
3
CH
2
CH
3
CH
3
CH
2
CH
3
N
N
+
ROH
O
N
O
O
N
OR
HO
Pilocarpic acid ester
Pilocarpine
FIGURE 9.5
Pilocarpic acid ester prodrug cyclization into pilocarpine.
O
O
R
1
R
1
Enzyme
+
N
CH
O
C
R
2
N
CH
OH
HO
C
R
2
N
-Acyloxyalkyl prodrug
N
-Hydroxyalkyl intermediate
Spontaneous (fast)
R
1
+
NH
HC
O
Drug
FIGURE 9.6
The double-prodrug principle.
