Biomedical Engineering Reference
In-Depth Information
The prodrug approach has been successfully utilized to overcome signii cant barriers for many
drugs aiming
1. To improve the oral bioavailability by increasing aqueous solubility, by increasing biomem-
brane permeability, and/or by improving (metabolic) stability
2. To increase the duration of pharmacological action
3. To decrease toxicity or adverse reactions
4. To obtain drug targeting using site-specii c biotransformation or site specii c transporters
The prodrug approach has been used over a span of more than three decades mainly as a means to
address drugability problems with drugs already introduced to the market. The aim has primarily been
to develop improved versions of such drugs or as a rescue for compounds with drugability problems
in late-stage development; and several drugs have been developed and are used in clinical practice as
prodrugs (e.g., pivampicillin, enalapril, and vanaciclovir). In modern drug design, prodrug strategies
are considered part of the drug discovery effort aiming to expand the chemical space of drugable mol-
ecules and, thus, it can be expected that many future drugs will appear as prodrugs.
The purpose of this chapter is to introduce the reader to the prodrug principle and discuss impor-
tant elements in prodrug strategies within drug discovery and development. Finally, we will provide
examples of achievements offered by prodrugs.
9.3 DESIGN OF PRODRUGS—CHEMICAL CONSIDERATIONS
Prodrugs are most often taken into consideration after identii cation of a pharmacological active
lead compound or structure. Consequently, the i rst step in prodrug design is identii cation of func-
tional groups such as hydroxyl, carboxyl, carbonyl, amide, NH-acidic, and/or amino groups in the
active compound that are available for chemical derivatization. Second, potentially bioreversible
derivatives such as esters,
N
-acyl,
N
-hydroxymethyl, or
N
-acyloxyalkyl derivatives,
N
-Mannich
bases, enaminones, and lactones may be synthesized and subjected to further testing. To this end,
the most important requirement for a prodrug is its ability to adequately regenerate the active drug
in vivo
. In addition to this, it must be chemically stable in the bulk form and together with common
excipients used in drug formulation leading to an acceptable shelf-life and, i nally, the toxicity of the
promoiety and the prodrug itself must be acceptable.
The necessary conversion or activation of the prodrug in the body to the active drug molecule
can take place by both enzymatic- and nonenzymatic-mediated reactions, which is discussed in the
following text.
9.3.1 P
RODRUGS
T
RANSFORMED
BY
E
NZYMATIC
R
EACTIONS
Prodrugs can be designed to target specii c enzymes in the body. This is based upon knowledge
and considerations on enzyme activity, specii city, tissue distribution, and abundance and can be
utilized to obtain the desired ability of a prodrug to overcome one or more barriers to development
of the active drug molecule.
The most common prodrugs are those requiring hydrolytic cleavage mediated by enzymatic
catalysis. Drugs containing hydroxyl, carboxyl, or amino functional groups can be converted into
prodrug esters or amides from which the active forms are readily regenerated by hydrolytic enzymes
such as esterases (see Section 9.4.1.2), amidases, peptidases, or phosphatases (see Section 9.4.1.1)
(Figure 9.3).
Less often prodrugs are designed to undergo reductive or oxidative processes mediated by
enzymes such as cytochrome P450, monoamine oxidases, azoreductases (see Section 9.4.3), or
nitroreductases. A novel prodrug principle (HepDirect
™
) has recently been introduced for highly site-
specii c delivery of phosphate drugs to the liver. These prodrugs consist of cyclic 1,3-propanyl esters
