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4 Design Principles and Development of Prodrugs for Multiply …
4.1 Definitions
The generally accepted definition of a prodrug is the one specified in the glossary
of terms used in medicinal chemistry by Wermuth et al. (1998), as follows:
“A prodrug is any compound that undergoes biotransformation before exhibiting
its pharmacological effects. Prodrugs can also be viewed as drugs containing specialized non-toxic protective groups used in a transient manner to alter or to eliminate
undesirable properties in the parent molecule.”
Thus, according to this definition, a prodrug has no inherent pharmacological
activity but is convertible to a compound or compounds that do. The biotransformations themselves may involve chemical conversion via enzymatic or non-enzymatic
processes.
Prodrugs are then normally classified into two general sub-groups, one designated as carrier-linked prodrugs (carrier prodrugs) and the other as bioprecursor
prodrugs. While a more recent alternative general classification has been proposed
based on whether the bioactivation occurs intracellularly or extracellularly (Zawilska
et al. 2013), the earlier classification, together with the sub-groups, is referred to in
this book as they are considered more useful from a medicinal chemistry design
viewpoint.
4.1.1 Carrier-Linked Prodrugs (Carrier Prodrugs)
Further to the IUPAC glossary of terms, “a carrier-linked prodrug (carrier prodrug)
is a prodrug that contains a temporary linkage to a given active substance with a
transient carrier group that produces improved physicochemical or pharmacokinetic
properties and that can be easily removed in vivo, usually by a hydrolytic cleavage.”
(Wermuth et al. 1998).
Whilst this is a clear general definition, researchers in the field have found it helpful
from the point of view of design parameters to differentiate further sub-divisions of
the carrier prodrug category. Although this adds some complications, such further
systemisation highlights gaps and supports pattern recognition endeavours. Carrierlinked prodrugs or carrier prodrugs can be designed in two parts (bipartite) composed
of one carrier group or promoiety directly attached to the drug or in three parts
(tripartite). In the latter case the carrier group is attached via a linker to the drug with
the linker being the extra part. Further delineation of the carrier prodrug category
(Wermuth et al. 1998; Parajuli et al. 2015; Abet et al. 2017) includes the following
identified sub-groups:
(i) a double prodrug, that is “a biologically inactive molecule which is transformed in vivo in two steps (enzymatically and/or chemically) to the active
species.” (Wermuth et al. 1998). This type of prodrug is also referred to
as a ‘pro-prodrug’ but it should perhaps be named, preferably, as a ‘preprodrug’. This pro-prodrug concept, which was proposed by Bundgaard in
4 Design Principles and Development of Prodrugs for Multiply …
4.1 Definitions
The generally accepted definition of a prodrug is the one specified in the glossary
of terms used in medicinal chemistry by Wermuth et al. (1998), as follows:
“A prodrug is any compound that undergoes biotransformation before exhibiting
its pharmacological effects. Prodrugs can also be viewed as drugs containing specialized non-toxic protective groups used in a transient manner to alter or to eliminate
undesirable properties in the parent molecule.”
Thus, according to this definition, a prodrug has no inherent pharmacological
activity but is convertible to a compound or compounds that do. The biotransformations themselves may involve chemical conversion via enzymatic or non-enzymatic
processes.
Prodrugs are then normally classified into two general sub-groups, one designated as carrier-linked prodrugs (carrier prodrugs) and the other as bioprecursor
prodrugs. While a more recent alternative general classification has been proposed
based on whether the bioactivation occurs intracellularly or extracellularly (Zawilska
et al. 2013), the earlier classification, together with the sub-groups, is referred to in
this book as they are considered more useful from a medicinal chemistry design
viewpoint.
4.1.1 Carrier-Linked Prodrugs (Carrier Prodrugs)
Further to the IUPAC glossary of terms, “a carrier-linked prodrug (carrier prodrug)
is a prodrug that contains a temporary linkage to a given active substance with a
transient carrier group that produces improved physicochemical or pharmacokinetic
properties and that can be easily removed in vivo, usually by a hydrolytic cleavage.”
(Wermuth et al. 1998).
Whilst this is a clear general definition, researchers in the field have found it helpful
from the point of view of design parameters to differentiate further sub-divisions of
the carrier prodrug category. Although this adds some complications, such further
systemisation highlights gaps and supports pattern recognition endeavours. Carrierlinked prodrugs or carrier prodrugs can be designed in two parts (bipartite) composed
of one carrier group or promoiety directly attached to the drug or in three parts
(tripartite). In the latter case the carrier group is attached via a linker to the drug with
the linker being the extra part. Further delineation of the carrier prodrug category
(Wermuth et al. 1998; Parajuli et al. 2015; Abet et al. 2017) includes the following
identified sub-groups:
(i) a double prodrug, that is “a biologically inactive molecule which is transformed in vivo in two steps (enzymatically and/or chemically) to the active
species.” (Wermuth et al. 1998). This type of prodrug is also referred to
as a ‘pro-prodrug’ but it should perhaps be named, preferably, as a ‘preprodrug’. This pro-prodrug concept, which was proposed by Bundgaard in