Medicinal Chemistry

between 1.5 and 3.0; in accord with these requirements, the molecule should not be too
polar, probably having no charged groups and fewer than three hydrogen-bonding
donors or acceptors.
The second route for traversal across the BBB is by active transport. This is an energy-
dependent process whereby a protein carrier physically shuttles the drug molecule across
the BBB. There are a number of molecular substrates that the brain requires for its nor-
mal functioning; these substances are not biosynthesized within the brain and are not able
to enter the brain by passive diffusion. Because of their importance to normal brain neu-
rochemistry, evolution has resulted in the existence of protein carriers to transport them
into the brain. D-glucose and L-phenylalanine are two such molecules, and there are a
number of others. Therefore, if a drug is designed as a structural analog of D-glucose or
L-phenylalanine, there is a possibility that it will be actively transported across the BBB.

3.5.3 Prodrug and Softdrug Design Considerations

Sometimes, ADME considerations can be used to the advantage of the drug designer.
This is particularly true when applied to the concept of a prodrug.A prodrug is a drug
molecule that is biologically inactive until it is activated by a metabolic process. The
active compound is released as a metabolite.
The purpose of a pro-drug can be to:

1. Increase or decrease the metabolic stability of a drug


2. Interfere with transport characteristics

154 MEDICINAL CHEMISTRY

Figure 3.9 The blood–brain barrier (BBB) is a major impediment to the delivery of drugs to the
brain. In the brain, in order for a drug molecule to leave a capillary and successfully journey to a
neuronal receptor, it must traverse multiple barriers. The walls of capillaries in the brain are dif-
ferent from those in non-brain tissues. Tight junctions prevent the drugs from readily crossing the
capillary. Next, in the brain, another type of cell, called an astrocyte, forms an additional barrier
that must be traversed. Astrocytes are not present outside of the brain.