Chemistry Reference
In-Depth Information
SUCCESSFUL EXAMPLES OF BIOISOSTERIC REPLACEMENTS IN
DRUG DESIGN
There are innumerous examples of successful drugs already introduced in the
clinical practice that are derivatives of other drugs or bioactive molecules, where
the implementation of bioisosteric replacements were a key step during their
design. One example is the development of clorpropamide from tolbutamide,
where the change of only one substituent led to a drug with better pharmaceutical
profile. Tolbutamide (Fig.
12
) is a first generation potassium channel blocker that
stimulates the secretion of insulin by the pancreas and is used in the treatment of
type II diabetes. Tolbutamide has a short time of action due to the fast metabolism
of the benzilic carbon of its structure. This led to the development of
clorpropramide (Fig.
12
), a tolbutamide derivative, where the methyl radical of
the aromatic ring was substituted by a chlorine, thus avoiding the CYP-450
oxidation of this methyl and making the Clorpropramide a drug with prolonged
time of action [40, 48].
Figure 12:
Structures of potassium channel blockers Tolbutamide and Clorpropramide.
Celecoxib (Fig.
13
) was the first anti-inflammatory drug with selective inhibitory
activity over COX-2 (cycloxigenase-2). It has low penetration on the BBB (Brain
Blood Barrier), presenting a Brain/Plasma ratio of 0.1 and, consequently, low
activity in inflammatory processes on the central nervous system (CNS). The
Brain/Plasma ratio is improved to 0.8 mainly by the introduction of a methyl
sulfone on Refecoxib (Fig.
13
), a less polar bioisoster of the original sulfonamide
present at celecoxib, allowing a higher penetration trough the BBB and a better
activity against inflammatory processes in the CNS [49].
