Biomedical Engineering Reference
In-Depth Information
I.5.3.1 Bioisosterism
In the broadest sense of the term, bioisosteres are dei ned as functional groups or molecules that
produce a similar biological effect. The tactics of bioisosterism, also named molecular mimicry, has
been extensively used by medicinal chemists in the optimization of drug molecules pharmacody-
namically or pharmacokinetically.
Bioisosteres have been classii ed as either classical or nonclassical. In classical bioisosterism,
similarities in certain physicochemical properties have enabled investigators to successfully exploit
several monovalent isosteres. These can be divided into the following groups: (1) l uorine versus
hydrogen replacements; (2) amino-hydroxy interchanges; (3) thiol-hydroxyl interchanges; (4) l uorine,
hydroxyl, amino, and methyl group interchanges (Grimm's hydride displacement law, referring to the
different number of hydrogen atoms in the isosteric groups to compensate for valence differences).
The nonclassical bioisosteres include all those replacements that are not dei ned by the classical
dei nition of bioisosteres. These isosteres are capable of maintaining similar biological activity by
mimicking the spatial arrangement, electronic properties, or some other physicochemical properties
of the molecule or functional group that are of critical importance. The concept of nonclassical bio-
isosterism, in particular, is often considered to be qualitative and intuitive, but there are numerous
examples of effective use of this concept in drug design (Chapters 15 and 16).
The conversion of the muscarinic acetylcholine receptor agonist arecoline, containing a hydrolyz-
able ester group, into different hydrolysis-resistant heterocyclic bioisosteres is illustrated in Figure I.5.
The annulated (I.1) and nonannulated (I.2 and I.3) bicyclic bioisosteres are potent muscarinic agonists.
Similarly, compounds I.4 and I.5 interact potently with muscarinic receptors as agonists, whereas
I.6, in which the 1,2,4-oxadiazole ester bioisosteric group of I.4 is replaced by an oxazole group, shows
reduced muscarinic agonist effects. Thus, the electronic effects associated with these heterocyclic
rings appear to be essential for muscarinic activity.
It must be emphasized that a bioisosteric replacement strategy, which has been successful for a
particular group of pharmacologically active compounds, cannot necessarily be effectively used in
other groups of compounds active at other pharmacological targets.
I.5.3.2 Stereochemistry
Receptors, enzymes, and other pharmacological targets, which by nature are composed of protein
constructs, are highly chiral. Thus, it is not surprising that chirality in the drug structures normally
plays an important role in pharmacological responses (Chapter 5). In racemic drug candidates, the
O
N
N
N
O
O
N
N
CH
3
N
CH
3
CH
3
O
N
O
O
CH
3
N
N
N
N
CH
3
CH
3
CH
3
CH
3
Arecoline
I.1
I.2
I.3
CH
3
CH
3
CH
3
N
N
N
N
N
O
O
S
N
N
N
CH
3
CH
3
CH
3
I.4
I.5
I.6
FIGURE I.5
Arecoline and analogues.
