Bioisosterism

In the broadest sense of the term, bioisosteres are defined 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 classified 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) fluorine versus hydrogen replacements; (2) amino-hydroxy interchanges; (3) thiol-hydroxyl interchanges; (4) fluorine, 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 defined by the classical definition 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.

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