Bioisosteres classical

The discovery and development of a candidate for clinical evaluation is a long process that involves small modifications to a lead compound to improve some of its properties, such as pharmacological activity, selectivity, and pharmacokinetics. This is often achieved by the medicinal chemists by replacing a functional group with groups sharing similar physical or chemical properties and maintaining similar activity, which are defined as bioisosteres. We will hereby provide a historical overview of the development and evolution of the concepts of isosterism and bioisosterism, followed by a selection of successful examples of bioisosteric modifications reported in the literature. 

The concept of isosterism was first introduced by Langmuir in 1919 to describe molecules that contain the same number and arrangement of electrons and have similar physicochemical properties [1]. Langmuir identified 21 types of isosteres, a few examples of which are reported in Table 2.1. 

In 1925, Grimm formulated his hydride displacement law, which states that the addition of a hydride to an atom produces a pseudoatom with the same physical properties as those present in the column immediately behind in the periodic table, as shown in Table 2.2 [2]. 

The concept of isosterism was later broadened by Erlenmeyer in 1932 to include elements, ions, or molecules with the same number of electrons at the valence level (Table 2.3) [3]. Erlenmeyer stated that elements in the same column of the periodic table are isosteres among themselves and also introduced the concept of electronically equivalent rings. 

Bioisoster in Medicinal Oicmistry, First Edition. Edited by Nathan Brown 

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The thiocarbonyl group is a classic bioisosteric replacement for the carbonyl group which has been widely exploited in medicinal chemistry. This is illustrated with the preparation of thioketones derived from thiocolchicine283 and isothiocolchicine284 which exhibited high antitubulin activity (equation 38). 

Some non-classical isosteres are reported in Table 15.5 and from a brief glance it can be noticed that they do not obey the steric and electronic definition of classical isosteres. A second notable characteristic of non-classical bioisosteres is that they do not have the same number of atoms as the substituent or moiety for which they are used as a replacement. 

FIGURE 15.10 Ligands for central cholinergic receptors with different non-classical bioisosteres of the pyridine ring. 

Examples from literature show that there are several non-classical bioisosteres for the pyridine system or the pyridazine system. Which is the rationale behind this in order to choose the most appropriate analog to start with An indication could be given by the comparison of the boiling points... 

Functional moieties which either fulfil or satisfy the original conditionalities put forward by Langmuir and Grimm are termed as classical bioisosteres . More explicitely, in animals the occurrence of several hormones, neurotransmitters etc., having almost idential structural features and above all similar biological activities may be classified as bioisosteres. 

Table 2.1. Evidently shows the various classical bioisosteres with their appropriate examples ...

S.No. Types of Classical Bioisosteres Various suitable examples... 

Following are the various salient features of classical bioisosteres ... 

Table 2.9. Classical Bioisosteres (Groups Within the Row Can Replace Each Other)...

Figure 8.8 Classical and non-classical bioisosteres (Reprinted with permission from, Showell, G.A., Mills, J.S. Chemistry challenges in lead optimization Silicon isosteres in drug discovery. Drug Discov. Today, 8, 551-556, copyright 2003, Elsevier.)...

Table 1.3 Some examples of classical bioisosteres - groups in each row are equivalent.

Bioisosterism is a key concept in modern medicinal chemistry. This chapter has provided an in-depth overview of the types of classical bioisosteric replacements with real-world exemplars of successful bioisosteric replacements from the literature. 

Figure 9.2 Structural analogs of classical bioisosteric replacement of antipsychotic drugs.

The only structural difference between these two examples (Fig. 18.19) is represented by the heteroatom which makes them classical bioisosteres since both oxygen and sulphur have the same valence. Both may be classified as mixed 5-HT/NA reuptake inhibitors but replacement of the oxygen atom with sulphur appears to shift the selectivity from NAT to SERT. 

Another interesting and important use of triazoles was in the generation of non-classical bioisosteres of potentially labile groups (ester, amide) with heterocycles capable of mimicking the same electrostatic potential maps [19] (Figure 2.2). 

Figure 2.2 Triazole as a non-classical bioisostere of labile esters.

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