Classical isostere

The concept of isosterism 481 has been used in medicinal chemistry. Molecules or groups which possess physicochemical similarity (e.g., similarity in size or the number of valence electrons) are called isosteres. The classical isosteres include, for instance, the following two pairs of groups ... 

A traditional isostere, or classical isostere, is an atom or group of atoms with similar spatial requirements (Table 11.4, page 281).10 Exchanging one for another imparts little change on the shape and volume of the molecule and therefore should not affect the binding (pharmacodynamics) of a compound. Changing one isostere for another, however,... 

Table 4.3 Examples of isosteres. Each horizontal row represents a group of structures that are isosteric. Classical isosteres were originally defined by Erlenmeyer as atoms, ions and molecules with identical shells of electrons. Bioisosteres are groups with similar structures that usually exhibit similar biological activities...

Thiocarbapyranoses are a quite rare compound class in the scenario of pyranoid carbasugars, although replacement of a hydroxyl group with a sulfurized moiety is a classical isosteric modification in medicinal chemistry. 

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. 

The substitution of —CH= by —N= in aromatic rings has been one of the most successful applications of classical isosterism (see Section III.D.). Interchange of trivalent atoms are found also in non aromatic rings. For example the 4-dimethylamino-antipyrine and its carba-isostere are about equally active as antipyretics (Figure 15.7). 

Apparently we are dealing here with a classical isosteric series F, Cl, Br, I, but sensitive to steric hindrance in the para position. Probably what happens in vivo, is para-hydroxyla-tion of the benzene ring. The best candidate becomes then the para-fluoro compound, since it is not bulkier than the unsubstituted compound while being biostable. 

The term non-classical isosterism is often used, interchangeably with the term bioisosterism, for example, when one has to deal with isosteres that do not possess the same number of atoms, but which have in common some key parameter of importance for the activity in a given series. Thus, the two GABAergic agonists isoguvacine and THIP (Fig. 13.3) possess similar pharmacological properties to GABA itself. The key parameters in these compounds are... 

The change from ester to amide (procaine — procainamide) has already been illustrated above as an example of classical isosterism. Similarly the lactone ring of the muscarinic agonist pilocarpine was changed into various, still active... 

Figure 2.35 shows an example of classical isosteric substitution of an amino group for a hydroxyl group in folic acid. The amino group is capable of mimicking the tautomeric forms of folic acid and providing the appropriate hydrogen bonds to the enzyme active site. 

It was with Erlenmeyer that the concept of bioisosterism was introduced to differentiate from classical isosteres, ensuring its relevance to medicinal chemistry. The introduction of ring equivalences is significant. This was the formalization of what we consider to be a bioisosteric comparison and is the first definition of most relevance to medicinal chemistry. 

Classical isosteres are traditionally categorized into the following distinct groupings [6] ... 

In extending and broadening the purer rules of classical isosterism, two scientists are credited with progressing the field of bioisosterism Friedman and Thornber. In 1951, Friedman 7] provided the first definition closest to what we call bioisosterism today... 

The first part of this book covers the historical aspects of bioisosterism, from its founding principles of isosterism from Langmuir through defined sets of classical isosteres and bioisosteres, to the potential consequences of bioisosteric replacement in context. 

Isosteres are stmctural elements that are deemed to have more or less equivalent chemical or physical properties, and they have been used extensively in modification of lead compounds in order to enhance dmg action. Table 9.1 shows some classical isosteres. The definition of an isostere is an atom or a group in which the peripheral layers of electrons are identical. However, this definition is not adhered to and, for instance, F is often considered as a substitute for H although it has three lone pairs of electrons in its peripheral layer whereas H does not have any. Thus the strict definition of isosteres quite quickly breaks down and, for instance, benzene can be substituted for by a number of ring types and carbonyl and carboxylate substituted by groups which are not that dose to them in stmcture. Thus isosteric substitution is not an exact science. 

In the case of duloxetme, a benzene ring has been replaced by a thiophene nucleus which is a commonly used approach during the process of lead modification. The number of atoms is not the same hence it may be described as a non-classical isostere The phenoxy group has also been transformed, which provides an example of a ring fusion, resulting in the presence of a naphthalenyl-oxy group. This dmg is non-selective, which makes it a mixed SERT/NAT inhibitor. It is indicated for the treatment of major depression, diabetic neuropathy and urinary incontinence. Duloxetine is used as the (S)-enantiomer hydrochloride salt and is available as capsules (30 mg). A typical adult daily dose for the treatment of major depression and diabetic neuropathy is 60 mg. In case of urinary incontinence, 40 mg twice daily have been recommended. 

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