Bioisosterism in Medicinal Chemistry

This chapter provides an overview of the history of bioisosterism from its begiim-ing in the early twentieth century to the present day. We also provide an overview of the importance of judicious bioisosteric replacement in lead optimization to assist in the path toward a viable clinical candidate and, ultimately, a drug. 

James Moir [1] first considered isosterism in all but name, in 1909. It was not until 1919 that the term isosterism was given to this phenomenon by Irving Langmuir [2] in his landmark paper Isomorphism, isosterism and covalence. The focus of this 

Bioisosteres in Medicinal Chemistry, First Edition. Edited by Nathan Brown 

However, Langmuir identified one distinct property that is substantially different between nitrous oxide and carbon dioxide, the freezing point —102 and —56°C, respectively. Evidence for this was assumed to be due to the freezing point being abnormally sensitive to even slight differences in structure.  

With this observation of the correlation between the structure and arrangement of electrons with physical properties, Langmuir defined the neologism calling them isosteres, or isosteric compounds. Langmuir defined isosterism as follows  

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BIOSTER a database of bioisosteres and bioanalogues, in Bioisosteres in Medicinal Chemistry, vol. 54 (ed. N. Brown), Wiley-VCH Verlag GmbH, Weinheim, pp. 55-74. 

Bioisosteric relations constitute one of the more familiar tools in medicinal chemistry. There are thus sets of atoms that can often be interchanged without much... 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

Thiophene-containing molecules can be found in both natural products and synthetic chemotherapeutics. Bithiophene 1, a naturally occurring nematocide, is isolated from the roots of Echinops spaerocephalus, whereas tiaprofenic acid, an anti-inflammatory agent, is a synthetic thiophene derivative. Moreover, thiophene is a useful template for four-carbon homologation via reduction [1], as well as a bioisostere of the benzene ring and other heterocycles in medicinal chemistry. 

Furan-containing molecules are found in both natural products and pharmaceuticals. At one time, furfural was produced in great quantities from corncobs. Perillene, a secondary plant metabolite, is an example of naturally occurring furans. Furan is frequently used as a bioisostere of a benzene ring in medicinal chemistry. For example, Ranitidine (Zantac) marketed by Glaxo was one of the first blockbuster drugs with annual sales over 1 billion dollars. 

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). 

Bioisosteric substitutions are a commonly used strategy in medicinal chemistry drug design as an approach to enhance the desired biological or physical... 

The phenothiazines and thioxanthenes have the characteristic of two phenyl groups fused to a central six-member ring giving a so-called 6-6-6 system. An ethylene is a commonly used bioisostere for a thio linkage in medicinal chemistry. Continued research in... 

The nse of the word isosterism has been largely taken beyond its original meaning when employed in medicinal chemistry and Thomber " proposes a loose and flexible definition of the term bioisostere ... 

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