Bioisostere is defined as substituents or substructures with similar biological properties and chemical and physical similarities.^1,2) This is an established strategy in medicinal chemistry for the design and discovery of new compounds.³⁾ In fact, angiotensin II receptor antagonists for the treatment of hypertension were developed by the introduction of tetrazole structure as carboxyl group bioisostere.⁴⁾

Recently, in addition to classical bioisosteres for carboxyl groups and amide bonds, bioisosteres corresponding to heterocycles and benzene rings have been developed and utilized. Spiro-building blocks containing small rings such as oxetane and azetidine have been used as bioisosteres for morpholine and piperazine, respectively.^5,6) Cubane, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, and bicyclo[3.1 .1]heptane structures have been used as bioisosteres of benzene rings.^7,8) Especially, disubstituted bicyclo[1.1.1]pentanes have been used as para-substituted benzenes,⁹⁾ and bicyclo[2.1.1]hexane and bicyclo[3.1.1]heptane structures have been used as meta-substituted benzene.^10,11) The introduction of these structures is expected to improve water solubility and pharmacokinetics by breaking the planarity due to the improvement of Fsp³.

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Morpholine Bioisostere

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Piperazine Bioisostere

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Benzene Bioisosteres

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para-Disubstituted Benzene Bioisosteres

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meta-Disubstituted Benzene Bioisosteres