Bioisosteric replacement of the ester with oxazole and other heteroaryls may not be universally effective, however, as demonstrated in the design and synthesis of a series of highly selective and potent phenylalanine derived CCR3 antagonists as anti-inflammatory agents. While compound 7 was highly effective in blocking both the binding and the functional activity of a number of CCR3 agonists, compound 8 lacks all CCR affinity which suggests a more subtle role for the ester moiety that the heterocycles were unable to mimic (10).
Amide - Bioisosteric replacements for an amide bond have been extensively studied because of their importance in peptide chemistry and the development of peptide mimetics. The most successful replacements were demonstrated in the design and development of HIV-1 protease inhibitors. Several review articles on the replacement of peptide bonds have been published (11,12).
Imidazole- or benzimidazole-derived amide bond replacements were successfully incorporated in the design of HIV-1 and MMP inhibitors (13,14). Recently, this replacement has also been applied to the synthesis of tripeptidyl peptidase II (TPPII) inhibitors. Under physiological conditions, butabindide 9, a potent inhibitor of the serine protease enzyme TPPII, underwent cyclization to form the diketopiperazine 10, which is void of any TPPII enzymatic activity. Bioisostere replacement of the amide moiety in 9 with imidazole generated compound 11 which maintained TPPII inhibitory activity, and avoids of the inherent chemical instability of 9(15).
9 10 11
In the course of searching for high affinity dopamine D3 receptor antagonists, conformatlonally restricted benzamide isosteres, such as pyrroles, oxazoles, and thiazoles were investigated. Replacement of the amide of 12 (sultopride) by a pyrrole ring led to compound 13 which maintained affinity for the dopamine D3 receptor and introduced modest selectivity over the dopamine D2 receptor (16). Replacement of the benzamide with oxazole resulted in compound 14 which exhibits dopamine D3 and dopamine D4 binding affinities comparable to those of the atypical neuroleptics sultopride and clozapine, respectively (17).
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