Carboxylic esters bioisosteres

Carboxylic esters are often unstable in vivo consequently many different bioisosteres for this functional group have been tried, most of them being small heterocycles. For a series of CDK2 inhibitors like 4 (Figure 8.10) this problem could be overcome through the use of an... 

Theme 2 recognizes carboxylic acids or bioisosteres of them. There is, however, a gradation of properties of this Motif that range from charged anionic carboxylate-like to uncharged ester-like with an intermediate... 

Hudzinski, P, Evrard, D. A., Bloomquist, W. E., Lacefield, W. B. Indazoles as indole bioisosteres synthesis and evaluation of the tro-panyl ester and amide of indazole-3-carboxylate as antagonists to the serotonin 5HT3 receptor. J. Med. Chem. 1987, 30, 1535—1537. 

The prototypical representatives of the group are the carboxylic acids. However, a huge number of bioisosteres such as sulfonic or phosphonic acids, tetrazoles or 3-hydrox-yisoxazoles are available (see Chapter 15). In addition functions like esters, amides, peptides, aldehydes, primary alcohols and related functions can work as prodrugs or bioprecursors (see Chapter 36). 

The oxyacetic acid residue of the monoxacetams is bioisosteric with the sulfate moiety of the monosulfactams. In addition, the presence of the carboxylate moiety provided opportunity for the preparation of esters that could act as orally absorbed prodrugs. Based on structure-activity relationships, SQ 82,291 (45) [90898-90-1]y C12H15N506S, the nonacidic methoxime side chain of which was necessary to maintain oral absorption of the prodrugs, was prepared. SQ 82,291 has a high, specific affinity for the PBP-3 transpeptidase of gram-negative bacteria. However, it lacks the isobutyric acid moiety of aztreonam (17) on the oxime residue and whereas the activity of SQ 82,291 vs the Enterobacteriaceae was maintained, antipseudomonal activity was significandy diminished (37). 

Figure 8.10 Some bioisosteric replacements for carboxylic acids (top) (Carini, D.J., et al. Nonpeptide angiotensin II receptor antagonists The discovery of a series of A-(Biphenylmethyl) imidazoles as potent, orally active antihypertensives. J. Med. Chem. 1991, 34, 2525-2547), esters (middle) (Kim, K.S., et al. Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2 Synthesis, X-ray crystallographic analysis, and biological activities. /. Med. Chem. 2002, 45, 3905-3927.), and amides (bottom) (Black, W.C., et al. Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K. Bioorg. Med. Chem. Lett. 2005,15,4741 744.) The clinical candidate odanacatib (bottom right) incorporates a trifluoroethylamine amide isostere. (Gauthier, J.Y., et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 2008,18,923-928.)...

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