Carboxylic acid (bio)isosteres in drug design

Abstract

The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biological membranes. To avoid some of these shortcomings while retaining the desired attributes of the carboxylic acid moiety, medicinal chemists often investigate the use of carboxylic acid (bio)isosteres. The same type of strategy can also be effective for a variety other purposes, for example, to increase the selectivity of a biologically active compound or to create new intellectual property. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context (i.e., the characteristic properties of the drug and the drug-target). As a result, screening of a panel of isosteres is typically required. In this context, the discovery and development of novel carboxylic acid surrogates that could complement the existing palette of isosteres remains an important area of research. The goal of this Minireview is to provide an overview of the most commonly employed carboxylic acid (bio)isosteres and to present representative examples demonstrating the use and utility of each isostere in drug design.

Figure 1

Representative examples of a) acyclic and b) cyclic carboxylic acid bioisosteres and their corresponding predicted logD values as determined using Pipeline Pilot version 8.0 (Accelrys, Inc., San Diego, USA).

Figure 2

The structures of GABA, glutamic acid and selected analogues.

Figure 3

Biologically active thiazolidinedione-containing compounds.

Figure 4

Examples of 3-hydroxyisoxazoles.

Figure 5

2,6-Difluorophenol-containing GABA aminotransferase inhibitors.

Figure 6

Schematic representation of hydrogen-bonding interactions of carboxylic acid 64 and hydroxyquinolin-2-one 65 within the binding site of d-amino acid oxidase.

Scheme 1

Deprotonation equilibrium of hydroxamic acid, and the tautomerisation between the N and O anion.

Scheme 2

Structure of carboxylic acid bioisosteres based on fluorinated alcohol and ketones. In the latter case, it is the hydrate form, which is present under physiological conditions, that is bioisosteric with the carboxylic acid moiety.

Scheme 3

Tautomers of 5-substituted tetrazoles.

Scheme 4

Cytochrome P450-mediated oxidation and ring opening of the thiazolidinedione heterocycle.

Scheme 5

Squaric acid (59), squaramide (60), and the general structures of related compounds.

Scheme 6

The keto-enol tautomerisation of tetronic (71) and tetramic (72) acids.

Scheme 7

Enol-ketone tautomers of cyclopentane-1,3-dione 74.

Scheme 8

The four possible tautomers (A–D) of sulfonimidamide 92.