Carboxylic acid (bio)isosteres in drug design.
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.
Department of Chemistry, University of Pennsylvania, 231 South 34th St., Philadelphia, PA 19104, USA. bcarlo@sas.upenn.edu
Carlo
C
Ballatore
Donna M
DM
Huryn
Amos B
AB
Smith
D001393:Azoles / Q000737:chemistry / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D005663:Furans / Q000737:chemistry / Q000378:metabolism; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism; D007659:Ketones / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D010757:Phosphorous Acids / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism; D013451:Sulfonic Acids / Q000737:chemistry / Q000378:metabolism
D001393:Azoles; D002264:Carboxylic Acids; D005663:Furans; D006877:Hydroxamic Acids; D007659:Ketones; D010757:Phosphorous Acids; D013449:Sulfonamides; D013451:Sulfonic Acids; C570063:phosphonic acid; C003422:tetronic acid