2,6-Difluorophenol as a Bioisostere of a Carboxylic Acid:  Bioisosteric Analogues of γ-Aminobutyric Acid

Journal of Medicinal Chemistry
1999.0

Abstract

3-(Aminomethyl)-2,6-difluorophenol (6) and 4-(aminomethyl)-2, 6-difluorophenol (7) were synthesized in eight and four steps, respectively, starting from 2,6-difluorophenol, to test the potential of the 2,6-difluorophenol moiety to act as a lipophilic bioisostere of a carboxylic acid. Compounds 6 and 7 are potential bioisosteric analogues of gamma-aminobutyric acid (GABA). Substrate studies and inhibition studies were carried out with pig brain gamma-aminobutyric acid aminotransferase; 6 and 7 are very poor substrates, but both inhibit the enzyme, indicating that the 2, 6-difluorophenol moiety appears to be able to substitute for a carboxylic acid to increase the lipophilicity of drug candidates.

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