Journal of Medicinal Chemistry 1999-01-28

2,6-Difluorophenol as a bioisostere of a carboxylic acid: bioisosteric analogues of gamma-aminobutyric acid.

J Qiu, S H Stevenson, M J O'Beirne, R B Silverman

Index: J. Med. Chem. 42(2) , 329-32, (1999)

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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.