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

J Med Chem. 1999 Jan 28;42(2):329-32. doi: 10.1021/jm980435l.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-Aminobutyrate Transaminase / antagonists & inhibitors
  • Animals
  • Brain / enzymology
  • Carboxylic Acids / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Phenols / chemistry
  • Phenols / pharmacology*
  • Swine
  • gamma-Aminobutyric Acid / analogs & derivatives*

Substances

  • Carboxylic Acids
  • Enzyme Inhibitors
  • Phenols
  • 2,6-difluorophenol
  • gamma-Aminobutyric Acid
  • 4-Aminobutyrate Transaminase