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Bioorg Med Chem. 2013 Feb 15;21(4):903-11. doi: 10.1016/j.bmc.2012.12.009. Epub 2012 Dec 20.

Probing the steric requirements of the γ-aminobutyric acid aminotransferase active site with fluorinated analogues of vigabatrin.

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  • 1Department of Chemistry, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.


We have synthesized three analogues of 4-amino-5-fluorohexanoic acids as potential inactivators of γ-aminobutyric acid aminotransferase (GABA-AT), which were designed to combine the potency of their shorter chain analogue, 4-amino-5-fluoropentanoic acid (AFPA), with the greater enzyme selectivity of the antiepileptic vigabatrin (Sabril®). Unexpectedly, these compounds failed to inactivate or inhibit the enzyme, even at high concentrations. On the basis of molecular modeling studies, we propose that the GABA-AT active site has an accessory binding pocket that accommodates the vinyl group of vigabatrin and the fluoromethyl group of AFPA, but is too narrow to support the extra width of the distal methyl group in the synthesized analogues.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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