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Synthesis and biological evaluation of 4-fluoroproline and 4-fluoropyrrolidine-2-acetic acid derivatives as new GABA uptake inhibitors
{Author}: Weiping Zhuang；Xueqing Zhao；Gang Zhao；Lihe Guo；Yunyang Lian；Jingming Zhou；Dongsheng Fang*
{Journal}: Bioorganic & Medicinal Chemistry
{Year}: 2009
{Volume}: 17
{Issue}: 18
{Pages}: 6540-6546
{Keywords}:GABA uptake inhibitor；GAT-1；4-Fluoropyroline；4-Fluoropyrrolidine-2-acetic acid
{Abstract}: Preparation for the N-alkylated derivatives of enantiomerically pure (2 S )-4-fluoroproline and (2 S )-4-fluoropyrrolidine-2-acetic acid is described. The final compounds were evaluated as potential GAT-1 uptake inhibitors via cultured cell lines expressing mouse GAT-1. Compared with their corresponding 4-hydroxy compounds, these derivatives exhibited slight improvement on their inhibitory potency, but still much weaker than their corresponding compounds with no substituents at the C-4 of the pyrrolidine moiety, with the most potent affinity being about 1/15 fold as that of Tiagabine. The drastic decrease of their affinity may arise from sharp reduction of their basicity due to strong inductive effect of the 4-fluorine. However the configuration of the C-4 linking fluorine did not have much influence on their affinity for GAT-1.
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