Structural modifications of (1S,3S)-3-amino-4-difluoromethylene-cyclopentanecarboxylic acid, a potent irreversible inhibitor of GABA aminotransferase

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:17

Article

Yuan, Hai ; Silverman, Richard B.

关键词: gamma-aminobutyric acid;    GABA;    GABA aminotransferase;    enzyme inactivator;    tetrazole isostere;    lipophilicity;   

DOI  :  10.1016/j.bmcl.2006.12.119

来源: Elsevier

【 摘 要 】

Low brain levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) lead to convulsions. Inhibition of GABA aminotransferase increases the concentration of GABA and can terminate the convulsions. Earlier we reported the synthesis of (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid (2), which is 186 times more potent an inactivator of GABA aminotransferase than the epilepsy drug S-vigabatrin. The corresponding dichloromethylene analogue of 2 (compound 3) has been made, but it shows only weak reversible inhibition of GABA aminotransferase. However, the tetrazole isostere of 2 (compound 4) has been found to be a time-dependent inactivator of GABA aminotransferase. Although it is 20 times less potent than carboxylic acid 2, it is 2.5 times more potent than S-vigabatrin. A calculation of the Clog P values indicates that 4 is the most lipophilic of the three, being 69 times more lipophilic than 2 and 55 times more lipophilic than S-vigabatrin, indicating potential for improved bioavailability. (c) 2007 Elsevier Ltd. All rights reserved.

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