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

Abstract
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 ClogP 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.
AuthorsHai Yuan, Richard B Silverman
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 17 Issue 6 Pg. 1651-4 (Mar 15 2007) ISSN: 0960-894X [Print] England
PMID17267220 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • (1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid
  • Carboxylic Acids
  • Cyclopentanes
  • Enzyme Inhibitors
  • Proline
  • 4-Aminobutyrate Transaminase
Topics
  • 4-Aminobutyrate Transaminase (antagonists & inhibitors)
  • Carboxylic Acids (chemical synthesis, pharmacology)
  • Chemical Phenomena
  • Chemistry, Physical
  • Cyclopentanes (chemical synthesis, pharmacology)
  • Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Kinetics
  • Proline (analogs & derivatives)
  • Structure-Activity Relationship

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