Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent gamma-aminobutyric acid aminotransferase inhibitor.
Previously it was found that a conformationally rigid analogue (2) of the epilepsy drug vigabatrin (1) did not inactivate gamma-aminobutyric acid aminotransferase (GABA-AT). A cyclic compound with an exocyclic double bond (6) was synthesized and was found to inactivate GABA-AT, but only in the absence of 2-mercaptoethanol. The corresponding difluoro-substituted analogue (14) was synthesized and was shown to be a very potent time-dependent inhibitor, even in the presence of 2-mercaptoethanol.
Pan
Yue
Y
Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, USA.
Qiu
Jian
J
Silverman
Richard B
RB
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D005461:Fluorine; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D020888:Vigabatrin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
C480544:3-amino-4-(difluoromethylidene)cyclopentanecarboxylic acid; D000596:Amino Acids; D003517:Cyclopentanes; D005461:Fluorine; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin