Synthesis and evaluation of mono-, di-, and trifluoroethenyl-GABA derivatives as GABA-T inhibitors.
The syntheses of four derivatives of gamma-vinyl-GABA, in which vinylic hydrogen atoms were replaced by fluorine, are described. With use of 5-ethenyl-2-pyrrolidinone as starting material, the E and Z isomers of 4-amino-6-fluoro-5-hexenoic acid were prepared. The 6,6-difluoro and 5,6,6-trifluoro analogues could be synthesized from 4-oxobutanoic acid tert-butyl ester and (2,2-difluoroethenyl)- and (trifluoroethenyl)lithium correspondingly. The compounds were tested as inhibitors of GABA-T, and their in vitro and in vivo biochemistry is reported. The most active derivative was (Z)-4-amino-6-fluoro-5-hexenoic acid; the structure-activity relationship in the series is discussed.
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000201:enzymology; D018756:GABA Antagonists; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011817:Rabbits; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013552:Swine; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives*
D018756:GABA Antagonists; D006845:Hydrocarbons, Fluorinated; D007202:Indicators and Reagents; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase