Fluorinated conformationally restricted gamma-aminobutyric acid aminotransferase inhibitors.
On the basis of the structures of several potent inhibitor molecules for gamma-aminobutryric acid aminotransferase (GABA-AT) that were previously reported, six modified fluorine-containing conformationally restricted analogues were designed, synthesized, and tested as GABA-AT inhibitors. The syntheses of all six molecules followed from a readily synthesized ketone intermediate. Three of the molecules were found to be irreversible inhibitors of GABA-AT with comparable or larger k(inact)/K(I) values than that of vigabatrin, a clinically used antiepilepsy drug, and the other three were reversible inhibitors. A possible mechanism for inactivation by one of the inactivators is proposed.
Lu
Hejun
H
Department of Chemistry, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, Illinois 60208-3113, USA.
Silverman
Richard B
RB
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry; D005461:Fluorine; D006536:Heptanes / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D020888:Vigabatrin / Q000737:chemistry
D000927:Anticonvulsants; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003517:Cyclopentanes; D006536:Heptanes; D005461:Fluorine; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin