Synthesis of cyclopropane isosteres of the antiepilepsy drug vigabatrin and evaluation of their inhibition of GABA aminotransferase.
The antiepilepsy drug vigabatrin (1; 4-aminohex-5-enoic acid; gamma-vinyl GABA) is a mechanism-based inactivator of the pyridoxal 5'-phosphate (PLP)-dependent enzyme gamma-aminobutyric acid aminotransferase (GABA-AT). Inactivation has been shown to proceed by two divergent mechanisms (Nanavati, S. M. and Silverman, R. B. (1991) J. Am. Chem. Soc. 113, 9341-9349), a Michael addition pathway (Scheme 2, pathway a) and an enamine pathway (Scheme 2, pathway b). Analogs of vigabatrin with a cyclopropyl or cyanocyclopropyl functionality in place of the vinyl group (2-5) were synthesized as potential inactivators of GABA-AT that can inactivate the enzyme only through a Michael addition pathway, but they were found to be only weak inhibitors of the enzyme.
Wang
Zhiyong
Z
Department of Chemistry, Northwestern University, Evanston, IL 60208-3113, USA.
Silverman
Richard B
RB
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D013237:Stereoisomerism; D020888:Vigabatrin / Q000737:chemistry* / Q000494:pharmacology
D000927:Anticonvulsants; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin