Synthesis of Cyclopropane Isosteres of the Antiepilepsy Drug Vigabatrin and Evaluation of their Inhibition of GABA Aminotransferase

Abstract

The antiepilepsy drug vigabatrin (1; 4-aminohex-5-enoic acid; γ-vinyl GABA) is a mechanism-based inactivator of the pyridoxal 5'-phosphate (PLP)-dependent enzyme γ-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.

Key Words:

• GABA
• GABA-AT
• Vigabatrin
• γ-Aminobutyric acid aminotransferase
• γ-Aminobutyric acid