New substrates and inhibitors of gamma-aminobutyric acid aminotransferase containing bioisosteres of the carboxylic acid group: design, synthesis, and biological activity.
A series of potential substrates of gamma-aminobutyric acid aminotransferase (GABA-AT) with lipophilic bioisosteres of the carboxylic acid group (2-7) were synthesized and tested. Most of the synthesized compounds showed substrate activities with GABA-AT; 1H-tetrazole-5-propanamine (6) was the best of those tested. The potential time-dependent inhibitor of GABA-AT, 1H-tetrazole-5-(alpha-vinyl-propanamine) (8), was designed based on the structures of 6 and the antiepilepsy drug vigabatrin (4-aminohex-5-enoic acid, 1). The synthesized compound 8 showed time-dependent inhibition of GABA-AT, but its potency is lower than that of vigabatrin. Methylation of the tetrazole group in 8 resulted in loss of time-dependent activity, suggesting that the tetrazole ring, the carboxylate bioisostere, exists in its deprotonated form in the enzyme active site.
Yuan
Hai
H
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* / Q000494:pharmacology; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008956:Models, Chemical; D013777:Tetrazoles / Q000737:chemistry; D020888:Vigabatrin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000737:chemistry*
D000927:Anticonvulsants; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D013777:Tetrazoles; C045574:1H-tetrazole; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin