A potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2 ',5 '-dioxospiro[chroman-4,4 '-imidazolidine]-2-carboxamide (Fidarestat): Its absolute configuration and interactions with the aldose reductase by X-ray crystallography

The absolute configuration of the aldose reductase (AR) inhibitor, (+)-(2S, 4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2- carboxamide (f idarestat), was established indirectly by single-crystal X-ray analysis of (+)-(2S,4S)-8-bromo-6-fluoro-2',5'-dioxospiro[ chroman-4,4'-imidazolidine]- 2-carboxylic acid (1). The crystal structure of human AR complexed with fid arestat was determined, and the specific inhibition activity was discussed on the basis of the three-dimensional interactions between them. The struct ure clarified that fidarestat was located in the active site by hydrophilic and hydrophobic interactions and that the carbamoyl group of fidarestat wa s a very effective substituent for affinity to AR and for selectivity betwe en AR and aldehyde reductase (AHR). Explanations for the differences betwee n the observed activities of fidarestat and its stereoisomer 2 were suggest ed by computer modeling.