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 (fidarestat), 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 fidarestat was determined, and the specific inhibition activity was discussed on the basis of the three-dimensional interactions between them. The structure clarified that fidarestat was located in the active site by hydrophilic and hydrophobic interactions and that the carbamoyl group of fidarestat was a very effective substituent for affinity to AR and for selectivity between AR and aldehyde reductase (AHR). Explanations for the differences between the observed activities of fidarestat and its stereoisomer 2 were suggested by computer modeling.
Oka
M
M
Rational Drug Design Laboratories, 4-1-1, Misato, Matsukawa-machi, Fukushima 960-1242, Japan. m_oka@mb6.skk-net.com
Matsumoto
Y
Y
Sugiyama
S
S
Tsuruta
N
N
Matsushima
M
M
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D048289:Imidazolidines; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D048289:Imidazolidines; C077139:fidarestat; D000449:Aldehyde Reductase