Alrestatin aldose reductase inhibitor

Aldose reductase inhibitors (SEDA-19, 397 SEDA-20, 399 SEDA-21, 447 SEDA-22, 477) have been developed for the treatment of secondary complications in diabetes (1,2). They include alrestatin, benurestat, epalrestat, fidarestat, imirestat, lidorestat, minalrestat, ponalrestat, ranirestat, risarestat, sorbinil, tolrestat, zenarestat, and zopolrestat (all rINNs). 

The aldose reductase inhibitors inhibit or reduce secondary complications induced by diabetes, specifically in tissues in which glucose uptake is not insulin-dependent (probably neural tissue, the lens, and glomeruli). Many of them (including alrestatin, imirestat, ponalrestat, and sorbinil) have been used in clinical trials, but have been withdrawn because of adverse effects or lack of effect (2). Their main adverse effects include fever, nausea, diarrhea, increases in liver enzymes, skin rashes, including toxic epidermal necrolysis and Stevens-Johnson syndrome, marked thrombocytopenia, lymphadenopathy, splenomegaly, and adult respiratory distress syndrome. 

ALDOSE REDUCTASE INHIBITORS (ARI) act at the enzyme aldose reductase, which is the first enzyme in the sorbitol (or polyol) pathway which converts glucose to sorbitol. It is thought that in hyperglycaemic states there may be an accumulation of sorbitol, leading to hyperosmotic pathology. ARI agents are under trial for use in the treatment of peripheral diabetic neuropathies, retinopathy and nephropathies. (These include tolrestat. also alrestatin, sorbinil, zenarestat and zopolrestat)... 

Most aldose reductase inhibitors (e.g. sorbinil, alrestatin, tolrestat and ponalrestat) inhibit the enzyme in a non-competitive or uncompetitive way - they compete neither with the substrate nor with the cofactor (NADPH). Therefore, an inhibitory binding site in the enzyme is postulated (Sarges, 1989). 

Tetramethyleneglutaric acid (TMG) (62) and alrestatin (AY-22,284) (63)) are known aldose reductase inhibitors. From natural products, a number of flavonoids have been reported to have aldose reductase inhibitory activity. Quercetin (64 1, R = H), quercitrin (64 2, R = L-rhamnose), rutin (64 3, R = rutinose (6-O-a -L-rhamnosyl-D-glucose)) and myricitrin (65 2, R = L-rhamnose) were much more effective inhibitors of aldose reductase from rat lens than TMG (62) and alrestatin (63) [66]. Quercetin with 3, 4 -dihydroxy substitution in ring C was more potent... 

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