Aldose Reductase Inhibitors: Structure–Activity Relationships and Therapeutic Potential

Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat.

“…Rather, these inhibitors (including zopolrestat) commonly show noncompetitive inhibition, which is likely a reflection of the following: (i) the sequential reaction mechanism of ALR2 with NADPH binding first (17), (ii) the conformational changes associated with binding and release of the coenzyme, inhibitor, and substrate, and (iii) the very tight affinity of the inhibitors (several with affinities 2-7 orders ofmagnitude greater than the Km values of substrates). The suggestion, based on these kinetic results, that the inhibitors bind at a site that is independent of the active site (4)(5)(6), is difficult to explain in structural terms given our results showing atomic interactions between the inhibitor and the active site. Moreover, in the ternary complex structure, the active site pocket (Fig.…”

“…Enhanced flux of glucose through the polyol pathway is believed to be linked to a number of diabetic complications, including neuropathy, nephropathy, and retinopathy (4)(5)(6). Since glucose is an extremely poor substrate, this accumulation is not usually significant except in patients with diabetes mellitus and chronic hyperglycemia.…”

“…There are two major classes of-these inhibitors characterized by a structural or functional group present-spirohydantoins and carboxylic acids (5)(6)(7). Inhibition and competition studies suggest that these compounds bind at a site independent of the substrate and coenzyme (5,6).…”

“…Inhibition and competition studies suggest that these compounds bind at a site independent of the substrate and coenzyme (5,6). One recent and promising (in vitro and in vivo) carboxylic acid inhibitor is zopolrestat (3,4-dihydro-4-oxo-3-{[5-(trifluoromethyl)-2-benzothiazolyl]methyl}-l-phthalazineacetic acid, compound 1 with atom numbers based on its crystal structure) (8).…”

Pharmacological Profiles of a Novel Aldose Reductase Inhibitor, SPR-210, and Its Effects on Streptozotocin-Induced Diabetic Rats

“…AR inhibitors can reduce the elevated tissue sor bitol contents through the inhibition of AR, the rate-limit ing enzyme of the polyol pathway. To date, a number of AR inhibitors (12,13) such as epalrestat (Ono Pharm., Osaka) (14,15), tolrestat (Ayerst, Princeton, NJ, USA) (16,17), zenarestat (FK-366; Fujisawa Pharma., Osaka) (18), zopolrestat (Pfizer, Groton, CT, USA) (19) and sor binil (Pfizer) (20)(21)(22) have been found to improve some dia betic complications in animal experiments and have been developed in clinical stages of evaluation. Although these compounds are effective in the nerves, few compounds are effective in other tissues, such as the lens and retina, which are vulnerable to hyperglycemia in the diabetic state.…”