Disease relevance of ZOPOLRESTAT

• The in vivo relationship of AR and HNE was explored by treating human GCA temporal artery-severe combined immunodeficiency (SCID) mouse chimeras with the AR inhibitors Sorbinil and Zopolrestat [1].
• In these diabetic hearts, ATP was significantly higher in zopolrestat hearts during ischemia, as were phosphocreatine and left ventricular-developed pressure on reperfusion [2].
• Treatment of diabetic rats for 14 weeks with the aldose reductase inhibitor zopolrestat resulted in a significant decrease in the frequency of neuroaxonal dystrophy compared with untreated diabetics [3].
• These data indicate that once-daily dosing of zopolrestat will provide suitable exposure in the treatment of diabetic complications [4].
• Collectively, these results suggest that Zopolrestat exerts a protective effect on the slowly developing diabetic cataract, as well as reducing albuminuria and proteinuria [5].

High impact information on ZOPOLRESTAT

• Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat [6].
• The zopolrestat fits snugly in the hydrophobic active site pocket and induces a hinge-flap motion of two peptide segments that closes the pocket [6].
• The aldose reductase inhibitor zopolrestat partially restored the levels of CAT, CuZnSOD, and GPX mRNA in the patients with nephropathy (P < 0.05) [7].
• Each group was exposed to 1 micromol/l zopolrestat, a specific inhibitor of aldose reductase, for 10 min, followed by 20 min of global ischemia and 60 min of reperfusion in the absence of zopolrestat [2].
• On the basis of the zopolrestat-binding model, we have proposed binding models for 10 other AR inhibitors [8].

Chemical compound and disease context of ZOPOLRESTAT

• The aldose reductase inhibitor, Zopolrestat, reduced proteinuria and albuminuria in streptozocin-induced diabetic rats compared with both untreated diabetic and age-matched controls [5].

Biological context of ZOPOLRESTAT

• The magnitude of the potential gender difference in exposure was relatively small and was unlikely to have had a meaningful impact on the pharmacokinetics of zopolrestat in dogs [9].
• The bioavailability in dogs of a 2 mg/kg oral dose of zopolrestat was 97.2% [9].
• Bioavailability, multiple-dose pharmacokinetics, and biotransformation of the aldose reductase inhibitor zopolrestat in dogs [9].
• 14C-labeled zopolrestat was orally administered to rats for a tissue distribution study and a bile duct cannulation metabolism study [10].
• Protein binding of zopolrestat was less extensive in plasma from diabetic rats than in plasma from normal rats [11].

Anatomical context of ZOPOLRESTAT

• The treatment with zopolrestat restored antigen-induced protein extravazation and mast cell degranulation in the pleural cavity of diabetic sensitized rats [12].
• The aldose-reductase inhibitors, sorbinil and zopolrestat, little affected high D-glucose-attenuated endothelial cell proliferation, while the enhanced proliferation of smooth muscle cells was prevented by aldose-reductase inhibitors [13].
• Treatment with an aldose reductase inhibitor, zopolrestat, normalized the elevated red blood cell sorbitol levels in diabetic rabbits [14].

Associations of ZOPOLRESTAT with other chemical compounds

• Potent, orally active aldose reductase inhibitors related to zopolrestat: surrogates for benzothiazole side chain [15].
• Using a fluorometric assay, it was determined that zopolrestat, an acetic acid-type inhibitor, bound to aldose reductase complexed with either NADPH or NADP+ [16].
• The enzyme mutant W20A severely affected the inhibitory potencies of a variety of commercially developed aldose reductase inhibitors (zopolrestat, tolrestat, FK366, AL1576, alrestatin, ponalrestat, and sorbinil) [17].
• Our findings show that zopolrestat restored the hyporesponsiveness of diabetic rats to antigen provocation, in parallel with impairment of alloxan-induced mast cell depletion and hypercorticolism, indicating that polyol pathway activity seems to play an important role in these phenomena [12].
• Consistent with molecular models, the inhibitory activity of Tolrestat, Sorbinil and Zopolrestat decreased 800-2000-fold when tested with the mutant enzyme in which Trp20 was replaced with alanine [18].

Gene context of ZOPOLRESTAT

• We have determined the 1.7 A resolution structure of the FR-1 in a ternary complex with NADPH and zopolrestat, a potent aldose reductase inhibitor [19].
• These increments were attenuated by zopolrestat, an AR inhibitor [20].
• There were significantly fewer CD31-positive vessels perfield in both groups treated with zopolrestat compared to the infusion-only group: group 2, 9 (7 - 12); group 3, 17 (13 - 38), compared to group 1, 37 (32 - 39), p < 0.05 [21].
• These data suggest that glycolytic flux in diabetic hearts is inhibited at glyceraldehyde-3-phosphate dehydrogenase and that inhibition of the polyol pathway with zopolrestat increases glycolytic flux in these hearts [22].
• The AGE-induced enhancement in TGF-beta1 and type IV collagen expression were suppressed by either zopolrestat or transfection with an AR antisense oligonucleotide [20].

Analytical, diagnostic and therapeutic context of ZOPOLRESTAT

• Structural analysis, especially by X-ray crystallography of two selected compounds, and molecular modeling comparisons with Zopolrestat were performed [23].
• As a consequence, 1999 saw the demise of two further compounds: recombinant growth factor by Roche-Genentech and the aldose reductase inhibitor zopolrestat, by Pfizer, both had reached phase III clinical trials [24].
• Diabetes was induced by intravenous injection of alloxan into fasted rats, 7 days before sensitization, and the aldose reductase inhibitor zopolrestat was administered after 3 days of diabetes induction, once a day during 18 consecutive days [12].

References