Sorbinil Sorbitol

Another complication of diabetes is blindness, which is due to blood vessel damage at the back of the eye (proliferative retinopathy), this accounts for about 12% of all blindness. In hyperglycemia, fructose is only slowly metabolized, and sorbitol accumulates in tissues. Because aldose reductase is found in kidneys, optic nerve, and peripheral neurons, retinopathy and painful neuropathies develop in poorly controlled or long-standing diabetes as a result of sugar alcohol (sorbitol) accumulation. Aldose reductase inhibitors, such as tokestat (5.129) or sorbinil (5.130), have been evaluated as agents to ameliorate these additional symptoms of diabetes. 

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)... 

The effects of sorbinil, its enantiomer, and the racemic form on calf lens AR in vitro, and in vivo on sorbitol accumulation in the sciatic nerve of diabetic rats, are shown in Table 8.5. At 1 x 10 6 M, ( - )-sorbinil was only marginally active (23%), while (+ )-sorbinil caused 98% inhibition. A limited number of sorbinil analogues with different substitution patterns have been disclosed they are shown in Table 8.5 together with their activities in vitro and in vivo. The racemic 6,7-dichloro, 6,8-dichloro and 6-chloro analogues (Nos. 5,6 and 7) are more potent in vitro than racemic sorbinil (No. 1) this is also the case in vivo for the 6,8-dichloro and the 6-chloro analogues, which inhibit sorbitol accumulation by 82 and 64%, compared with 45% for (+ )-sorbinil, at a dose of 0.75 mg/kg p.o. in the streptozotocin-induced diabetic rat. An account of the development of sorbinil, and additional structure-activity relationships in that series, has recently appeared [60]. 

Tissue Location and Role of Aldose Reductase in Animal Models of Diabetic Complications. Aldose reductase (AR) has been located immunohistochemically in many tissues of the dog and rat, most notably, in corneal epithelium, retina, optic nerve, kidney papillae, aortic endothelium and smooth muscle cells as well as peripheral nerve and lens. AR has also been measured in human and monkey retinal mural cells. These cells are thought to provide the structural support for retinal capillaries and their loss is the first abnormality seen in clinical diabetic retinopathy. In addition, AR-like activity has been reported in a human retinoblastoma cell line and sorbinil inhibits this activity in these cells. Finally, a recent report has demonstrated that AR is present in isolated capillaries from bovine retina and cerebral cortex. Therefore, AR appears to be present in all tissues which are uniquely susceptible to deterioration during prolonged exposure to the hyperglycemia of diabetes. Accumulation of the products of the polyol pathway, sorbitol and fructose, has been demonstrated in these tissues and, where tested, sorbinil and other AR inhibitors have been shown to inhibit this accumulation. 

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