Aldose reductase diabetic complications

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Kador PF The role of aldose reductase in the development of diabetic complications. Med Res Rev 1988 8 325. 

Dvornik, D. (1987). Animal models of diabetic complications and their relation to aldose reductase inhibition. In Aldose Reductase Inhibition (ed. D. Porte) pp. 153-219. McGraw-Hill, New York. 

Rhetsinine (2), isolated from the hot water extract of Evodia rutae-carpa (family Rutaceae), was found to inhibit aldose reductase with an IC50 value of 24.1 /rM furthermore, the isolate inhibited sorbitol accumulation by 79.3% at 100 This compound could find potential use in the treatment of diabetic complications. Tetramethylpyrazine (3), one of the active components in Qing Huo Yi Hao, displayed strong antioxidant and endothelial protective effects, which can be comparable as Qing Huo Yi Hao this result indicated that some therapeutic potential of Qing Huo Yi Hao for vascular complications of diabetes may be attributed to the presence of tetramethylpyrazine (3). ... 

Fidarestat is an aldose reductase inhibitor. It was being developed (Phase II/III) for complications of diabetes, but it seems to have been discontinued. Two other aldose reductase inhibitors, lidorestat and SPR-210, are currently in development for the treatment of diabetes complications (Figure 8.85). 

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. 

P. F. Kador, J. H. Kinoshita, N. E. Sharpless (1985). Aldose-reductase inhibitors a potential new class of agents for the pharmacological control of certain diabetic complications. J. Med. Chem. 28 841-849. 

C. A. Lipinski, N. J. Hutson (1984). Aldose-reductase inhibitors as a new approach to the treatment of diabetic complications. Annu. Rep. Med. Chem. 19 169-177. 

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. 

Drugs that selectively inhibit the aldose reductase enzyme represent a possible method for reducing peripheral neuropathies and other microvascular complications associated with poorly controlled type 1 or type 2 diabetes.26,45 This enzyme, which is located in... 

Chung SS, Chung SK. Aldose reductase in diabetic microvascular complications. Curr Drug Targets. 2005 6 475-486. 

Suzen S, Buyukbingol E. Recent studies of aldose reductase enzyme inhibition for diabetic complications. Curr Med Chem. 2003 10 1329-1352. 

In Ayurveda and folklore medicines, cinnamon is used in the treatment of diabetes. Cinnamon is reported to reduce the blood glucose level in non-insulin-dependent diabetics. Therapeutic studies have proved the potential of cinnamaldehyde as an antidiabetic agent. Cinnamaldehyde inhibits aldose reductase, a key enzyme involved in the polyol pathway. This enzyme catalyses the conversion of glucose to sorbitol in insulin-insensitive tissues in diabetic patients. This leads to accumulation of sorbitol in chronic complications of diabetes, such as cataract, neuropathy and retinopathy. Aldose-reductase inhibitors prevent conversion of glucose to sorbitol, thereby preventing several diabetic complications (Lee, 2002). 

Tomlinson. D.R. era/. (1994) Aldose reductase inhibitors and their potential for the treatment of diabetic complications. Trends Pharmacol. Sci.. 15.293-297. 

Although aldose reductase is a widely distributed enzyme system, its general physiological role remains to be convincingly proven. Its only experimentally documented role is its participation in the generation of diabetic complications. 

The participation of aldose reductase in the development of diabetic complications is assumed to be based on a triad of tissue effects sorbitol accumulation, myo-inositol depletion and decreased activity of Na/K-ATPase. These alterations, first described in the ocular lens, also occur in other tissues like the renal glomerulus, peripheral nerves and the retina. The enhanced activity of aldose reductase may therefore be involved in the development of diabetic neuropathy, diabetic retinopathy and diabetic nephropathy, although it may not be the sole factor underlying these complications. 

The presence of aldose reductase in many tissues, which may not be involved in diabetic complications, makes unwanted effects likely, although isozymic differences in the enzyme in different tissues may be possible. Since aldose reductase inhibitors are not yet regularly used and since the effects of long-term inhibition of aldose reductase are not yet known, knowledge on possible unwanted effects is scarce. Information on side effects is therefore based only on individual reports. 

Recently, antidiabetic activity has been reported for some spirohydantoins. Thus compounds of type 138-145 are potent inhibitors of aldose reductase activity and sorbitol accumulation, being particularly useful in treatment of chronic diabetic complications.344-352... 

Some of quercetin s potentially useful vs. potentially harmful properties have been reviewed by Alan Gaby, MD., in an editorial in the May 1998 issue of the Townsend Letter for Doctors Patients. It acts as an inhibitor for the enzyme phosphodiesterase, and hence may possibly act against asthma. Also, it may act against allergies by inhibiting the release of histamine. Quercetin is also an inhibitor for the enzyme aldose reductase, which is involved in diabetic complications. Perhaps most interestingly, it inhibits the enzyme reverse transcriptase (or RNA-directed DNA polymerase), involved in the action of retroviruses such as the AIDS virus or HIV (and retroviruses may also be involved in cancer formation). 

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