Aldose reductase inhibitors actions

Diabetes has also continued as a target for drug discovery. Compound (59) has a hypoglycemic profile of activity produced by an extra pancreatic mechanism of action <86AFI770). TAT (W) is a highly potent aldose reductase inhibitor which should be useful in treating the complications of diabetes such as neuropathy <93MI 212-04). 

Tawata, M., K. Aida, T. Noguchi, Y. Ozaki, S. Kume, H. Sasaki, M. Chin, and T. Onaya Anti-Platelet Action of Isoliquiritigenin, an Aldose Reductase Inhibitor in Licorice. Eu. J. Pharmac., 212, 87 (1992). 

Tawata M, Aida K, Noguchi T, OzaM Y, Kume S, Sasaki H, Chin M, Onaya T (1992) Antiplatelet action of isoliquiritigenin, an aldose reductase inhibitor in licorice. Eur J Pharmacol... 

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[. 

Although benzopiperazinones (l,2,3,4-tetrahydroquinoxalin-2-ones) are structurally related to benzodiazepines, their use in drug discovery is less well established. Examples of biological activity of benzopiperazinones include their action as inhibitors of aldose reductase [208], as partial agonists of the y-aminobutyric acid (GABA)/benzodiazepine receptor complex [209, 210], and as angiotensin II receptor antagonists [211]. In addition, derivatives with antiviral acti vity associated vfith HIV have been reported [212, 213]. 

Model I has been applied to a wide variety of drug responses, such as the reduction of fever (8, 20) or pain (19) by anti-inflammatory drugs, anticoagulant action of warfarin (3,9), reduction in blood sorbitol levels by inhibitors of aldose reductase (21), cortisol suppressive effects of corticosteroids (22), luteinizing hormone suppression by the synthetic hormone cetrorelix (23), reduction in the levels of tumoral phospho-EGFR (epidermal growth factor receptor) by cetuximab (24), inhibition of dihydrotestosterone (25), the suppression of T-lymphocyte influx into the blood by corticosteroids (26), and the acid-inhibitory effects of H2-receptor antagonists (27). 

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). 

Z. Iqbal, S. Ali, J. Iqbal, Q. Abbas, I. Z. Qureshi, S. Hameed, Bioorg. Med. Chem. Lett. 2013, 23,488—491. Dual action spi-robicycloimidazolidine-2,4-diones antidiabetic agents and inhibitors of aldose reductase-an enzyme involved in diabetic complications. 

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