Aldo-keto reductases are NAD(P)H-dependent oxidoreductases that are best characterized as glucose reducing agents. They are involved in the pathophysiology of diabetic complications. These enzymes also metabolize products of lipid peroxidation, thus contributing in certain circumstances to an inflammatory response.
Aldose reductase (AR, AKR1B1), besides being involved in diabetic complications through glucose reduction, effectively reduces aldehydes formed by lipid peroxidation, as well as their conjugates with glutathione, to the corresponding alcohols, which mediate inflammatory signals in the body.
It is very well documented that chronic inflammation is associated with cancer progression. Epidemiological studies suggest that more than 25% of all cases of cancer are closely related to chronic infection and chronic inflammation. Increased expression of aldo-keto reductases in tumors of lung, breast, prostate, cervix, testes and colon has been observed, and the role of aldo-keto reductases in the etiology of colorectal carcinoma has been confirmed.
Although a number of inhibitors of aldo-keto reductases have been extensively studied, none of them demonstrated sufficient efficiency in human clinical trials without adverse side effects. Thus, there is still a need for the development of new, efficient and safe inhibitors of aldo-keto reductases AKR1B1 and AKR1B10 as potential drugs for diabetic complications, inflammatory diseases and cancer.
3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (cemtirestat) has been designed and patented as a highly efficient and selective inhibitor of aldose reductase with antioxidant properties. Recently, the ability of cemtirestat to alleviate the symptoms of peripheral neuropathy in ZDF and STZ-induced diabetic rats has been described. Extremely low cytotoxicity of cemtirestat was demonstrated in vitro and, in addition, no significant changes were observed in Wistar rats in a 120-day toxicology test.
Although cemtirestat exhibits effective inhibition of aldo-keto reductases AKR1B1 and AKR1B10, it would be advantageous to improve its pharmacokinetic properties when administered orally and parenterally.
A team of inventors from an established Slovak scientific and research institute and an established Slovak university has managed to solve the above mentioned shortcomings by using a therapeutic strategy based on the administration of a prodrug (cemtirestat disulfide) of the active drug (cemtirestat). In this strategy (prodrug strategy), the release of the active drug occurs after chemical or metabolic activation of the inactive prodrug at the site of desired effect. This approach can significantly increase the availability of the drug at the site of action and reduce toxicity compared to direct drug administration.
Cemtirestat disulfide was synthesized and tested to obtain a prodrug of an effective inhibitor of aldose reductase. Given the key role of aldo-keto reductases AKR1B1 and AKR1B10 in the etiology of several types of cancer associated with chronic inflammation, it is assumed that the release of cemtirestat within tumor cells by reduction of its prodrug would increase the efficiency and especially the selectivity of the drug.
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