Aldose Reductase Enzyme and its Implication to Major Health Problems of the 21st Century

Author(s): Polyxeni Alexiou, Kyriaki Pegklidou, Maria Chatzopoulou, Ioannis Nicolaou, Vassilis J. Demopoulos.

Journal Name:Current Medicinal Chemistry

Volume 16 , Issue 6 , 2009

Abstract:

Aldose reductase enzyme (ALR2) of the polyol metabolic pathway, apart from its role as detoxifying enzyme towards toxic aldehydes, osmoregulator in the kidney and regulator of sperm maturation, was first found to be implicated in the etiology of the long term diabetic complications. However, to date, emerging reports have suggested that under normal glucose concentration, ALR2 may be up-regulated by factors other than hyperglycemia and therefore be involved also in other pathological processes that have become major threats to human health in the 21st century. Such pathologies are a number of cardiac disorders, inflammation, mood disorders, renal insufficiency and ovarian abnormalities. In addition, ALR2 was found to be over-expressed in different human cancers such as liver, breast, ovarian, cervical and rectal cancers. Although several aldose reductase inhibitors (ARIs) have progressed to the clinical level, only one is currently on the market. Thus, attention is currently targeted to discover ARIs of distinct chemical structures, being neither hydantoin nor carboxylic acid derivatives. The present review focuses on the molecular mechanisms by which ALR2 is implicated in a number of pathologies, on various aspects concerning its catalytic mechanism and its active site, and on the main classes of ARIs that have been developed to date, as well as on reported (quantitive) structure-activity relationships. The presented data aim to support the notion that ARIs are of pharmacotherapeutic interest for the pharmaceutical community and highlight essential aspects for the development of efficient and potent ARIs.

Keywords: Aldose reductase enzyme and aldose reductase inhibitors, long-term diabetic complications, cardiovascular disorders, inflammation, mood disorders, renal insufficiency, ovarian abnormalities, cancer

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Article Details

VOLUME: 16
ISSUE: 6
Year: 2009
Page: [734 - 752]
Pages: 19
DOI: 10.2174/092986709787458362
Price: $58