Ponalrestat: a potent and specific inhibitor of aldose reductase

Biochemical Pharmacology
W H WardD P Tuffin

Abstract

Many of the complications of diabetes appear to be closely linked to increased conversion of tissue glucose to sorbitol which is catalysed by aldose reductase (aldehyde reductase 2, ALR2). Inhibition of ALR2 could, therefore, lead to a reduction in the development of diabetic complications. Ponalrestat ["Statil" (a trademark, the property of Imperical Chemical Industries PLC), "Prodiax" (a trademark, the property of Merck, Sharp and Dohme), ICI 128436, MK538] inhibits ALR2 from a number of sources. Until now, the mechanism of this inhibition has not been fully elucidated. In this paper, we present a detailed mechanism for inhibition of bovine lens ALR2 by ponalrestat. Treatment of humans with some ALR2 inhibitors leads to side-effects, some of which may result from interactions with other enzymes. Aldehyde reductase (ALR1) is probably the most closely related enzyme to ALR2. Inhibition of ALR1 from bovine kidney was, therefore, investigated in order to assess the specificity of ponalrestat. The values of Ki and Kies (apparent dissociation constants for inhibitor from enzyme-inhibitor and enzyme-inhibitor-substrate complexes, respectively) for the interactions of ponalrestat with ALR1 and ALR2 has been calculated by non-linear f...Continue Reading

References

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Citations

Jan 1, 1994·Journal of Diabetes and Its Complications·D DvornikM Kraml
Jan 1, 1992·Journal of Diabetes and Its Complications·D Dvornik
Oct 5, 2013·Expert Opinion on Drug Discovery·Maria ChatzopoulouVassilis J Demopoulos
Oct 1, 1992·Biochemical Medicine and Metabolic Biology·A Bhatnagar, S K Srivastava
Sep 1, 1993·The Histochemical Journal·G Bou-GhariosI Olsen
Jun 24, 2008·Journal of Intellectual & Developmental Disability·David McConnellGwynnyth Llewellyn
Dec 16, 2004·Bioorganic & Medicinal Chemistry·Federico Da SettimoEnrico Boldrini

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