Alrestatin is an inhibitor of aldose reductase, an enzyme involved in the pathogenesis of complications of diabetes mellitus, including diabetic neuropathy.
Aldose reductase is a monomeric, cytosolic enzyme that catalyzes the NADPH-dependent reduction of carbonyl compounds. Alrestatin is an aldose reductase inhibitor that inhibits the wild type aldose reductase, R311A mutant and R308A mutant with IC50 values of 148, 119, and 67.3 µM[3]. In rat vascular smooth muscle cells, alrestatin at 10 μM minimized high glucose-induced accumulation of Angiotensin II in cells and media, and attenuated the decrease in Angiotensin I level in media[4]. The intraperitoneal administration of alrestatin in rats immediately after pyloric ligation inhibited gastric acid secretion with an ED50 value of 90 mg/kg. The oral administration of alrestatin 1 h before pyloric ligation also inhibited gastric acid secretion with an ED50 of 180 mg/kg. Alrestatin induced ulcer formation in rats with an ED50 of 330 mg/kg via intraperitoneal administration[5].
作用机制
Alrestatin is an orally active aldose reductase inhibitor that binds preferentially to the enzyme/NADP+ complex. The mutation of the Trp20 residue (W20A) greatly affected the binding of alrestatin and enzyme inhibition.
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