Sorbinil
(Synonyms: 索比尼尔) 目录号 : GC37666Sorbinil 是一种醛糖还原酶抑制剂 (ARI)。Sorbinil 在治疗糖尿病和糖尿病并发症方面发挥治疗作用,降低 AR 活性和抑制多元醇途径,发现它比人类使用的其它 ARI 更安全。
Cas No.:68367-52-2
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Sorbinil, is an Aldose reductase inhibitor (ARI).Sorbinil plays therapeutic role in treating diabetes and diabetic complications, decreases AR activity and inhibits polyol pathway, it to be found comparatively safer than other ARIs for human use[1].
[1]. Huang Q, et al. Sorbinil, an Aldose Reductase Inhibitor, in Fighting Against Diabetic Complications. Med Chem. 2019;15(1):3-7.
Cas No. | 68367-52-2 | SDF | |
别名 | 索比尼尔 | ||
Canonical SMILES | O=C([C@@]12C3=CC(F)=CC=C3OCC1)NC(N2)=O | ||
分子式 | C11H9FN2O3 | 分子量 | 236.2 |
溶解度 | DMSO: ≥ 20µmg/mL | 储存条件 | Store at 2-8°C |
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Sorbinil, an Aldose Reductase Inhibitor, in Fighting Against Diabetic Complications
Med Chem 2019;15(1):3-7.PMID:29792152DOI:10.2174/1573406414666180524082445.
Background: Aldose reductase (AR) is involved in the pathogenesis of diabetes, which is one of the major threats to global public health. Objective: In this review article, we have discussed the role of Sorbinil, an AR inhibitor (ARI), in preventing diabetic complications. Results: AR contributes in diabetes by generating excess intracellular superoxide and other mediators of oxidative stress through polyol pathway. Inhibition of AR activity thus might be a potential approach for the management of diabetic complications. Experimental evidences indicated that Sorbinil can decrease AR activity and inhibit polyol pathway. Both in vitro and animal model studies reported the efficacy of Sorbinil in controlling the progression of diabetes. Moreover, Sorbinil has been found to be comparatively safer than other ARIs for human use. But, it is still in earlyphase testing for the treatment of diabetic complications clinically. Conclusion: Sorbinil is an effective ARI, which could play therapeutic role in treating diabetes and diabetic complications. However, advanced clinical trials are required for Sorbinil so that it could be applied with the lowest efficacious dose in humans.
Sorbinil prevention of diabetic-like retinopathy in the galactose-fed rat model
Invest Ophthalmol Vis Sci 1995 Nov;36(12):2368-80.PMID:7591626doi
Purpose: To determine if the retinal microangiopathies of the galactose-fed rat model of diabetic retinopathy can be prevented with the aldose reductase inhibitor Sorbinil. Methods: Sprague-Dawley rats were fed 50% d-galactose with or without Sorbinil (0.05% wt/wt), mixed biweekly with fresh diet. Rats in each group were examined frequently by slit lamp and were killed after 8, 16, and 24 months. Computer-assisted morphometry was performed on wholemounts of elastase retinal digest preparations. Results: Cataracts developed in all galactose-fed untreated rats within 3 weeks but not in the sorbinil-treated rats even after 24 months. At 8 months, the galactose-fed untreated rats exhibited statistically significant increases in the mean capillary width, the percent of retinal area occupied by capillaries (capillary density), and the percent of microvascular area with capillaries > 20 microns wide (dilated channels), compared to controls. At 16 months, the galactose-fed untreated rats showed statistically significant increases over controls in both total mean capillary length and density, and two of the four rats examined had microaneurysms. At 24 months, all the galactose-fed untreated rats had microaneurysms and extensive areas with hypercellular meshworks composed of dilated channels characteristic of intraretinal microvascular abnormalities (IRMA). By contrast, galactose-fed, sorbinil-treated rats, at 24 months, had no IRMA and showed no statistically significant differences from control rats in any of the parameters measured morphometrically. Conclusions: All the galactose-induced retinal microangiopathies were prevented with Sorbinil. Aldose reductase inhibitors may be beneficial in ameliorating the similar vascular lesions characteristic of human diabetic retinopathy, though the mechanism remains obscure.
The Sorbinil trap: a predicted dead-end complex confirms the mechanism of aldose reductase inhibition
Biochemistry 2000 Aug 15;39(32):9967-74.PMID:10933817DOI:10.1021/bi000789q.
Kinetic and crystallographic studies have demonstrated that negatively charged aldose reductase inhibitors act primarily by binding to the enzyme complexed with oxidized nicotinamide dinucleotide phosphate (E.NADP(+)) to form a ternary dead-end complex that prevents turnover in the steady state. A recent fluorescence study [Nakano and Petrash (1996) Biochemistry 35, 11196-11202], however, has concluded that inhibition by Sorbinil, a classic negatively charged aldose reductase inhibitor, results from binding to the enzyme complexed with reduced cofactor (E.NADPH) and not binding to E.NADP(+). To resolve this controversy, we present transient kinetic data which show unequivocally that Sorbinil binds to E.NADP(+) to produce a dead-end complex, the so-called Sorbinil trap, which prevents steady-state turnover in the presence of a saturating concentration of aldehyde substrate. The reported fluorescence binding results, which we have confirmed independently, are further shown to be fully consistent with the proposed Sorbinil trap mechanism. Our conclusions are supported by KINSIM simulations of both pre-steady-state and steady-state reaction time courses in the presence and absence of Sorbinil. Thus, while Sorbinil binding indeed occurs to both E.NADPH and E.NADP(+), only the latter dead-end complex shows significant inhibition of the steady-state turnover rate. The effect of tight-binding kinetics on the inhibition patterns observed for zopolrestat, another negatively charged inhibitor, is further examined both experimentally and with KINSIM, with the conclusion that all reported aldose reductase inhibition can be rationalized in terms of binding of an alrestatin-like inhibitor at the active site, with no need to postulate a second inhibitor binding site.
Sorbinil partially prevents decreased erythrocyte deformability in experimental diabetes mellitus
Diabetes 1987 Sep;36(9):1010-3.PMID:3609495DOI:10.2337/diab.36.9.1010.
The ability of red blood cells (RBCs) to undergo an adaptation in shape that permits passage through the smallest vessels is reportedly impaired in diabetes. Several hypotheses have been proposed to explain decreased erythrocyte deformability, which has been implicated in the pathogenesis of microvascular complications, but the mechanisms responsible for this change have not been clearly delineated. In view of the fact that sorbitol accumulates in RBCs in diabetes and the postulate that increased sorbitol could alter deformability properties, we examined the influence of the aldose reductase inhibitor Sorbinil on erythrocyte deformability. Erythrocyte deformability, determined as the volume of RBCs (VRBC) filtered per minute through 4.7-micron pore size filters, was significantly reduced in samples from diabetic rats compared with samples from controls (0.76 +/- 0.03 vs. 0.97 +/- .02 ml RBC/min; P less than .001). In contrast, deformability of RBCs from diabetic animals treated with Sorbinil was significantly greater than in untreated diabetes, although not completely normalized (0.88 +/- 0.02; P less than .01 vs. diabetic, and P less than .02 vs. control). The reduced deformability characterizing cells from diabetic rats and its partial prevention by Sorbinil persisted even when RBCs were washed to eliminate hyperglycemia and hyperviscous plasma. Thus, hyperviscosity per se is not responsible for the decreased deformability, and Sorbinil can partially prevent this change despite persistent hyperglycemia. This effect may derive from Sorbinil's action as an aldose reductase inhibitor and/or its ability to influence physicochemical properties of the erythrocyte membrane.
Does Sorbinil bind to the substrate binding site of aldose reductase?
Biochem Pharmacol 1992 Dec 15;44(12):2427-9.PMID:1472112DOI:10.1016/0006-2952(92)90693-d.
With benzyl alcohol as the varied substrate, Sorbinil was found to be a competitive inhibitor of aldose reductase, an enzyme implicated in the etiology of secondary diabetic complications. The K(is Sorbinil) and the Vmax/Km (V/K) benzyl alcohol decreased at low pH with a pK of 7.5 and 7.7, respectively. These observations suggest that both Sorbinil and benzyl alcohol bind to the same site on the enzyme. Active site inhibition by Sorbinil is consistent with non-competitive inhibition patterns of Sorbinil with nucleotide coenzyme or aldehyde as the varied substrate in the direction of aldehyde reduction.