Tolrestat
(Synonyms: 托雷斯萘,AY-27773) 目录号 : GC37812
An aldose reductase inhibitor
Cas No.:82964-04-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Animal experiment: | For a period of four days, rats weighing about 70 g are given unlimited access to water and Chow supplemented with 20% (wt/wt) galactose and tolrestat at various dose levels. Rats used as control receive chow containing galactose (20%, wt/wt) or glucose (20%, wt/wt). The rats are killed; the lenses and sciatic nerves are removed and homogenized in 5% trichloroacetic acid; the deproteinized extracts are then analyzed for galactitol by a modification of a method for glycerol determination. The values obtained in the group fed 20% glucose are used for background correction. |
References: [1]. Sestanj K, et al. N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]- N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitor. J Med Chem. 1984 Mar;27(3):255-6. | |
Tolrestat is an aldose reductase inhibitor (IC50 = 35 nM for the bovine lens enzyme).1 Dietary administration of tolrestat decreases sciatic nerve galactitol accumulation in a rat model of galactosemia (ED50 = 7.3 mg/kg per day) and sciatic nerve sorbitol accumulation (ED50 = 4.8 mg/kg per day) in a rat model of diabetes induced by streptozotocin . It also decreases urinary total protein exretion in a rat model of STZ-induced diabetes when administered at a dose of 25 mg/kg per day.2 Topical administration of tolrestat (2 and 3% in 10 μl four times per day) decreases levels of galactitol in the lens of and inhibits cataract formation in rats fed a high-galactose diet.3
1.Sestanj, K., Bellini, F., Fung, S., et al.N-[5-(trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]- N-methylglycine (Tolrestat), a potent, orally active aldose reductase inhibitorJ. Med. Chem.27(3)255-256(1984) 2.McCaleb, M.L., McKean, M.L., Hohman, T.C., et al.Intervention with the aldose reductase inhibitor, tolrestat, in renal and retinal lesions of streptozotocin-diabetic ratsDiabetologia34(10)695-701(1991) 3.Banditelli, S., Boldrini, E., Vilardo, P.G., et al.A new approach against sugar cataract through aldose reductase inhibitorsExp. Eye Res.69(5)533-538(1999)
| Cas No. | 82964-04-3 | SDF | |
| 别名 | 托雷斯萘,AY-27773 | ||
| Canonical SMILES | O=C(O)CN(C(C1=C2C=CC(OC)=C(C(F)(F)F)C2=CC=C1)=S)C | ||
| 分子式 | C16H14F3NO3S | 分子量 | 357.35 |
| 溶解度 | DMSO: ≥ 100 mg/mL (279.84 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7984 mL | 13.9919 mL | 27.9838 mL |
| 5 mM | 0.5597 mL | 2.7984 mL | 5.5968 mL |
| 10 mM | 0.2798 mL | 1.3992 mL | 2.7984 mL |
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Tolrestat kinetics
Clin Pharmacol Ther 1984 Oct;36(4):493-9.PMID:6478735DOI:10.1038/clpt.1984.209.
The kinetics of Tolrestat, a potent inhibitor of aldose reductase, were examined. Serum concentrations of Tolrestat and of total 14C were measured after dosing normal subjects and subjects with diabetes with 14C-labeled Tolrestat. In normal subjects, Tolrestat was rapidly absorbed and disappearance from serum was biphasic. Distribution and elimination t 1/2s were approximately 2 and 10 to 12 hr, respectively, after single and multiple doses. Unchanged Tolrestat accounted for the major portion of 14C in serum. Radioactivity was rapidly and completely excreted in urine and feces in an approximate ratio of 2:1. Findings were much the same in subjects with diabetes. In normal subjects, the kinetics of oral Tolrestat were independent of dose in the 10 to 800 mg range. Repetitive dosing did not result in unexpected cumulation. Tolrestat was more than 99% bound to serum protein; it did not compete with warfarin for binding sites but was displaced to some extent by high concentrations of tolbutamide or salicylate.
[Tolrestat in the therapy of diabetic peripheral neuropathy: is this drug really useful?]
Clin Ter 1995 Dec;146(12):793-99.PMID:8681499doi
The authors have studied the effect of the treatment with an aldose reductase inhibitor, Tolrestat, on the peripheral diabetic neuropathy during a placebo controlled randomised trial. 74 diabetics affected by peripheral neuropathy were divided in two groups of 39 (group A) and 35 (group B) patients comparable as to age, sex, duration of diabetes and severity of the neurological symptoms. The group A was treated with Tolrestat orally 200 my once daily for six months, the group B was treated with placebo. After six months an improvement of analysed symptoms (pain and paraesthesias) and objective assessments (NCV-DB) was observed in patients treated with Tolrestat (group A) significantly higher than in patients treated with placebo (group B). A light improvement was found also during a control effected after three months of treatment with Tolrestat. The improvement after six months of therapy was mild but significant; therefore the authors conclude that the Tolrestat is an useful drug in the treatment of the peripheral diabetic neuropathy in addition to attainment of a better glycemia's control.
Tolrestat pharmacokinetics in rat peripheral nerve
J Diabetes Complications 1994 Jan-Mar;8(1):18-26.PMID:8167382DOI:10.1016/1056-8727(94)90006-x.
The clinical efficacy of an aldose reductase (AR) inhibitor in diabetic polyneuropathy depends on its bioavailability at the site(s) of AR in peripheral nerves. Accordingly, the link between the concentration of the AR inhibitor, Tolrestat, and the extent of its inhibition of the AR-catalyzed polyol production was investigated in sciatic nerves of galactosemic rats. Tolrestat was administered by gavage (1 x 150 mg/kg, or 5, and 15 mg/kg/day for 15 days to attain steady state as estimated from the 53-h half-life of Tolrestat determined in rat nerve); subsequently, at six time intervals, ranging from 4 to 59 days, rats were given access for 4 days to a 20% galactose diet, and killed. At every time point, the composite Tolrestat concentration in the nerve correlated with the percentage decrease in nerve galactitol (r = 0.857, p = 0.0015). Because the latter should reflect the extent of nerve AR inhibition by Tolrestat, the concentration of "free" Tolrestat available at the site(s) of AR in the nerve was estimated from the Tolrestat concentration/percent AR inhibition plot obtained in vitro. The estimated amount of Tolrestat present at the site(s) of nerve AR represented 0.4% of the composite Tolrestat concentration measured in the nerve. The results support the view that the effectiveness of an AR inhibitor in peripheral nerve depends on its pharmacokinetics in the nerve, i.e., on its uptake, nonspecific binding to cellular constituents, and elimination.
Tolrestat acts atypically as a competitive inhibitor of the thermostable aldo-keto reductase Tm1743 from Thermotoga maritima
FEBS Lett 2020 Feb;594(3):564-580.PMID:31573681DOI:10.1002/1873-3468.13630.
Tolrestat and epalrestat have been characterized as noncompetitive inhibitors of aldo-ketone reductase 1B1 (AKR1B1), a leading drug target for the treatment of type 2 diabetes complications. However, clinical applications are limited for most AKR1B1 inhibitors due to adverse effects of cross-inhibition with other AKRs. Here, we report an atypical competitive binding and inhibitory effect of Tolrestat on the thermostable AKR Tm1743 from Thermotoga maritima. Analysis of the Tm1743 crystal structure in complex with Tolrestat alone and epalrestat-NADP+ shows that Tolrestat, but not epalrestat, binding triggers dramatic conformational changes in the anionic site and cofactor binding pocket that prevents accommodation of NADP+ . Enzymatic and molecular dynamics simulation analyses further confirm Tolrestat as a competitive inhibitor of Tm1743.
Tolrestat in the primary prevention of diabetic neuropathy
Diabetes Care 1995 Apr;18(4):536-41.PMID:7497865DOI:10.2337/diacare.18.4.536.
Objective: To compare the effects of Tolrestat and placebo in patients with subclinical diabetic neuropathy. Research design and methods: Non-insulin-dependent diabetes mellitus (NIDDM) patients with early involvement of the autonomic nervous system were identified by only one pathological (outside the 99% confidence interval of the normal population) squatting test (vagal or sympathetic). Fifty-seven patients entered a randomized, placebo-controlled, double-blind, parallel 52-week study of Tolrestat at a dose of 200 mg/day. Cardiovascular reflex tests (squatting vagal and sympathetic tests, pressure gain, deep breathing, lying-to-standing, Valsalva maneuver, and orthostatic hypertension), vibration thresholds, tendon reflexes, and muscle strength were assessed throughout the study. Results: At 12 months, nerve function significantly improved in patients receiving Tolrestat and deteriorated in patients taking placebo. At baseline, the squatting vagal test was normal in 16 patients in the Tolrestat group and in 15 patients in the placebo group. At 12 months, 25 patients taking Tolrestat had a normalized squatting test, but only 6 patients taking placebo did (P = 0.02). Vibration perception threshold improved by a value of 6 +/- 3 V in the Tolrestat group (P < 0.001) and deteriorated by a value of 3 +/- 1.8 V (P < 0.001) in the placebo group. Conclusions: Tolrestat may be useful in the primary prevention of diabetic neuropathy.