Draflazine
(Synonyms: 曲氟嗪,R-75231; R88021) 目录号 : GC35899
Draflazine (R-75231) 是一种 ENT1 抑制剂。Draflazine (R-75231) 在 CFA 机械痛觉过敏模型，热力学和机械痛觉过敏的卡拉胶炎症模型中完全逆转了超敏反应。
Cas No.:120770-34-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Draflazine (R-75231) is a ENT1 inhibitor. Draflazine (R-75231) completely reverses the hypersensitivity in the complete Freund's adjuvant (CFA) model of mechanical hyperalgesia and the carrageenan inflammation model of thermal and mechanical hyperalgesia[1]. ENT1[1]
[1]. Maes SS, et al. Antihyperalgesic activity of nucleoside transport inhibitors in models of inflammatory pain in guinea pigs. J Pain Res. 2012;5:391-400.
| Cas No. | 120770-34-5 | SDF | |
| 别名 | 曲氟嗪,R-75231; R88021 | ||
| Canonical SMILES | O=C(NC1=C(Cl)C=C(N)C=C1Cl)CN2C(C(N)=O)CN(CCCCC(C3=CC=C(F)C=C3)C4=CC=C(F)C=C4)CC2 | ||
| 分子式 | C30H33Cl2F2N5O2 | 分子量 | 604.52 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6542 mL | 8.271 mL | 16.542 mL |
| 5 mM | 0.3308 mL | 1.6542 mL | 3.3084 mL |
| 10 mM | 0.1654 mL | 0.8271 mL | 1.6542 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Nucleoside transport inhibition by Draflazine in unstable coronary disease
Eur J Clin Pharmacol 1996;51(1):7-13.PMID:8880045DOI:10.1007/s002280050153.
Objectives: In a randomised, double-blind, placebo controlled study, we evaluated the tolerability and safety of Draflazine, a nucleoside transport inhibitor, in the treatment of patients with unstable angina and non-Q-wave infarction. Methods: Twenty-one patients were randomised to treatment with Draflazine 3.5 mg or matching placebo given as an i.v. infusion and haemodynamic and symptomatic tolerability were investigated. Myocardial ischaemia was evaluated by means of vectorcardiography and blood analysis of the MB fraction of creatine kinase. Results: The study drug was well tolerated by all patients and it did not cause any adverse haemodynamic effects, nor other serious adverse events. Three patients in the placebo group reported five adverse events, as compared to a single adverse event in the Draflazine group. Cardiovascular events were detected in 7 patients in the placebo group and in 5 patients receiving Draflazine. The mean duration of chest pain during the 24 hour observation period was 91.4 min in the placebo group compared to 75.5 min in Draflazine treated patients. Neither the vectorcardiographic nor biochemical measures of ischaemia differed between treatment groups. Conclusion: Nucleoside transport inhibition by Draflazine was well tolerated by patients with unstable coronary disease. It seems to be a promising method of adenosine enhancement in acute myocardial ischaemia. The potential cardioprotective effect of the drug needs further evaluation in larger trials.
Studies of the nucleoside transporter inhibitor, Draflazine, in the human myocardium
Br J Pharmacol 1994 May;112(1):137-42.PMID:8032635DOI:10.1111/j.1476-5381.1994.tb13043.x.
1. The aim of the present study was to determine the effect of the nucleoside transporter inhibitor, Draflazine, on the force of contraction in human myocardium and the affinity of the compound for the nucleoside transporter. Nucleoside transport inhibitors, like Draflazine, are of potential importance for cardiopreservation of donor hearts for heart transplantation. 2. Functional experiments were performed in isolated electrically driven (1 Hz, 1.8 mmol l-1 Ca2+) human atrial trabeculae and ventricular papillary muscle strips. The affinity of Draflazine for the myocardial nucleoside transporter was studied in isolated membranes from human ventricular myocardium and human erythrocytes in radioligand binding experiments using [3H]-nitrobenzylthioinosine ([3H]-NBTI). Dipyridamole was studied for comparison. 3. In membranes from human myocardium and erythrocytes, [3H]-NTBI labelled 1.18 pmol mg-1 protein and 23.0 pmol mg-1 protein, respectively, nucleoside transporter molecules with a KD value of 0.8 nmol l-1. Draflazine concentration-dependently inhibited binding of [3H]-NBTI to myocardial and erythrocyte membranes with a K(i)-value of 4.5 nmol l-1. The potency as judged from the K(i) values was ten times greater than that of dipyridamole in both myocardial and erythrocyte membranes. 4. Draflazine, at concentrations up to 100 mumol l-1, did not produce negative inotropic effects in atrial and ventricular myocardium. (-)-N6-phenylisopropyladenosine (R-PIA) and carbachol did not reduce force of contraction in ventricular myocardium, but exerted concentration-dependent direct negative inotropic effects in atrial myocardium. 5. The data provide evidence that Draflazine specifically binds to the nucleoside transporter of the human heart and erythrocytes with high affinity. The compound does not produce negative inotropic effects at concentrations as high as 100 micromol 1-1.6. Draflazine could be a useful agent for cardio preservation because it does not produce cardio depressant effects. Thus, it may be possible to perfuse explanted hearts directly with this agent without the hazard of cardiodepression.
Affinity, binding kinetics and functional characterization of Draflazine analogues for human equilibrative nucleoside transporter 1 (SLC29A1)
Biochem Pharmacol 2020 Feb;172:113747.PMID:31830468DOI:10.1016/j.bcp.2019.113747.
In the last decade it has been recapitulated that receptor-ligand binding kinetics is a relevant additional parameter in drug discovery to improve in vivo drug efficacy and safety. The equilibrative nucleoside transporter-1 (ENT1, SLC29A1) is an important drug target, as transporter inhibition is a potential treatment of ischemic heart disease, stroke, and cancer. Currently, two non-selective ENT1 inhibitors (dilazep and dipyridamole) are on the market as vasodilators. However, their binding kinetics are unknown; moreover, novel, more effective and selective inhibitors are still needed. Hence, this study focused on the incorporation of binding kinetics for finding new and improved ENT1 inhibitors. We developed a radioligand competition association assay to determine the binding kinetics of ENT1 inhibitors with four chemical scaffolds (including dilazep and dipyridamole). The kinetic parameters were compared to the affinities obtained from a radioligand displacement assay. Three of the scaffolds presented high affinities with relatively fast dissociation kinetics, yielding short to moderate residence times (RTs) at the protein (1-44 min). While compounds from the fourth scaffold, i.e. Draflazine analogues, also had high affinity, they displayed significantly longer RTs, with one analogue (4) having a RT of over 10 h. Finally, a label-free assay was used to evaluate the impact of divergent ENT1 inhibitor binding kinetics in a functional assay. It was shown that the potency of compound 4 increased with longer incubation times, which was not observed for Draflazine, supporting the importance of long RT for increased target-occupancy and effect. In conclusion, our research shows that high affinity ENT1 inhibitors show a large variation in residence times at this transport protein. As a consequence, incorporation of binding kinetic parameters adds to the design criteria and may thus result in a different lead compound selection. Taken together, this kinetic approach could inspire future drug discovery in the field of ENT1 and membrane transport proteins in general.
Population analysis of the non-linear red blood cell partitioning of Draflazine following various infusion durations
Eur J Clin Pharmacol 1997;53(1):57-63.PMID:9349931DOI:10.1007/s002280050337.
Objective: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor Draflazine were investigated in 19 healthy male and female subjects (age range 22-55 years) after a 15-min i.v. infusion of 1 mg, immediately followed by infusions of variable rates (0.25, 0.5 and 1 mg.h-1) and variable duration (2-24 h). Methods: The parameters describing the capacity-limited specific binding of Draflazine to the nucleoside transporters located on erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of Draflazine (RBC occupancy) was evaluated as a pharmacodynamic endpoint. Results: The population typical value for the dissociation constant Kd (%CV) was 0.648 (12) ng.ml-1 plasma, expressing the very high affinity of Draflazine for the erythrocytes. The typical value of the specific maximal binding capacity Bmax (%CV) was 155 (2) ng.ml-1 RBC. The interindividual variability (%CV) was moderate for Kd (38.9%) and low for Bmax (7.8%). As a consequence, the variability in RBC occupancy of Draflazine was relatively low, allowing the justification of only one infusion scheme for all subjects. The specific binding of Draflazine to the red blood cells was a source of non-linearity in Draflazine pharmacokinetics. Steady-state plasma concentrations of Draflazine virtually increased dose-proportionally and steady state was reached at about 18 h after the start of the continuous infusion. The t1/2 beta averaged 11.0-30.5 h and the mean CL from the plasma was 327 to 465 ml.min-1. The disposition of Draflazine in whole blood was different from that in plasma. The mean t1/2 beta was 30.2 to 42.2 h and the blood CL averaged 17.4-35.6 ml.min-1. Conclusion: Although the pharmacokinetics of Draflazine were non-linear, the data of the present study demonstrate that Draflazine might be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed by an infusion of 1 mg.h-1, the RBC occupancy of Draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen could be justified in patients.
Population analysis of the non linear red blood cell partitioning and the concentration-effect relationship of Draflazine following various infusion rates
Br J Clin Pharmacol 1997 Jun;43(6):603-12.PMID:9205820DOI:10.1046/j.1365-2125.1997.00593.x.
Aims: To investigate the impact of the specific red blood cell binding on the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor Draflazine after i.v. administration at various infusion rates. It was also aimed to relate the red blood cell (RBC) occupancy of Draflazine to the ex vivo measured adenosine breakdown inhibition (ABI). Methods: Draflazine was administered to healthy volunteers as a 15-min i.v. infusion of 0.25, 0.5, 1, 1.5 and 2.5 mg immediately followed by an infusion of the same dose over 1 h. Plasma and whole blood concentrations were measured up to 120 h post dose, and were related to the ex vivo measured ABI, serving as a pharmacodynamic endpoint. The capacity-limited specific binding of Draflazine to the nucleoside transporter located on the erythrocytes was evaluated by a population approach. Results: The estimate of the population parameter typical value (%CV) of the binding constant Kd and the maximal specific binding capacity (Bmax) was 0.385 (3.5) ng ml-1 plasma and 158 (2.1) ng ml-1 RBC, respectively. The non-specific binding was low. The specific binding to the erythrocytes was a source of non-linearity in the pharmacokinetics of Draflazine. The total plasma clearance of Draflazine slightly decreased with increasing doses, whereas the total clearance in whole blood increased with increasing doses. The sigmoidal Emax equation was used to relate the plasma and whole blood concentration of Draflazine to the ex vivo determined ABI. In plasma, typical values (%CV) of Emax, IC50 and Hill factor were 81.4 (1.9)%, 3.76 (9.3) ng ml-1 and 1.06 (3.4), respectively. The relationship in whole blood was much steeper with population parameter typical values (%CV) of Emax, IC50 and Hill factor of 88.2 (2.0)%, 65.7 (2.8) ng ml-1 and 4.47 (5.5), respectively. The RBC occupancy of Draflazine did not coincide with the ex vivo measured ABI. The observed relationship between RBC occupancy and ABI was not directly proportional but similar for all studied infusion schemes. Conclusions: The findings of this study show that the occupancy of the nucleoside transporter by Draflazine should be at least 90% in order to inhibit substantially adenosine breakdown in vivo. On the basis of these findings it is suggested that a 15 min infusion of 1 mg Draflazine followed by an infusion of 1 mg h-1 could be appropriate in patients undergoing a coronary artery bypass grafting.