Odiparcil
(Synonyms: SB-424323) 目录号 : GC36792
Odiparcil (SB-424323) 是一种具有口服活性 beta-d-thioxyloside 类似物，具有抗血栓形成活性，可降低不良出血事件的风险，Odiparcil (SB-424323) 是一种间接凝血酶抑制剂，通过激活抗凝血酶 II (肝素辅助因子 II) 发挥其抗凝血作用。
Cas No.:137215-12-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Odiparcil (SB-424323) is an orally active beta-d-thioxyloside analog with antithrombotic activity associated with a reduced risk of adverse bleeding events. Odiparcil (SB-424323) is indirect thrombin inhibitor that exerts its anticoagulant effect through activation of antithrombin II (heparin cofactor II) [1][2]. Thrombin[2]
[1]. Myers AL, et al. Characterization of total plasma glycosaminoglycan levels in healthy volunteers following oral administration of a novel antithrombotic odiparcil with aspirin or enoxaparin. J Clin Pharmacol. 2008 Oct;48(10):1158-70 [2]. Levy JH, et al. Novel oral anticoagulants: implications in the perioperative setting. Anesthesiology. 2010 Sep;113(3):726-45.
| Cas No. | 137215-12-4 | SDF | |
| 别名 | SB-424323 | ||
| Canonical SMILES | O=C1OC2=CC(OC3[C@H](O)[C@@H](O)[C@H](O)CS3)=CC=C2C(C)=C1 | ||
| 分子式 | C15H16O6S | 分子量 | 324.35 |
| 溶解度 | DMSO : 100 mg/mL (308.31 mM; Need ultrasonic) | 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 | 3.0831 mL | 15.4154 mL | 30.8309 mL |
| 5 mM | 0.6166 mL | 3.0831 mL | 6.1662 mL |
| 10 mM | 0.3083 mL | 1.5415 mL | 3.0831 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Odiparcil, a potential glycosaminoglycans clearance therapy in mucopolysaccharidosis VI-Evidence from in vitro and in vivo models
PLoS One 2020 May 15;15(5):e0233032.PMID:32413051DOI:10.1371/journal.pone.0233032.
Mucopolysaccharidoses are a class of lysosomal storage diseases, characterized by enzymatic deficiency in the degradation of specific glycosaminoglycans (GAG). Pathological accumulation of excess GAG leads to multiple clinical symptoms with systemic character, most severely affecting bones, muscles and connective tissues. Current therapies include periodic intravenous infusion of supplementary recombinant enzyme (Enzyme Replacement Therapy-ERT) or bone marrow transplantation. However, ERT has limited efficacy due to poor penetration in some organs and tissues. Here, we investigated the potential of the β-D-xyloside derivative Odiparcil as an oral GAG clearance therapy for Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). In vitro, in bovine aortic endothelial cells, Odiparcil stimulated the secretion of sulphated GAG into culture media, mainly of chondroitin sulphate (CS) /dermatan sulphate (DS) type. Efficacy of Odiparcil in reducing intracellular GAG content was investigated in skin fibroblasts from MPS VI patients where Odiparcil was shown to reduce efficiently the accumulation of intracellular CS with an EC50 in the range of 1 μM. In vivo, in wild type rats, after oral administrations, Odiparcil was well distributed, achieving μM concentrations in MPS VI disease-relevant tissues and organs (bone, cartilage, heart and cornea). In MPS VI Arylsulphatase B deficient mice (Arsb-), after chronic oral administration, Odiparcil consistently stimulated the urinary excretion of sulphated GAG throughout the treatment period and significantly reduced tissue GAG accumulation in liver and kidney. Furthermore, Odiparcil diminished the pathological cartilage thickening observed in trachea and femoral growth plates of MPS VI mice. The therapeutic efficacy of Odiparcil was similar in models of early (treatment starting in juvenile, 4 weeks old mice) or established disease (treatment starting in adult, 3 months old mice). Our data demonstrate that Odiparcil effectively diverts the synthesis of cellular glycosaminoglycans into secreted soluble species and this effect can be used for reducing cellular and tissue GAG accumulation in MPS VI models. Therefore, our data reveal the potential of Odiparcil as an oral GAG clearance therapy for MPS VI patients.
Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with Odiparcil
J Inherit Metab Dis 2022 Mar;45(2):340-352.PMID:34910312DOI:10.1002/jimd.12467.
Mucopolysaccharidosis (MPS) disorders are a group of rare, progressive lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) and classified according to the deficient enzyme. Enzyme replacement therapy (ERT) of MPS VI has limited effects on ophthalmic, cardiovascular, and skeletal systems. Odiparcil is an orally available small molecule that results in the synthesis of odiparcil-linked GAGs facilitating their excretion and reducing cellular and tissue GAG accumulation. Improve MPS treatment was a Phase 2a study of the safety, pharmacokinetics/pharmacodynamics, and efficacy of two doses of Odiparcil in patients with MPS VI. The core study was a 26-week, randomized, double-blind, placebo-controlled trial in patients receiving ERT and an open-label, noncomparative, single-dose cohort not receiving ERT. Patients aged ≥ 16 years receiving ERT were randomized to Odiparcil 250 or 500 mg twice daily or placebo. Patients without ERT received Odiparcil 500 mg twice daily. Of 20 patients enrolled, 13 (65.0%) completed the study. Odiparcil increased total urine GAGs (uGAGs), chondroitin sulfate, and dermatan sulfate concentrations. A linear increase in uGAG levels and Odiparcil exposure occurred with increased Odiparcil dose. Odiparcil demonstrated a good safety and tolerability profile. Individual analyses found more improvements in pain, corneal clouding, cardiac, vascular, and respiratory functions in the Odiparcil groups vs placebo. This study confirmed the mechanism of action and established the safety of Odiparcil with clinical beneficial effects after only a short treatment duration in an advanced stage of disease. Further assessment of Odiparcil in younger patients is needed.
MPS VI associated ocular phenotypes in an MPS VI murine model and the therapeutic effects of Odiparcil treatment
Mol Genet Metab 2022 Feb;135(2):143-153.PMID:34417096DOI:10.1016/j.ymgme.2021.07.008.
Maroteaux - Lamy syndrome (mucopolysaccharidosis type VI, MPS VI) is a lysosomal storage disease resulting from insufficient enzymatic activity for degradation of the specific glycosaminoglycans (GAG) chondroitin sulphate (CS) and dermatan sulphate (DS). Among the most pronounced MPS VI clinical manifestations caused by cellular accumulation of excess CS and DS are eye disorders, in particular those that affect the cornea. Ocular manifestations are not treated by the current standard of care, enzyme replacement therapy (ERT), leaving patients with a significant unmet need. Using in vitro and in vivo models, we previously demonstrated the potential of the β-D-xyloside, Odiparcil, as an oral GAG clearance therapy for MPS VI. Here, we characterized the eye phenotypes in MPS VI arylsulfatase B deficient mice (Arsb-) and studied the effects of Odiparcil treatment in early and established disease models. Severe levels of opacification and GAG accumulation were detected in the eyes of MPS VI Arsb- mice. Histological examination of MPS VI Arsb- eyes showed an aggregate of corneal phenotypes, including reduction in the corneal epithelium thickness and number of epithelial cell layers, and morphological malformations in the stroma. In addition, colloidal iron staining showed specifically GAG accumulation in the cornea. Orally administered Odiparcil markedly reduced GAG accumulation in the eyes of MPS VI Arsb- mice in both disease models and restored the corneal morphology (epithelial layers and stromal structure). In the early disease model of MPS VI, Odiparcil partially reduced corneal opacity area, but did not affect opacity area in the established model. Analysis of GAG types accumulating in the MPS VI Arsb- eyes demonstrated major contribution of DS and CS, with some increase in heparan sulphate (HS) as well and all were reduced with Odiparcil treatment. Taken together, we further reveal the potential of Odiparcil to be an effective therapy for eye phenotypes associated with MPS VI disease.
A comparison of the beta-D-xyloside, Odiparcil, to warfarin in a rat model of venous thrombosis
J Thromb Haemost 2006 Sep;4(9):1989-96.PMID:16961606DOI:10.1111/j.1538-7836.2006.02064.x.
Background: A significant need exists for new chronic oral anticoagulation therapies to replace warfarin. Previous studies have shown that beta-D-xylosides, which prime glycosaminoglycan (GAG) synthesis, have antithrombin and antithrombotic activity. In the following report, a new orally active beta-D-xyloside (Odiparcil) has been characterized in a rat model of venous thrombosis and its efficacy and bleeding liability compared to warfarin. Additionally, studies were conducted to investigate Odiparcil's ex vivo antithrombin and antiplatelet activity, and also to explore the potential utility of protamine sulfate as a neutralizing agent. Methods and results: In vivo thrombosis studies were conducted in a rat inferior vena cava model, and bleeding studies in a rat tail transection model. Following oral dosing, warfarin and Odiparcil produced dose-related suppression of thrombus formation. A therapeutically relevant dose of warfarin in this model (international normalized ratio; INR 3.0) achieved approximately 65% inhibition of thrombus formation. Warfarin caused dose-related significant increases in bleeding indices. Odiparcil antithrombotic activity was limited by its mechanism to a maximum suppression of thrombus formation of 65-70%, and did not prolong bleeding indices. Additionally, odiparcil-induced heparin cofactor II (HCII)-dependent antithrombin activity was shown to be a function of dermatan sulfate-like GAG production. Other than thrombin-related effects, no Odiparcil effects on platelet function were observed. In antidote studies, it was demonstrated that odiparcil-induced antithrombotic activity could be partially neutralized by protamine sulfate. Conclusions: These experiments suggest that an antithrombotic approach based upon xyloside induction of circulating GAGs may have the potential to approximate the efficacy of warfarin and yet with a reduced risk to hemostasis.
Current and Emerging Direct Oral Anticoagulants: State-of-the-Art
Semin Thromb Hemost 2019 Jul;45(5):490-501.PMID:31216588DOI:10.1055/s-0039-1692703.
Anticoagulant drugs comprise a specific subcategory of antithrombotic agents that act to inhibit blood coagulation at various stages, reducing clot development and ultimately lowering the risk of developing new-onset or recurrent thrombosis. Although the long history of anticoagulant drugs has been characteristically shaped by coumarin and heparin derivatives, a new generation of direct oral anticoagulants (DOACs), which specifically inhibit thrombin or activated factor X, combine many advantages of their progenitor drugs, and hence are prepotently revolutionizing the landscape of antithrombotic therapy. Several drugs (apixaban [BMS-562247], dabigatran [BIBR953], edoxaban [DU-1766], rivaroxaban [BAY 59-7939]) have already received widespread approval by national or supranational medicinal agencies. This narrative article provides a state-of-the-art for these and for several other DOACs at different stages of clinical evaluation (betrixaban, darexaban, eribaxaban, letaxaban, nokxaban), and certain others whose development has been discontinued (AZD-0837, fidexaban, LY517717, Odiparcil, otamixaban, TTP889, and ximelagatran). What clearly emerges from our analysis is that DOACs sharing very similar mechanisms of action are still characterized by different efficacy and safety profiles. This not only depends on biochemical, biological, and pharmacokinetic characteristics, but also on lack of standardization between different clinical trials in terms of targeted disease, patient recruitment, sample size, duration and endpoints, as well as lack of harmonization around procedures used for drug licensing. These factors contribute to challenging the minds of physicians, who may find difficulty navigating their way through multiple indications, different pharmacological profiles, various side effects, and specific drug-to-drug interactions. Such considerations also burden laboratory professionals, who may face organizational and economic challenges in developing and/or implementing multiple assays to assess the pharmacodynamics (effect on coagulation) or pharmacokinetics (drug levels) of DOACs.