Bimosiamose (TBC 1269)
(Synonyms: TBC-1269) 目录号 : GC33908
A pan-selectin inhibitor
Cas No.:187269-40-5
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
Bimosiamose is a pan-selectin inhibitor (IC50s = 88, 20, and 86 ?M for E-, P-, and L-selectin, respectively).1 It reduces adhesion of HL-60 cells to E- and P-selectin when used at a concentration of 129 ?M.2 In vivo, bimosiamose (200 mg/kg) reduces skin scaliness, induration, and erythema in a patient-derived xenograft mouse model of psoriasis. It decreases hepatic alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and myeloperoxidase (MPO) levels and reduces neutrophil infiltration in a rat model of severe hepatic ischemia-reperfusion injury.1 Bimosiamose also prevents nematode-induced late airway reactivity in sheep and reduces airway hyperresponsiveness in a mouse model of asthma.3
1.Palma-Vargas, J.M., Toledo-Pereyra, L., Dean, R.E., et al.Small-molecule selectin inhibitor protects against liver inflammatory response after ischemia and reperfusionJ. Am. Coll. Surg.185(4)365-372(1997) 2.Friedrich, M., Bock, D., Philipp, S., et al.Pan-selectin antagonism improves psoriasis manifestation in mice and manArch. Dermatol. Res.297(8)345-351(2008) 3.Aydt, E., and Wolff, G.Development of synthetic pan-selectin antagonists: A new treatment strategy for chronic inflammation in asthmaPathobiology70(5)297-301(2002)
| Cas No. | 187269-40-5 | SDF | |
| 别名 | TBC-1269 | ||
| Canonical SMILES | OC[C@H]([C@@H](O)[C@H](O)[C@@H]1O)O[C@@H]1OC(C=C2)=C(C3=CC(CC(O)=O)=CC=C3)C=C2CCCCCCC(C=C4)=CC(C5=CC(CC(O)=O)=CC=C5)=C4O[C@H]6O[C@@H]([C@@H](O)[C@H](O)[C@@H]6O)CO | ||
| 分子式 | C46H54O16 | 分子量 | 862.91 |
| 溶解度 | DMSO: 125 mg/mL (144.86 mM); 0.1 M NaOH: 25 mg/mL (28.97 mM; ultrasonic and adjust pH to 10 with NaOH) | 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 | 1.1589 mL | 5.7943 mL | 11.5887 mL |
| 5 mM | 0.2318 mL | 1.1589 mL | 2.3177 mL |
| 10 mM | 0.1159 mL | 0.5794 mL | 1.1589 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。
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The anti-inflammatory effects of a selectin ligand mimetic, TBC-1269, are not a result of competitive inhibition of leukocyte rolling in vivo
J Leukoc Biol 2005 Jan;77(1):59-66.PMID:15466915DOI:10.1189/jlb.1103573.
Selectins and their ligands support leukocyte rolling, facilitating the subsequent firm adhesion and migration that occur during inflammation. TBC-1269 (Bimosiamose), a structural mimetic of natural selectin ligands, inhibits P-, E-, and L-selectin in vitro, has anti-inflammatory effects in vivo, and recently underwent phase II clinical trials for childhood asthma and psoriasis. We studied whether the anti-inflammatory effects of TBC-1269 could be related to leukocyte rolling in vivo. Although TBC-1269 inhibited rolling of a murine leukocyte cell line on murine P-selectin in vitro and thioglycollate-induced peritonitis in vivo, it did not alter leukocyte rolling in mouse cremaster venules. TBC-1269 reduced neutrophil recruitment in thioglycollate-induced peritonitis in wild-type and P-selectin-/- mice but not in E-selectin-/- mice. We suggest that the in vivo effects of TBC-1269 may be mediated through E-selectin but do not appear to involve leukocyte rolling.
The pharmacokinetics of subcutaneously injected Bimosiamose disodium in healthy male volunteers
Biopharm Drug Dispos 2007 Dec;28(9):475-84.PMID:17876866DOI:10.1002/bdd.574.
Bimosiamose is a novel synthetic pan-selectin antagonist developed for the treatment of acute and chronic inflammatory disorders. Therefore the pharmacokinetics of Bimosiamose disodium were studied in healthy male volunteers after single and multiple subcutaneous injections. A randomized, double-blind, placebo-controlled dose escalation trial was carried out. The subjects received subcutaneous injections of placebo or 100, 200 or 300 mg Bimosiamose disodium into the abdomen. Plasma and urine concentrations of Bimosiamose were determined. The maximum plasma concentration was 2.17+/-0.70 microg/ml and the AUC(0-infinity) 11.1+/-2.9 h microg/ml after the highest dose on day 1 (mean+/-SD). For the apparent clearance CL/f 28.7+/-7.3 l/h and the terminal half life t(1/2) 3.7+/-0.6 h were calculated. The mean residence time MRT(infinity) of 5.5 to 6.3 h for s.c. injection exceeded that after i.v. infusion due to an extended absorption time. For multiple dosing, constant pre-dose concentrations of about 20 ng/ml may be reached after two subsequent doses of 200 or 300 mg Bimosiamose disodium once daily. Almost 15% of the administered drug was excreted unchanged in urine. Moreover, Bimosiamose was well tolerated.
Tolerability and pharmacokinetics of inhaled Bimosiamose disodium in healthy males
Br J Clin Pharmacol 2007 Apr;63(4):451-8.PMID:17067318DOI:10.1111/j.1365-2125.2006.02775.x.
Aims: The aim of these first-in-human studies was to investigate the tolerability and the pharmacokinetics of Bimosiamose disodium (TBC1269Z) administered by inhalation. Methods: Two randomized, double-blind, placebo-controlled Phase I trials were performed in healthy males. In a single-dose escalating study 48 subjects received doses of 2-140 mg Bimosiamose disodium by inhalation and in a multiple-dose study 32 subjects received 8-70 mg Bimosiamose disodium twice daily. In both studies 4 ml of the drug solution was administered via nebulizer over 15 min. Adverse events, vital signs, ECG, clinical laboratory parameters and forced expiratory volume in 1 s (FEV(1)) data were recorded and nasopharyngeal examinations were performed to address the safety and tolerability. Blood was collected for the determination of plasma concentrations of Bimosiamose. Results: All subjects completed the study. No deaths or severe adverse events occurred. Eleven mild adverse events occurred in the dose-escalation study and 34 in the multiple-dose study after inhalation of Bimosiamose disodium. Adverse events were more frequent at the highest dose (140 mg) of the dose-escalation study. For placebo treatment one moderate adverse event was observed in the dose-escalation study after placebo treatment, eight mild and three moderate adverse events occurred in the multiple-dose study. Bimosiamose was detected in plasma (maximum concentration 64 ng ml(-1)) only at doses > or =50 mg given twice daily and 105 mg once daily. For the highest dose a median value of 5746 h ng ml(-1) was determined for the AUC over the entire period of treatment of the multiple-dose study. Conclusion: The results suggest that single and multiple inhalation of Bimosiamose disodium up to 70 mg is well tolerated in healthy males. Systemic bioavailability after inhalation is low.
Blockade of cell adhesion by a small molecule selectin antagonist attenuates myocardial ischemia/reperfusion injury
Eur J Pharmacol 2003 Nov 28;481(2-3):217-25.PMID:14642789DOI:10.1016/j.ejphar.2003.09.040.
Reperfusion injury is related closely to inflammatory reactions such as the activation and accumulation of neutrophils. We investigated the efficacy of a novel small molecule selectin antagonist (Bimosiamose) in a rat model of transient left coronary artery occlusion (30 min) and reperfusion (24 h). Treatment with Bimosiamose (25 mg/kg, intravenously at reperfusion) showed a significant reduction in infarction area/area at risk of approximately 41% compared to vehicle control (P=0.01) and preserved the left ventricular function. The accumulation of polymorphonuclear neutrophils at the site of area at risk was decreased significantly, accompanied by 78% reduction of the myeloperoxidase activity. Parallel-plate flow chamber analysis revealed that Bimosiamose showed a significant inhibition in rolling (62%, P<0.001) and adhesion (38%, P<0.05) of HL-60 cells to activated human umbilical vein endothelial cells compared with vehicle control. This study demonstrates for the first time that Bimosiamose, a novel small molecule selectin antagonist, attenuates significantly ischemia/reperfusion injury.
Development of synthetic pan-selectin antagonists: a new treatment strategy for chronic inflammation in asthma
Pathobiology 2002;70(5):297-301.PMID:12771513DOI:10.1159/000070746.
Asthma is characterized by chronic inflammation of large and small airways maintained by extravasation of leukocytes from the bloodstream into the surrounding peribronchial tissue. The process of extravasation is of crucial importance in inflammation and is mediated by a sequenced and concerted action between different adhesion molecules on endothelial cells and ligands on leukocytes. In this context, initial rolling and tethering is generally considered to be the primary event which is mediated by selectins, a family of glycoproteins comprised of E-, P- and L-selectin. Their role in asthma has been demonstrated in a variety of animal models, showing that all three selectins are involved in the chronic inflammation in asthma. Therefore, selectins are an attractive target where pan-selectin antagonism is the desired treatment strategy. Here, we give an overview of the status of the preclinical and clinical development of Bimosiamose, the most advanced synthetic pan-selectin antagonist as a treatment for asthma.