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| Targets |
Bimosiamose targets the selectin family, including E-selectin (CD62E), P-selectin (CD62P), and L-selectin (CD62L). Selectins are structurally related carbohydrate-binding proteins expressed on vascular endothelial cells and leukocytes, mediating the initial rolling of leukocytes on activated vascular endothelium, which is a crucial step in the initiation and maintenance of inflammation. As a pan-selectin antagonist, Bimosiamose simultaneously inhibits all three selectins, thereby blocking the leukocyte-endothelial adhesion cascade. The IC50 values against E-selectin, P-selectin, and L-selectin are 88 μM, 20 μM, and 86 μM, respectively. In HL-60 cell binding assays to P-selectin, Bimosiamose exhibits an IC50 of 70 μM.
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| ln Vitro |
Bimosiamose (TBC-1269) prevents the first rolling phase of recruitment, which is what prevents neutrophils from being drawn to inflammatory areas. Inhibiting cell recruitment, bimosiamose (TBC-1269) had no cytotoxic effects on neutrophils [1].
In vitro, Bimosiamose inhibits neutrophil recruitment to inflammatory sites by blocking the initial rolling phase of recruitment. In parallel-plate flow chamber experiments, Bimosiamose significantly inhibits HL-60 cell rolling (62% inhibition) and adhesion (38% inhibition) to activated human umbilical vein endothelial cells (HUVEC), and also inhibits E-selectin- or P-selectin-dependent lymphocyte adhesion under flow conditions. At a concentration of 129 μM, it reduces HL-60 cell adhesion to E-selectin and P-selectin. Importantly, Bimosiamose exhibits no cytotoxic effect on neutrophils, acting primarily through functional adhesion blockade. |
| ln Vivo |
Treatment with bimosiamose (TBC-1269; 25 mg/kg; i.v.; Sprague-Dawley rats) resulted in a marked improvement in survival. When TBC-1269 was given 15 minutes prior to reperfusion, the best overall survival rate of 70% was seen. Six hours following reperfusion, liver enzyme levels also significantly decreased. Additionally, neutrophil migration greatly improved (81%). Scores for histological damage also increased [1].
Bimosiamose demonstrates significant in vivo anti-inflammatory activity in various animal models. In a rat model of myocardial ischemia/reperfusion (I/R), intravenous administration of 25 mg/kg Bimosiamose at reperfusion significantly reduces the infarction area/area at risk by approximately 41% compared to vehicle control, decreases myocardial myeloperoxidase (MPO) activity by 78%, and preserves left ventricular function. In a hepatic I/R model, administration 15 minutes before reperfusion yields a best overall survival rate of 70%, improves neutrophil migration by 81%, and significantly reduces liver enzyme levels. In a mouse xenograft model of psoriasis, 200 mg/kg reduces skin scaliness, induration, and erythema. In a rat model of kidney allograft transplantation, Bimosiamose prolongs graft survival (mean survival time 8.8±0.75 days) and reduces intragraft production of cytokines and chemokines. |
| Enzyme Assay |
The affinity of Bimosiamose for selectins can be assessed using in vitro receptor-binding competition assays. The standard procedure is as follows: First, recombinant E-selectin, P-selectin, or L-selectin proteins are immobilized onto 96-well high-affinity binding plates (incubated overnight at 4°C). The wells are then blocked with blocking buffer (e.g., PBS containing 1% BSA) for 1-2 hours at room temperature to reduce nonspecific binding. Serial dilutions of Bimosiamose (e.g., 0.1 μM to 1,000 μM) are mixed with fluorescently or radioactively labeled known selectin ligands (e.g., sLe^x analogs) and added to the wells, followed by incubation at room temperature or 37°C for 1-2 hours to allow competition. After washing, remaining bound signals are detected using a fluorescence plate reader or scintillation counter. Competition curves are plotted, and the concentration of Bimosiamose required to inhibit 50% of labeled ligand binding (IC50) is calculated using nonlinear regression analysis. Additionally, surface plasmon resonance (SPR) technology can be employed to determine the binding kinetic parameters (ka, kd, and K_D) between Bimosiamose and immobilized selectin proteins in real time.
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| Cell Assay |
The in vitro cellular activity of Bimosiamose can be assessed using HL-60 cell adhesion assays. The standard procedure is as follows: First, human umbilical vein endothelial cells (HUVEC) or selectin-expressing cells are cultured to confluence and treated with 10 ng/mL TNF-α for 4-6 hours or 10 μM histamine to induce E-selectin or P-selectin expression. Fluorescently labeled (e.g., Calcein-AM) HL-60 cells are pre-incubated with various concentrations of Bimosiamose (e.g., 0.1-1000 μM) at 37°C for 15-30 minutes. The pretreated HL-60 cells are then added to the selectin-activated endothelial monolayer and incubated under static or flow conditions (e.g., parallel-plate flow chamber at 1-2 dyn/cm² shear stress) for 15-30 minutes. After gentle washing with buffer to remove non-adherent cells, adherent cells are counted under a fluorescence microscope or quantified using a fluorescence plate reader. The percentage inhibition of adhesion for Bimosiamose-treated groups relative to controls is calculated, and IC50 values are fitted. Cytotoxicity control experiments (e.g., LDH release assay or MTT assay) should be performed in parallel to confirm that the observed inhibitory effects are due to adhesion blockade rather than cytotoxicity.
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| Animal Protocol |
Animal/Disease Models: Ischemia-reperfusion (I/R) SD (SD (Sprague-Dawley)) rats (200-225g) [1]
Doses: 25 mg/kg Route of Administration: intravenous (iv) (iv)injection Experimental Results: Compared with the control group, the survival rate was significant Increase. The in vivo efficacy of Bimosiamose is commonly evaluated using a rat model of myocardial ischemia/reperfusion (I/R) injury. The standard procedure is as follows: Male Sprague-Dawley rats (200-225 g body weight) are anesthetized with intraperitoneal pentobarbital sodium (50 mg/kg), intubated for mechanical ventilation, and subjected to left thoracotomy at the fourth intercostal space to expose the heart. A 6-0 suture is passed under the left anterior descending coronary artery (LAD), which is occluded for 30 minutes to induce myocardial ischemia (confirmed by ST-segment elevation on ECG). Reperfusion is achieved by releasing the ligature for 24 hours. Bimosiamose is dissolved in sterile saline and administered as a single intravenous injection at 25 mg/kg via the tail vein at the onset of reperfusion. Control rats receive an equal volume of saline. At the end of reperfusion, hearts are excised and stained with TTC to quantify infarct area. MPO activity is measured to assess neutrophil infiltration. Blood samples are collected before and after treatment to evaluate liver function indicators (ALT, AST). Survival curves are recorded (observed every 6 hours) and analyzed using the Kaplan-Meier method. |
| ADME/Pharmacokinetics |
The pharmacokinetic profile of Bimosiamose has been studied in healthy male volunteers. Following intravenous administration (0.5-30 mg/kg), the maximum plasma concentration (Cmax) is 675±11 μg/mL, with a tmax of 0.36±0.13 hours, elimination half-life (t1/2) of 4.1±1.0 hours, and AUC(0-∞) of 1,360±393 h·μg/mL at the 30 mg/kg dose. Clearance and apparent volume of distribution decrease with increasing dose (22±6 mL/kg/h and 40±13 mL/kg, respectively, at the highest dose), while mean residence time increases to 1.8±0.35 hours. Following inhaled administration, systemic bioavailability is low, with detectable plasma concentrations (Cmax 64 ng/mL) observed only at higher doses (≥50 mg twice daily or 105 mg once daily). Bimosiamose has a high topological polar surface area (TPSA 273.36), multiple hydrogen bond donors (10), and a LogP of 5.95.
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| Toxicity/Toxicokinetics |
The toxicological profile of Bimosiamose has been primarily assessed through multiple Phase I clinical trials in healthy volunteers, demonstrating a favorable safety and tolerability profile. In two Phase I trials (single-dose escalation and multiple-dose studies) involving over 80 healthy male subjects receiving inhaled doses ranging from 2-140 mg, no deaths or severe adverse events occurred. Eleven mild adverse events were observed in the dose-escalation study and 34 mild adverse events in the multiple-dose study, with adverse events being slightly more frequent at the highest dose (140 mg). In a human endotoxemia model, intravenous infusion of 30 mg/kg Bimosiamose was reported to be safe and well tolerated. In vitro studies confirm that Bimosiamose exhibits no cytotoxic effect on neutrophils. In animal studies, no overt organ toxicity was observed following high-dose administration, with protective reductions in liver enzymes (ALT, AST) detected only in ischemia models.
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| References | |
| Additional Infomation |
Drug Indication
This drug has been investigated for the treatment of asthma, psoriasis and psoriasis-related diseases, atopic dermatitis, inflammatory diseases (not specified), and chronic obstructive pulmonary disease (COPD). |
| Molecular Formula |
C46H54O16
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| Molecular Weight |
862.922
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| Exact Mass |
862.341
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| CAS # |
187269-40-5
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| Related CAS # |
Bimosiamose disodium;187269-60-9
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| PubChem CID |
9811353
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
1051.0±65.0 °C at 760 mmHg
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| Flash Point |
309.7±27.8 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.649
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| LogP |
3.04
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| Hydrogen Bond Donor Count |
10
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| Hydrogen Bond Acceptor Count |
16
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| Rotatable Bond Count |
19
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| Heavy Atom Count |
62
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| Complexity |
1270
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| Defined Atom Stereocenter Count |
10
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| SMILES |
C1=CC(=CC(=C1)C2=C(C=CC(=C2)CCCCCCC3=CC(=C(C=C3)O[C@@H]4[C@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O)C5=CC=CC(=C5)CC(=O)O)O[C@@H]6[C@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O)CC(=O)O
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| InChi Key |
RYWCQJDEHXJHRI-XJMXIVSISA-N
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| InChi Code |
InChI=1S/C46H54O16/c47-23-35-39(53)41(55)43(57)45(61-35)59-33-15-13-25(19-31(33)29-11-5-9-27(17-29)21-37(49)50)7-3-1-2-4-8-26-14-16-34(60-46-44(58)42(56)40(54)36(24-48)62-46)32(20-26)30-12-6-10-28(18-30)22-38(51)52/h5-6,9-20,35-36,39-48,53-58H,1-4,7-8,21-24H2,(H,49,50)(H,51,52)/t35-,36-,39-,40-,41+,42+,43+,44+,45+,46+/m1/s1
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| Chemical Name |
2,2'-(hexane-1,6-diylbis(6'-(((2R,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-[1,1'-biphenyl]-3',3-diyl))diacetic acid
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| Synonyms |
TBC 1269 TBC1269 TBC-1269Bimosiamose
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~115.89 mM)
0.1 M NaOH : ~25 mg/mL (~28.97 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.90 mM) (saturation unknown) in 5% DMSO + 40% PEG300 +5% Tween-80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1589 mL | 5.7943 mL | 11.5886 mL | |
| 5 mM | 0.2318 mL | 1.1589 mL | 2.3177 mL | |
| 10 mM | 0.1159 mL | 0.5794 mL | 1.1589 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01108913 | COMPLETED | Drug: Bimosiamose Drug: Placebo |
Chronic Obstructive Pulmonary Disease | Revotar Biopharmaceuticals AG | Phase 2 | |
| NCT00962481 | COMPLETED | Drug: Bimosiamose Drug: Placebo |
Chronic Obstructive Pulmonary Disease (COPD) | Revotar Biopharmaceuticals AG | Phase 2 | |
| NCT00823693 | COMPLETED | Drug: Bimosiamose Cream Drug: Placebo Cream |
Psoriasis | Revotar Biopharmaceuticals AG | Phase 2 |
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