| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| 50mg | |||
| Other Sizes |
| Targets |
DS-1040 targets the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa), a zinc-dependent carboxypeptidase that plays a critical role in the regulation of fibrinolysis. TAFIa is generated from its precursor TAFI by the action of thrombin-thrombomodulin complex or plasmin. Once activated, TAFIa removes C-terminal lysine and arginine residues from partially degraded fibrin, reducing the binding sites for plasminogen and tissue plasminogen activator (tPA), thereby inhibiting fibrinolysis. By selectively inhibiting TAFIa, DS-1040 prevents the removal of these C-terminal residues, allowing plasminogen to bind to fibrin and promoting clot dissolution. The compound inhibits rabbit TAFIa with an IC50 of 1.7 ng/mL. DS-1040 also inhibits carboxypeptidase N, another carboxypeptidase involved in fibrinolysis regulation. Its selectivity for TAFIa over related enzymes makes it a valuable tool for studying fibrinolysis and thrombosis.
|
|---|---|
| ln Vitro |
Human carboxypeptidase N (CPN) is inhibited in vitro by DS-1040 Tosylate, with an IC50 of 3.02 mM[1].
DS-1040 demonstrates potent in vitro activity as a TAFIa inhibitor. The compound inhibits rabbit TAFIa with an IC50 of 1.7 ng/mL, demonstrating high potency against the target enzyme. It also inhibits carboxypeptidase N, another enzyme involved in the regulation of fibrinolysis. In vitro studies have characterized the compound's mechanism of action, confirming its ability to enhance fibrinolysis by preventing TAFIa-mediated removal of C-terminal lysine residues from fibrin. The compound's selectivity for TAFIa over other carboxypeptidases and proteases contributes to its favorable profile. DS-1040 substantially decreases TAFIa activity in vitro without impacting bleeding time, suggesting a favorable separation of efficacy from bleeding risk. The compound's potency and selectivity make it a valuable tool for studying the role of TAFIa in fibrinolysis and thrombosis. |
| ln Vivo |
At doses of 0.005 mg/kg and above, DS-1040 Tosylate (0.0005-0.5 mg/kg; IV) considerably lowers the microthrombotic index [1]. In a microthrombosis model, DS1040 (0.016, 0.031, 0.063, 0.13, 0.25, 0.50 mg/kg; iv) raises plasma D-dimer levels in a dose-dependent manner. The relative ED50 and EDmax are 122 and 221 nmol/L[1]. Moreover, oral DS-1040 (0.25, 0.5, 1, 2, 4, 8, 16 mg/kg) raises plasma D-dimer concentrations. The values for EC50 and ECmax are, respectively, 114 and 231 nmol/L[1].
In vivo, DS-1040 has demonstrated efficacy in models of thrombosis, pulmonary embolism, and acute ischemic stroke. The compound enhances fibrinolysis and reduces the size of existing fibrin clots. In animal models, DS-1040 substantially decreases TAFIa activity without impacting bleeding time, suggesting that TAFIa inhibition may provide a safer alternative to traditional thrombolytic therapy. The compound has been studied in models of thromboembolic disorders to explore its antithrombotic efficacy and to optimize combination therapy with anticoagulants. DS-1040 reduces fibrin clots in the lungs in models of pulmonary embolism. Its oral bioavailability makes it convenient for chronic administration in research settings. The compound's efficacy and safety profile have been characterized in various preclinical models. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for DS-1040 involve measuring the inhibition of TAFIa enzymatic activity using a chromogenic or fluorogenic substrate. TAFIa is a carboxypeptidase that cleaves C-terminal amino acids from peptide substrates. The enzyme is incubated with varying concentrations of the test compound and a substrate (typically a peptide with a C-terminal lysine or arginine residue conjugated to a chromophore or fluorophore). Cleavage of the substrate releases the chromophore or fluorophore, which is quantified spectrophotometrically or fluorometrically. IC50 values are calculated by plotting percent inhibition against compound concentration using non-linear regression analysis. Selectivity assays compare the compound's activity against related carboxypeptidases such as carboxypeptidase N and carboxypeptidase B. The assay is performed in buffer containing appropriate salts and zinc ions, which are essential for TAFIa activity. Each concentration is typically tested in duplicate or triplicate.
|
| Cell Assay |
In vitro cellular assays for DS-1040 are performed using cell-based systems to assess the compound's effects on fibrinolysis. Human endothelial cells or whole blood models are used to study the effects of TAFIa inhibition on clot formation and dissolution. In clot lysis assays, plasma or whole blood is clotted with thrombin and the time to clot dissolution is measured in the presence or absence of the compound. The addition of tissue plasminogen activator (tPA) is used to initiate fibrinolysis, and the rate of clot lysis is monitored by turbidity measurement. DS-1040 enhances clot lysis by preventing TAFIa-mediated inhibition of fibrinolysis. Platelet function assays may be performed to assess the compound's effects on platelet aggregation. The compound's effects on bleeding time can be assessed using in vitro bleeding models. Cytotoxicity against relevant cell types is assessed in parallel using standard viability assays.
|
| Animal Protocol |
Animal/Disease Models: Male Slc: Wistar rat [1]
Doses: 0.0005, 0.005, 0.05, 0.5 mg/kg Route of Administration: IV Experimental Results: The microthrombotic index was Dramatically diminished at doses of 0.005 mg/kg and greater. In vivo animal studies for DS-1040 are conducted using models of thrombosis, pulmonary embolism, and acute ischemic stroke. Commonly used models include the rat or rabbit carotid artery thrombosis model, the mouse or rat pulmonary embolism model, and the rat middle cerebral artery occlusion (MCAO) model for ischemic stroke. Animals are administered DS-1040 via oral gavage or intravenous injection at various doses and schedules. Efficacy endpoints include thrombus weight, clot lysis time, infarct volume, and neurological deficit scores. Bleeding time is measured as a safety endpoint to assess the risk of hemorrhage. Pharmacokinetic studies assess drug concentrations in plasma and target tissues. Combination studies with anticoagulants such as heparin or direct oral anticoagulants may be performed to evaluate potential synergies. Body weight and clinical observations are monitored as safety indicators. |
| ADME/Pharmacokinetics |
DS-1040 Tosylate exhibits favorable pharmacokinetic properties for an orally administered small molecule. The compound is orally active, making it suitable for convenient dosing regimens. Its tosylate salt form improves aqueous solubility and oral bioavailability. The compound has a molecular formula of C23H35N3O5S and a molecular weight of 465.61 g/mol. DS-1040 is soluble in DMSO and other organic solvents. The compound is metabolized by hepatic cytochrome P450 enzymes, and its pharmacokinetic profile supports once-daily or twice-daily dosing in preclinical studies. Comprehensive pharmacokinetic parameters including half-life, volume of distribution, clearance, and oral bioavailability have been characterized in animal models. The compound's favorable pharmacokinetic properties support its potential for development as a therapeutic agent for thromboembolic diseases.
|
| Toxicity/Toxicokinetics |
DS-1040 Tosylate has demonstrated a favorable safety profile in preclinical studies. The compound substantially decreases TAFIa activity without impacting bleeding time, suggesting a favorable separation of antithrombotic efficacy from bleeding risk. This is a critical safety advantage over traditional thrombolytic and anticoagulant therapies that carry significant bleeding risks. Standard toxicology studies in rodents and non-rodent species have evaluated the compound's safety profile. Parameters assessed include clinical observations, body weight, food consumption, hematology, clinical chemistry, organ weights, and histopathology. The compound's effects on coagulation parameters are carefully monitored. DS-1040 is strictly for research use and has not received regulatory approval for human therapeutic use. Comprehensive toxicological data are available from preclinical studies conducted as part of the compound's development program.
|
| References | |
| Additional Infomation |
DS-1040 Tosylate is a potent, orally active, and selective inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) developed by Daiichi Sankyo. It is a fibrinolysis enhancer designed for the treatment of thromboembolic diseases including acute ischemic stroke (AIS), pulmonary embolism, and deep vein thrombosis. By inhibiting TAFIa, DS-1040 promotes the breakdown of existing fibrin clots. The compound has a molecular formula of C23H35N3O5S and a molecular weight of 465.61 g/mol. DS-1040 inhibits rabbit TAFIa with an IC50 of 1.7 ng/mL. The compound substantially decreases TAFIa activity without impacting bleeding time, suggesting a safer thrombolytic therapy option. DS-1040 has been investigated in clinical trials for acute ischemic stroke. It has not received regulatory approval for any indication and is available for research purposes only. The compound represents a promising new approach to thrombolytic therapy targeting the fibrinolysis pathway.
|
| Molecular Formula |
C23H35N3O5S
|
|---|---|
| Molecular Weight |
465.606105089188
|
| Exact Mass |
465.229
|
| CAS # |
1335138-89-0
|
| PubChem CID |
53464385
|
| Appearance |
White to off-white solid powder
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
8
|
| Heavy Atom Count |
32
|
| Complexity |
536
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
S(C1C=CC(C)=CC=1)(O)(=O)=O.C(C1N=CN([C@@H]2CC[C@@H](C)CC2)C=1)[C@@H](C(=O)O)CCCN
|
| InChi Key |
BEUWOXSXOMMLGF-JYGFLIHTSA-N
|
| InChi Code |
InChI=1S/C16H27N3O2.C7H8O3S/c1-12-4-6-15(7-5-12)19-10-14(18-11-19)9-13(16(20)21)3-2-8-17;1-6-2-4-7(5-3-6)11(8,9)10/h10-13,15H,2-9,17H2,1H3,(H,20,21);2-5H,1H3,(H,8,9,10)/t12?,13-,15?;/m0./s1
|
| Chemical Name |
(2S)-5-amino-2-[[1-(4-methylcyclohexyl)imidazol-4-yl]methyl]pentanoic acid;4-methylbenzenesulfonic acid
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~214.77 mM)
H2O : ≥ 50 mg/mL (~107.39 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (10.74 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 5 mg/mL (10.74 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 5 mg/mL (10.74 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 100 mg/mL (214.77 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1477 mL | 10.7386 mL | 21.4772 mL | |
| 5 mM | 0.4295 mL | 2.1477 mL | 4.2954 mL | |
| 10 mM | 0.2148 mL | 1.0739 mL | 2.1477 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
