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Purity: ≥98%
Tafamidis meglumine (formerly Fx-1006; PF-06291826; Vyndaqel and Vyndamax), the meglumine salt of tafamidis, is a potent and selective
transthyretin (TTR) stabilizer, is an approved drug for the amelioration of
transthyretin-related hereditary amyloidosis (also familial amyloid
polyneuropathy, or FAP), a rare but deadly neurodegenerative disease. It
shows comparable potency and efficacy to the mutumant homotetramers
V30M-TTR, V122I-TTR and wild type WT-TTR, with EC50s of 2.7-3.2 μM.
Tafamidis inhibits amyloidogenesis. The drug was approved by the
European Medicines Agency in November 2011 and by the Japanese
Pharmaceuticals and Medical Devices Agency in September 2013. Tafamidis
functions by kinetic stabilization of the correctly folded tetrameric
form of the transthyretin (TTR) protein.
| Targets |
TTR (transthyretin) (EC50 = 2.7-3.2 μM)
|
|---|---|
| ln Vitro |
Tafamidis kinetically stabilizes TTR by inertly binding the two common polarin sites of the tetramer with negative affinity (Kds ∼2 nM and ∼200 nM) [1]. After 72 hours at pH 4.4-4.5, tacramamide (0-7.2 μM) quantitatively suppresses WT-TTR amyloidosis [1].
|
| ln Vivo |
ATTR amyloidosis is a systemic, debilitating and fatal disease caused by transthyretin (TTR) amyloid accumulation. RNA interference (RNAi) is a clinically validated technology that may be a promising approach to the treatment of ATTR amyloidosis. The vast majority of TTR, the soluble precursor of TTR amyloid, is expressed and synthesized in the liver. RNAi technology enables robust hepatic gene silencing, the goal of which would be to reduce systemic levels of TTR and mitigate many of the clinical manifestations of ATTR that arise from hepatic TTR expression. To test this hypothesis, TTR-targeting siRNAs were evaluated in a murine model of hereditary ATTR amyloidosis. RNAi-mediated silencing of hepatic TTR expression inhibited TTR deposition and facilitated regression of existing TTR deposits in pathologically relevant tissues. Further, the extent of deposit regression correlated with the level of RNAi-mediated knockdown. In comparison to the TTR stabilizer, tafamidis, RNAi-mediated TTR knockdown led to greater regression of TTR deposits across a broader range of affected tissues. Together, the data presented herein support the therapeutic hypothesis behind TTR lowering and highlight the potential of RNAi in the treatment of patients afflicted with ATTR amyloidosis[2].
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| Enzyme Assay |
Immunoturbidity Assay for Stabilization of TTR Tetramer in Human Plasma.[1]
Urea denaturation of TTR in human plasma and chemical crosslinking was performed as described (see text and Fig. 6.) with minor modifications, except that TTR was quantified by immunoturbidity. Human plasma samples were thawed on ice and insoluble material was removed by centrifugation. For each, 4 µL was removed, and the initial TTR concentrations were determined by immunoturbidity. For each stabilization determination, 80 µL aliquots of each plasma sample were retained and 1.6 µL of either 5% dimethyl sulfoxide (DMSO) or 360 µM tafamidis in 5% DMSO was added. After incubation at room temperature for 15 minutes, 120 µL of urea buffer (8 M urea, 40 mM sodium phosphate, 80 mM KCl, pH 7.4) was added and samples were mixed and incubated at room temperature for the indicated time (typically 48 h). All samples were cross-linked with 3.2 µL of 25% glutaraldehyde. After 4 minutes, the reaction was quenched with 5.6 µL of 1.85 M NaBH4 (freshly prepared in 0.1 N NaOH) and incubated for 5 minutes. Postdenaturation TTR concentrations (4 µL) were determined by immunoturbidity. Olympus OSR6175 reagent and Prealbumin Calibrator ODR3029 were used according to the manufacturers’ instructions. To assess the correlation between the two detection methods, we analyzed plasma samples after urea treatment and glutaraldehyde crosslinking in parallel by Western blot and immunoturbidity. In the control samples, the amount of TTR detected by immunoturbidity decreased from an initial value of 22 mg/dL to 3 mg/dL after 3 d in urea. In the presence of tafamidis, 13 mg/dL of TTR remained; a level that was in good agreement with results from the Western blot assay (Fig. S3A).
|
| Animal Protocol |
Evaluation of tafamidis in hTTR V30M HSF1± mice[2]
Tafamidis/meglumine (tafamidis) and its respective meglumine only control (meglumine) were prepared as previously described. Four hundred microliters of 2 mg/ml tafamidis (0.8 mg total) or its respective meglumine control were administered via subcutaneous injection to 15-month-old hTTR V30M HSF1± mice on days 0, 3, 5, 7, 10, 12, 14, 17, 19, 21, 24, 26, 28, 31, 33, 35 and 38. TTR tissue deposition was evaluated on day 52 as described earlier. To confirm tafamidis-mediated stabilization of serum TTR, serum TTR tetramer stability was analyzed on days -7, 9, 23 and 37 using a modified version of a previously described TTR tetramer stability assay. See Supplementary Figure 2 for more detail on assay conditions and tetramer detection and quantitation. To quantify the extent of stabilization, % TTR tetramer stabilization was calculated using the following equation as previously described.
|
| References |
[1]. Bulawa, C.E., et al., Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A, 2012. 109(24): p. 9629-34.
[2]. Preclinical evaluation of RNAi as a treatment for transthyretin-mediated amyloidosis. Amyloid. 2016 Jun;23(2):109-18. |
| Additional Infomation |
Tafamidis meglumine is an organoammonium salt obtained by combining tafamidis with one molar equivalent of 1-deoxy-1-(methylamino)-D-glucitol. Used for the amelioration of transthyretin-related hereditary amyloidosis. It has a role as a central nervous system drug. It contains a tafamidis(1-).
Fx-1006A is a small molecule compound with the potential to treat genetic disorders, such as familial amyloid cardiomyopathy (FAC) and familial amyloid polyneuropathy (FAP). Tafamidis Meglumine is a soft gelatin capsule formulation containing the meglumine salt form of tafamidis, a small molecule and pharmacological chaperone with potential disease-modifying activity. Tafamidis binds to and stabilizes wild-type and variant (V122I) transthyretin (TTR), thereby preventing tetramer dissociation into monomers; this prevents misfolding of the TTR protein and inhibits the formation of TTR amyloid fibrils and the subsequent deposition of these insoluble protein clusters in peripheral nerve tissues and organs. TTR is a 127 amino acid transport protein for thyroxine and retinol and is secreted by the liver. |
| Molecular Formula |
C21H24CL2N2O8
|
|---|---|
| Molecular Weight |
503.329864501953
|
| Exact Mass |
502.091
|
| Elemental Analysis |
C, 50.11; H, 4.81; Cl, 14.09; N, 5.57; O, 25.43
|
| CAS # |
951395-08-7
|
| Related CAS # |
Tafamidis;594839-88-0
|
| PubChem CID |
24970412
|
| Appearance |
Typically exists as White to off-white solids at room temperature
|
| LogP |
1.53
|
| tPSA |
176.51
|
| SMILES |
OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNC.O=C(C1=CC=C2N=C(C3=CC(Cl)=CC(Cl)=C3)OC2=C1)O
|
| InChi Key |
DQJDBUPLRMRBAB-WZTVWXICSA-N
|
| InChi Code |
InChI=1S/C14H7Cl2NO3.C7H17NO5/c15-9-3-8(4-10(16)6-9)13-17-11-2-1-7(14(18)19)5-12(11)20-131-8-2-4(10)6(12)7(13)5(11)3-9/h1-6H,(H,18,19)4-13H,2-3H2,1H3/t4-,5+,6+,7+/m.0/s1
|
| Chemical Name |
(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
|
| Synonyms |
Fx 1006A; PF-06291826; Fx-1006A; PF 06291826; Fx1006A PF06291826; Tafamidis meglumine; Vyndaqel; 951395-08-7; Fx-1006A; Fx1006A; Fx 1006A; UNII-ZU7CF08A1A; ZU7CF08A1A;
|
| 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 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 : ~12.5 mg/mL (~24.83 mM)
H2O : < 0.1 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (2.48 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 12.5 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: ≥ 1.25 mg/mL (2.48 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 12.5 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: ≥ 1.25 mg/mL (2.48 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9868 mL | 9.9338 mL | 19.8677 mL | |
| 5 mM | 0.3974 mL | 1.9868 mL | 3.9735 mL | |
| 10 mM | 0.1987 mL | 0.9934 mL | 1.9868 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.
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