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Purity: ≥98%
Tafamidis (also known as Fx-1006 or PF-06291826; Vyndaqel and Vyndamax), a potent and selective transthyretin (TTR) stabilizer, is a medication approved in several countries for use in delaying disease progression in adults with certain forms of transthyretin amyloidosis.
| Targets |
TTR (transthyretin) (EC50 = 2.7-3.2 μM)
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|---|---|
| ln Vitro |
TTR is kinetically stabilized when tacamimeis binds to the two tetramer's typically conserved polarin binding sites with negative coupling (Kd = ∼2 nM and ∼200 nM) [1]. After 72 hours at =4.4-4.5, tacramids (0-7.2 μM) dose-dependently suppresses WT-TTR amyloidosis [1].
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| 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].
In a phase II/III clinical trial of tafamidis in V30M TTR-FAP patients, this kinetic stabilizer demonstrated clinical efficacy over 18 mo of treatment. Relative to placebo controls, patients receiving tafamidis had 52% less neurologic deterioration, 53% and 80% preservation of large- and small-nerve fiber function, and improved nutritional status, outcomes that are associated with an improved quality of life. The tafamidis preclinical data presented within, when considered in concert with the clinical efficacy data, provide unique pharmacologic evidence supporting the amyloid hypothesis, the notion that lowering the efficiency of the amyloid cascade halts the degeneration of the peripheral and autonomic nervous system[1]. |
| Enzyme Assay |
Tafamidis Binds with High Affinity to TTR at Its T4-Binding Sites. Tafamidis Stabilizes the Weaker TTR Dimer–Dimer Interface. Tafamidis Binds Selectively to TTR in Human Plasma. Tafamidis Stabilizes WT, V30M, and V122I TTR in Human Plasma. Tafamidis Stabilizes a Broad Range of Pathogenic TTR Variants.
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. To compare the efficacy of the tetramer stabilization approach to that of RNAi-mediated TTR knockdown, we evaluated tafamidis in the hTTR V30M HSF1± model and quantified the impact of TTR tetramer stabilization on the regression of preexisting TTR deposits. To compensate for differences in dose frequency and route of administration, mice were administered excess tafamidis (>100× on mg/kg basis) to enable sufficient TTR tetramer stabilization. Although administration of tafamidis resulted in a significant and clinically relevant degree of serum TTR tetramer stabilization, only moderate TTR deposit regression was observed in the sciatic nerve and dorsal root ganglion; consistent regression was not observed in other tissues examined. It should be noted that the study duration was chosen to allow a more direct comparison with siTTR1 (Figure 3) and, as such, it is possible that longer term administration of tafamidis may have resulted in greater deposit regression in the hTTR V30M HSF1± model. However, in these conditions, TTR lowering seems to be more effective. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Tafamidis reaches a Cmax of 1430.93ng/mL with a Tmax of 1.75h fasted and 4h fed. The AUC of tafamidis is 47,864.31ng\*h/mL. A 20mg oral dose of tafamidis is approximately 59% recovered in the feces, largely as unchanged drug. Approximately 22% of a 20mg oral dose is recovered in the urine, mostly as the glucuronide metabolite. The apparent volume of distribution at steady state is 18.5L. The oral clearance of tafamidis is 0.263L/h. The apparent total clearance is 0.44L/h. Metabolism / Metabolites Tafamidis is largely not subject to first pass or oxidative metabolism, being 90% unchanged after in in vitro experiments. Preclinical data suggest tafamidis is mainly metabolized through glucuronidation and excreted in bile. Biological Half-Life The half life of tafamidis is 49h. |
| Toxicity/Toxicokinetics |
Protein Binding
Tafamidis 99.9% protein bound in plasma, mostly to transthyretin. |
| References | |
| Additional Infomation |
Tafamidis is a member of the class of 1,3-benzoxazoles that is 1,3-benzoxazole-6-carboxylic acid in which the hydrogen at position 2 is replaced by a 3,5-dichlorophenyl group. Used (as its meglumine salt) for the amelioration of transthyretin-related hereditary amyloidosis. It has a role as a central nervous system drug. It is a member of 1,3-benzoxazoles, a monocarboxylic acid and a dichlorobenzene. It is a conjugate acid of a tafamidis(1-).
Tafamidis and tafamidis meglumine (FX-1006A) are benzoxazole derivatives developed by FoldRX. Tafamidis is structurally similar to diflusinal. Tafamidis was granted an EMA market authorisation on 16 November 2011 and FDA approval on 3 May 2019. See also: Tafamidis Meglumine (has salt form). Drug Indication Tafamidis is indicated to treat cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults. FDA Label Mechanism of Action Genetic mutations or natural misfolding of transthyretin destabalizes transthyretin tetramers, leading to their dissociation and aggregation in tissues, and disrupting the normal function of these tissues. Tafamidis binds to transthyretin tetramers at the thyroxin binding sites, stabilizing the tetramer, reducing the availability of monomers for amyloidogenesis. Pharmacodynamics Tafamidis stabilizes transthyretin tetramers, reducing the amount of monomers available for amyloidogenesis. It has a long duration of action as it is given once daily, and a wide therapeutic window. |
| Molecular Formula |
C14H7CL2NO3
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|---|---|
| Molecular Weight |
308.1163
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| Exact Mass |
306.98
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| Elemental Analysis |
C, 54.58; H, 2.29; Cl, 23.01; N, 4.55; O, 15.58
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| CAS # |
594839-88-0
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| Related CAS # |
Tafamidis meglumine;951395-08-7;Tafamidis-d3
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| PubChem CID |
11001318
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| Appearance |
Typically exists as white to off-white solids at room temperature
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
486.7±40.0 °C at 760 mmHg
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| Flash Point |
248.1±27.3 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.677
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| LogP |
5.29
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
20
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| Complexity |
371
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C(C([H])=C(C=1[H])C1=NC2C([H])=C([H])C(C(=O)O[H])=C([H])C=2O1)Cl
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| InChi Key |
TXEIIPDJKFWEEC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H7Cl2NO3/c15-9-3-8(4-10(16)6-9)13-17-11-2-1-7(14(18)19)5-12(11)20-13/h1-6H,(H,18,19)
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| Chemical Name |
2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
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| Synonyms |
Fx-1006, PF06291826; Fx1006, PF-06291826; Fx 1006, Fx-1006A; PF 06291826; Tafamidis; Vyndaqel; TAFAMIDIS; 594839-88-0; Vyndamax; FX-1006; 2-(3,5-Dichlorophenyl)-1,3-Benzoxazole-6-Carboxylic Acid; 2-(3,5-Dichlorophenyl)-6-benzoxazole carboxylic acid; tafamidisum; 8FG9H9D31J;
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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 : ~37.5 mg/mL (~121.71 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (8.11 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: 2.5 mg/mL (8.11 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (8.11 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 | 3.2455 mL | 16.2274 mL | 32.4549 mL | |
| 5 mM | 0.6491 mL | 3.2455 mL | 6.4910 mL | |
| 10 mM | 0.3245 mL | 1.6227 mL | 3.2455 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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