TTR (transthyretin) (EC50 = 2.7-3.2 μM)

Tafamidis 通过以负亲和力（Kds ∼2 nM 和 ∼200 nM）惰性结合四聚体的两个常见极化蛋白位点，在动力学上稳定 TTR [1]。 pH 4.4-4.5 72 小时后，tacramamide (0-7.2 μM) 定量抑制 WT-TTR 淀粉样变性 [1]。

在一项针对V30M TTR-FAP患者的tafamidis II/III期临床试验中，这种动力学稳定剂在18个月的治疗中显示出临床疗效。与安慰剂对照组相比，接受tafamidis治疗的患者神经系统恶化减少了52%，大小神经纤维功能分别保留了53%和80%，营养状况得到改善，这些结果与生活质量的提高有关。当与临床疗效数据相结合时，其中提供的tafamidis临床前数据提供了支持淀粉样蛋白假说的独特药理学证据，即降低淀粉样蛋白级联反应的效率可以阻止外周神经和自主神经系统的退化[1]。

塔法米迪斯在其T4结合位点与TTR具有高亲和力结合。Tafamidis稳定较弱的TTR二聚体-二聚体界面。塔法米迪斯选择性地与人血浆中的TTR结合。塔法米迪斯稳定人血浆中的WT、V30M和V122I TTR。塔法米迪斯可稳定多种致病性TTR变体。<小时> 人血浆中TTR四聚体稳定性的免疫浊度测定。[1]

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TTR在人血浆中的尿素变性和化学交联如所述进行（参见文本和图6），除了通过免疫浊度对TTR进行定量外，进行了轻微的修改。将人血浆样品在冰上解冻，并通过离心除去不溶性物质。对于每种，去除4µL，并通过免疫浊度测定初始TTR浓度。对于每次稳定性测定，保留80µL等分的每份血浆样品，并加入1.6µL的5%二甲基亚砜（DMSO）或360µM的5%二甲亚砜中的太酰胺。在室温下孵育15分钟后，加入120µL尿素缓冲液（8M尿素、40mM磷酸钠、80mM KCl，pH 7.4），将样品混合并在室温下温育指定时间（通常为48小时）。所有样品均用3.2µL 25%戊二醛交联。4分钟后，用5.6µL 1.85 M NaBH4（在0.1 N NaOH中新鲜制备）猝灭反应并孵育5分钟。通过免疫浊度测定变性后TTR浓度（4µL）。根据制造商的说明使用Olympus OSR6175试剂和Prealbumin校准器ODR3029。为了评估两种检测方法之间的相关性，我们通过蛋白质印迹和免疫浊度平行分析了尿素处理和戊二醛交联后的血浆样品。在对照样品中，在尿素中3天后，通过免疫浊度检测到的TTR的量从22 mg/dL的初始值降低到3 mg/dL。在存在太酰胺的情况下，残留13 mg/dL的TTR；该水平与来自蛋白质印迹测定的结果非常一致（图S3A）。

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.

[1]. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9629-34.

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.
See also: Tafamidis (has active moiety).

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Drug Indication
Investigated for use/treatment in amyloidosis.
Neuropathic heredofamilial amyloidosis

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Mechanism of Action
Fx-1006A is a first-in-class, disease-modifying compound that is designed to inhibit the formation of amyloid deposits by preventing the misfolding and deposition of the transthyretin protein (TTR), which is associated with amyloidosis.

C21H24CL2N2O8

503.329864501953

502.091

C, 50.11; H, 4.81; Cl, 14.09; N, 5.57; O, 25.43

951395-08-7

Tafamidis;594839-88-0

24970412

Typically exists as White to off-white solids at room temperature

1.532

176.51

7

10

8

33

506

4

[C@@H](O)([C@@H](O)CNC)[C@H](O)[C@H](O)CO.ClC1C=C(Cl)C=C(C2=NC3C=CC(=CC=3O2)C(=O)O)C=1

DQJDBUPLRMRBAB-WZTVWXICSA-N

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

(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid

Fx 1006A; PF-06291826; Fx-1006A; PF 06291826; Fx1006A PF06291826; Tafamidis meglumine; Vyndaqel; 951395-08-7; Fx-1006A; Fx1006A; Fx 1006A; UNII-ZU7CF08A1A; ZU7CF08A1A;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~12.5 mg/mL (~24.83 mM)
H2O : < 0.1 mg/mL

配方 1 中的溶解度: ≥ 1.25 mg/mL (2.48 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 12.5 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 1.25 mg/mL (2.48 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 12.5 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 1.25 mg/mL (2.48 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 12.5 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。