TAK-441（化合物 11d）（0.03–1000 nM，48 h）在 Gli-luc 报告基因中表现出良好的溶解度和较强的活性，IC50 值为 4.4 nM[1]。 TAK-441（0.03-1000 nM，48 h）抑制 Gli1 mRNA，在肿瘤和皮肤中的 IC50 值分别为 0.0457 和 0.113 mg/ml[1]。雄激素撤退诱导的 Shh 上调不受 TAK-441（0.5-500 nM，48-72 小时）的影响。然而，通过干扰肿瘤基质的旁分泌 Hh 信号传导，TAK-441（0.5-500 nM，48-72 小时）会导致 LNCaP 异种移植物进展更慢，对去势产生抵抗[3]。

在 BALB/c-nu/nu 小鼠中，TAK-441（化合物 11d）（口服；10 mg/kg、100 mg/kg）表现出良好的暴露和良好的口服吸收[1]。 TAK-441（口服，1 和 25 mg/kg，每日一次，持续 14 天）表现出强大的抗癌功效，可通过增加 TAK-441 在 Ptc1+/-p53-/- 小鼠中的溶解度来产生剂量依赖性血浆和肿瘤浓度接受髓母细胞瘤同种异体移植[1]。口服给药后，TAK-441（静脉注射，1 mg/kg；口服，10 mg/kg）可在大鼠和狗中产生足够的暴露量[1]。在异种移植小鼠中，TAK-441（口服；1、10 和 25 mg/kg）具有剂量依赖性抗癌功效；抑制肿瘤发展的IC50值为0.075 mg/ml[1]。 BALB/c-nu/nu 小鼠口服和通过 Alzet 输注（100 mg/kg，单剂量）施用的 TAK-441 的药代动力学参数[1]。 Cmax (lg/mL) AUC (lgh/mL) 化合物 小鼠 PK 10mg/kg 小鼠 PK 100mg/kg Cmax (lg/mL) AUC (lgh/mL) 1 2.65 12.1 3.63 32.3 11d 5.62 28.3 21.5 206

细胞活力测定[1]
细胞类型： NIH3T3/Gli-luc 细胞
测试浓度： 0.03–1000 nM
孵育时间：48小时
实验结果：证明了可接受的溶解度和有效的Hh抑制活性。

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细胞毒性测定[3]
细胞类型： LNCaP 细胞
测试浓度： 0.5-500 nM
孵育时间：48-72 h
实验结果：雄激素剥夺条件下不影响LNCaP细胞体外活力Shh的上调。

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蛋白质印迹分析[3]
细胞类型： LNCaP、C4-2、DU145 和 PC3 细胞
测试浓度：
孵育持续时间：
实验结果： 反映雄激素反应性 PCa，在 LNCaP 和 C4-2 细胞中表达 Shh 和 Dhh，并反映在 LNCaP 和 C4-2 细胞中限制性表达 CRPC DU145 和 PC3 细胞。

Animal/Disease Models: rats and dogs[1]
Doses: 1 mg/kg, 10 mg/kg
Route of Administration: iv, 1 mg/kg; po, 10 mg/kg
Experimental Results: Compd Mouse PK 10mg/kg Vss(mL/kg ) CL (mL/h/kg) AUC0–24h,iv(ng h/mL) AUC0–24h,po(ng h/mL) F (%) Rat 681.6 ± 81.6 397.9 ± 10.1 2532.3 ± 69.1 8031.8 ± 1218.6 31.7 Dog 2181.3 ± 82.8 161.3 ± 35.6 5101.5 ± 685.5 45405.6 ± 5812.0 90.3 ± 8.8 Animal/Disease Models: BALB/c-nu/nu (nude) mice[1]
Doses: 10 mg/kg, 100 mg/kg
Route of Administration: oral; 10 mg/kg, 100 mg/kg
Experimental Results: Inhibits Gli1 mRNA in the tumor and skin with IC50 values of 0.0457 mg/mL and 0.113 mg/mL, respectively.

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Animal/Disease Models: Ptc1+/-p53-/- mice[1]
Doses: 1 and 25 mg/ kg
Route of Administration: po (oral gavage) 1 and 25 mg/kg, QD for 14 days
Experimental Results: demonstrated strong antitumor activity and resulted in a dose-dependent PK profile by improving solubility.

[1]. Tomohiro Ohashi, et al. Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: modification of the core skeleton for improved solubility. Bioorg Med Chem. 2012
[2]. Akifumi Kogame, et al. Pharmacokinetic and pharmacodynamic modeling of hedgehog inhibitor TAK-441 for the inhibition of Gli1 messenger RNA expression and antitumor efficacy in xenografted tumor model mice. Drug Metab Dispos
[3]. Naokazu Ibuki, et al. TAK-441, a novel investigational smoothened antagonist, delays castration-resistant progression in prostate cancer by disrupting paracrine hedgehog signaling. Int J Cancer. 2013 Oct 15;133(8):1955-66.

C28H31N4O6F3

576.564

1186231-83-3

1186231-83-3

CCC1=CC2=C(C(N1CC(C3=CC=CC=C3)=O)=O)C(OCC(F)(F)F)=C(N2C)C(NC4CCN(C(CO)=O)CC4)=O

TAK441; TAK441; TAK 441

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: >10mM Water: Ethanol:

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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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。