GSK2239633A

[¹²⁵I]-TARC-CCR4 ( pIC50 = 7.96 )

GSK2239633A 是人 CCR4 的变构拮抗剂。 GSK2239633A 抑制 [125I]-TARC 与人 CCR4 的结合，pIC50 为 7.96±0.11，还抑制胸腺和活化调节趋化因子诱导 (TARC) 诱导的分离人 CD4+ CCR4+ T 的 F-肌动蛋白含量增加- pA2 为 7.11±0.29 的细胞[1]。测量了 GSK2239633A（化合物 3）对 CCL17 诱导的人 CD4+ CCR4+ T 细胞 F-肌动蛋白含量增加的影响。 pEC50 值为 8.79±0.22[2]。

静脉给药后，血浆 GSK2239633A 显示出快速、双相分布和缓慢的终末消除（t1/2：13.5 小时），表明 GSK2239633A 是一种低至中等清除率的药物。口服给药后，GSK2239633A 的血液浓度迅速达到 Cmax（中位 tmax：1.0-1.5 小时）。 GSK2239633A 的估计生物利用度较低，确定的最大值仅为 16%[1]。 GSK2239633A（化合物 9）在临床前动物研究中表现出良好的药代动力学数据（大鼠和比格犬的生物利用度分别为 85% 和 97%）[3]。

趋化因子诱导的 CD4⁺ 丝状 (F)-肌动蛋白含量增加前十天。藻红蛋白和异硫氰酸荧光素偶联的抗 CCR4 和抗人 CD4 抗体用于对外周血单核细胞 (PBMC) 进行染色。随后在 37°C 下与 GSK2239633A (1 μM) 或载体 (0.1% DMSO) 一起孵育 30 分钟后，用激动剂刺激细胞 15 秒。添加 3% 甲醛以结束测定。使用 Alexa flor-647 鬼笔环肽染色的固定细胞对每个样品 1000 个 CD4⁺ CCR4⁺ 细胞的平均荧光强度进行分析。这以同一样本平均强度中 CD4+ CCR4 细胞的百分比给出[2]。

Rats and Dogs: In order to assist in the prediction of the likely human pharmacokinetics using precedented physiological scaling techniques, pharmacokinetics are determined in male Wistar Han rats (277-305 g) or male Sprague Dawley (crl:CD(SD)) rats (277-305 g) and male Beagle dogs (14-16 kg; aged approximately 3-4 years) following single oral and intravenous administration. Compounds (GSK2239633A, for example) are administered intravenously and orally to two rats per compound per route. For intravenous (IV) and oral (PO) administration, nominal doses of 1 mg/kg are utilized, and studies are carried out using standard animal husbandry procedures. Rats are kept in regulated environments and kept in standard holding cages with free access to food and water. All animals have a temporary cannula placed into the vein in their tails to collect serial blood samples. The cannula is placed into a vein that is distinct from the one used for dosing in the animals receiving intravenous doses. After the last dosage on each phase of the study, the dogs are kept in slings for a maximum of two hours. Compounds (such as GSK2239633A) are administered to two male Beagle dogs in a cross-over design either intravenously (bolus, 0.5 mg/kg) using an angiocath or orally (gavage, 1 mg/kg). For the first two hours after the dose, serial blood samples are drawn from the cephalic vein using an angiocath; for the duration of the study, venipuncture is used instead.

[1]. Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study. BMC Pharmacol Toxicol. 2013 Feb 28;14:14.

[2]. Antagonism of human CC-chemokine receptor 4 can be achieved through three distinct binding sites on the receptor. Pharmacol Res Perspect. 2013 Dec;1(2):e00019.

[3]. Identification of pyrazolopyrimidine arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists. Bioorg Med Chem. 2017 Oct 15;25(20):5327-5340.

C24H25CLN4O5S2

549.062102079391

548.1

C, 52.50; H, 4.59; Cl, 6.46; N, 10.20; O, 14.57; S, 11.68

1240516-71-5

Solid powder

CC(C)(C(=O)NCC1=CC(=CC=C1)CN2C3=C(C(=CC=C3)OC)C(=N2)NS(=O)(=O)C4=CC=C(S4)Cl)O

YTEVTHHGQMUPHC-UHFFFAOYSA-N

InChI=1S/C24H25ClN4O5S2/c1-24(2,31)23(30)26-13-15-6-4-7-16(12-15)14-29-17-8-5-9-18(34-3)21(17)22(27-29)28-36(32,33)20-11-10-19(25)35-20/h4-12,31H,13-14H2,1-3H3,(H,26,30)(H,27,28)

N-[[3-[[3-[(5-chlorothiophen-2-yl)sulfonylamino]-4-methoxyindazol-1-yl]methyl]phenyl]methyl]-2-hydroxy-2-methylpropanamide

GSK-2239633A; GSK 2239633A; GSK2239633A

2934.99.9001

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)

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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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。