PF-04449913
(Synonyms: 格拉斯吉布,PF-04449913) 目录号 : GC16230
A Smo antagonist
Cas No.:1095173-27-5
Sample solution is provided at 25 µL, 10mM.
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PF-04449913 is an orally bioavailable inhibitor of smoothened with IC50 value of 5nM [1].
In the Hedgehog (Hh) signaling pathway, the combination of Hh ligands and their receptor Patched leads to the activation of smoothened and subsequently activation of three transcription factors Gli1, Gli2 and Gli3. It then leads to the proliferation of cells. As an antagonist of smoothened, PF-04449913 is developed for treatment of cancer [1].
PF-04449913 is found not to inhibit cytochrome P450 and is negative in Ames and micronucleus assays suggesting it as a safe drug. In the preclinical studies, PF-04449913 shows a half-life of 30 h and an oral bioavailability of 55% in humans. It also has low plasma clearance of 1.03 mL/min/kg and moderate volume of distribution (2.7 L/kg) [1].
References:
[1] Munchhof MJ, Li Q, Shavnya A, Borzillo GV, Boyden TL, Jones CS, LaGreca SD, Martinez-Alsina L, Patel N, Pelletier K, Reiter LA, Robbins MD, Tkalcevic GT. Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened. ACS Med Chem Lett. 2011 Dec 21;3(2):106-11.
| Animal experiment [1]: | |
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Animal models |
Rats and dogs |
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Dosage form |
1 mg/kg and 0.5 mg/kg, Oral dosing |
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Application |
In rats and dogs, PF-04449913 had high clearance in rat and low clearance in dog with CL of 31 and 3.9 mL/min/kg, respectively. The oral bioavailabilities of PF-04449913 in rat and dog were 33 and 68%, respectively. PF-04449913 had moderate volume distribution of 4.8 and 4.3 L/kg and t1/2 of 1.4 and 2.9 h, respectively. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| Clinical Trial [2]: | |
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Disease models |
Patients with advanced solid tumors |
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Dosage form |
80 mg-640 mg, orally administered once daily, continuous 28-day |
|
Application |
In patients with advanced solid tumors, the first-cycle dose-limiting toxicity (DLT) rate at the 640 mg dose level was 33.3%, and the maximum tolerated dose (MTD) of PF-04449913 was estimated to be 320mg once daily. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. PF-04449913 modulated hedgehog signaling at the dose levels tested and downregulated GLI1 expression in the skin of patients by >80%. |
|
Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
|
References: [1] Munchhof MJ, Li Q, Shavnya A, Borzillo GV, Boyden TL, Jones CS, LaGreca SD, Martinez-Alsina L, Patel N, Pelletier K, Reiter LA, Robbins MD, Tkalcevic GT. Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened. ACS Med Chem Lett. 2011 Dec 21;3(2):106-11. [2]. Wagner AJ1, Messersmith WA2, Shaik MN3, et al. A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2015 Mar 1;21(5):1044-51. |
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| Cas No. | 1095173-27-5 | SDF | |
| 别名 | 格拉斯吉布,PF-04449913 | ||
| 化学名 | 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea | ||
| Canonical SMILES | CN1CCC(CC1C2=NC3=CC=CC=C3N2)NC(=O)NC4=CC=C(C=C4)C#N | ||
| 分子式 | C21H22N6O | 分子量 | 374.44 |
| 溶解度 | ≥ 20.15mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6707 mL | 13.3533 mL | 26.7065 mL |
| 5 mM | 0.5341 mL | 2.6707 mL | 5.3413 mL |
| 10 mM | 0.2671 mL | 1.3353 mL | 2.6707 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet