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PF-04449913

现货
Catalog No.
B3283
Smoothened拮抗剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,200.00
Ship with 10-15 days
5mg
¥ 1,030.00
现货
25mg
¥ 3,830.00
Ship with 10-15 days

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Background

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.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt374.44
Cas No.1095173-27-5
FormulaC21H22N6O
Solubility≥20.15mg/mL in DMSO
Chemical Name1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea
SDFDownload SDF
Canonical SMILESN#CC1=CC=C(NC(N[C@@H]2CCN(C)[C@@H](C3=NC4=CC=CC=C4N3)C2)=O)C=C1
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

动物实验[1]:

动物模型

大鼠和狗

剂量

1 mg/kg和0.5 mg/kg, 口服

应用

在大鼠和狗中,PF-04449913在大鼠中具有高清除率,在狗中具有低清除率,CL分别为31和3.9mL/min/kg。PF-04449913在大鼠和狗中的口服生物利用度分别为33%和68%。 PF-04449913的体积分数分别为4.8和4.3 L/kg,t1/2分别为1.4和2.9 h。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同,这是由实验系统的误差引起的,属于正常现象。

临床试验 [2]:

疾病模型

晚期实体瘤患者

剂量

80 mg-640 mg, 口服每日一次,连续28天

应用

在晚期实体瘤患者中,640 mg剂量水平的第一周期剂量限制毒性(DLT)率为33.3%,PF-04449913的最大耐受剂量(MTD)估计为每日一次320mg。PF-04449913通常以80至320mg的剂量每天一次耐受性良好。PF-04449913在测试的剂量水平下调节hedgehog信号,并下调超过80%的患者皮肤中的GLI1表达。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同,这是由实验系统的误差引起的,属于正常现象。

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.

质量控制

质量控制和MSDS

批次:

化学结构

PF-04449913