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PF-04449913

Catalog No.
B3283
Antagonist of smoothened
Grouped product items
SizePriceStock Qty
10mM (in 1mL DMSO)
$120.00
In stock
5mg
$103.00
In stock
25mg
$383.00
In stock

Tel: +1-832-696-8203

Email: [email protected]

Worldwide Distributors

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[[email protected]@H]2CCN(C)[[email protected]@H](C3=NC4=CC=CC=C4N3)C2)=O)C=C1
Shipping ConditionEvaluation sample solution: ship with blue ice. All other available sizes: ship with RT, or blue ice upon request.
General tipsFor obtaining a higher solubility, please warm the tube at 37°C and shake it in the ultrasonic bath for a while. Stock solution can be stored below -20°C for several months.

Protocol

Animal experiment [1]:

Animal models

Rats and dogs

Dosage form

1 mg/kg and 0.5 mg/kg, Oral dosing

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.

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]:

Disease models

Patients with advanced solid tumors

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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