WHI-P97

Catalog No.S5904 Batch:S590401

Technical Data

Formula	C₁₆H₁₃Br₂N₃O₃
Molecular Weight	455.10	CAS No.	211555-05-4
Solubility (25°C)*	In vitro	DMSO	8 mg/mL (17.57 mM)
		Water	Insoluble
		Ethanol	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

WHI-P97 is a potent inhibitor of JAK-3 with an estimated Ki value of 0.09 μM in modeling studies and a measured IC50 value of 2.5 μM in EGFR kinase inhibition assays.

Targets

JAK3 ^[1]

In vitro

Treatment of mast cells with WHI-P97 inhibited the translocation of 5-lipoxygenase (5-LO) from the nucleoplasm to the nuclear membrane and consequently 5-LO-dependent leukotriene (LT) synthesis after IgE receptor/FcεRI crosslinking by >90% at low micromolar concentrations. WHI-P97 does not directly inhibit the enzymatic activity of 5-LO, but prevented its translocation to the nuclear membrane without affecting the requisite calcium signal^[1].

In vivo

WHI-P97 was very well tolerated in mice, with no signs of toxicity at dose levels ranging from 5 μg/kg to 50 mg/kg, and LD10was not reached at a 50 mg/kg dose level when administered as a single i.p. or i.v. bolus dose. Therapeutic WHI-P97 concentrations, which inhibit mast cell leukotriene synthesis in vitro, could easily be achieved in vivo after the i.v. or i.p. administration of a single nontoxic 40 mg/kg bolus dose of WHI-P97. WHI-P97 showed promising biological activity in a mouse model of allergic asthma at nontoxic dose levels. Treatment of ovalbumin-sensitized mice with WHI-P97 prevented the development of airway hyper-responsiveness to methacholine in a dose-dependent fashion. WHI-P97 inhibited the eosinophil recruitment to the airway lumen after the ovalbumin challenge in a dose-dependent fashion. WHI-P97 had an elimination half-life (t_1/2) of 58.9 min and systemic clearance (CL) of 891 ml/h/kg in CD-1 mice and a t_1/2 of 84.2 min and CL of 1513 ml/h/kg in BALB/c mice. The values for AUC and Cmaxwere 107.3 μM·h and 296.7 μM, respectively, in CD-1 mice, and 58.4 μM·h and 212.7 μM, respectively, in BALB/c mice. The large volume of distribution [322 ml/kg in CD-1 mice and 415 ml/kg in BALB/c mice; ∼6-fold greater than the plasma volume (50 ml/kg)] suggests that WHI-P97 may be extensively partitioned into extravascular compartments^[1].

Protocol (from reference)

Cell Assay:^{^[1]}	Cell lines RBL-2H3 cells Concentrations 30 μM Incubation Time 30 min Method RBL-2H3 cells were cultured overnight on 22- × 22-mm coverslips at a cell density of 0.01 × 10⁶/ml with 0.24 mg/ml DNP-IgE. Sensitized RBL-2H3 cells were then treated with 30 μM WHI-P97, WHI-P131, or vehicle before challenge with 20 ng/ml DNP-BSA at 37°C. After stimulation with DNP-BSA, the cells were fixed in cold methanol for 30 min, permeabilized in cold acetone, and blocked with 1% BSA containing nonimmune goat serum. Staining of mast cells with primary and secondary antibodies followed by confocal laser scanning microscopy.
Animal Study:^{^[1]}	Animal Models female CD-1 or male BALB/c mice Dosages 40 mg/kg Administration i.v. and i.p.

Cell Assay:^{^[1]}

Cell lines
RBL-2H3 cells
Concentrations
30 μM
Incubation Time
30 min
Method
RBL-2H3 cells were cultured overnight on 22- × 22-mm coverslips at a cell density of 0.01 × 10⁶/ml with 0.24 mg/ml DNP-IgE. Sensitized RBL-2H3 cells were then treated with 30 μM WHI-P97, WHI-P131, or vehicle before challenge with 20 ng/ml DNP-BSA at 37°C. After stimulation with DNP-BSA, the cells were fixed in cold methanol for 30 min, permeabilized in cold acetone, and blocked with 1% BSA containing nonimmune goat serum. Staining of mast cells with primary and secondary antibodies followed by confocal laser scanning microscopy.

Animal Study:^{^[1]}

Animal Models
female CD-1 or male BALB/c mice
Dosages
40 mg/kg
Administration
i.v. and i.p.

References

[1] Malaviya R, et al. J Pharmacol Exp Ther. 2000, 295(3):912-26.

Selleck's WHI-P97 has been cited by 1 publication

Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model [ J Med Chem, 2020, 31]	PubMed: 32191458

Revisiting Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: An Improved Computational Model [ J Med Chem, 2020, 31]

PubMed: 32191458

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SHIPPING AND STORAGE
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