Molecular Weight (MW)

440.54

Formula

C26H28N6O

CAS No.

1254036-71-9 (free base);

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: 88 mg/mL (199.8 mM)

Water: <1 mg/mL

Ethanol: 8 mg/mL (18.2 mM)

SMILES

CC(C)N(CC1)CCN1CC2=CN=C(C3=CC(C4=CC=CC5=C4C=CN5)=CC6=C3C=NN6)O2.[H]Cl

Synonyms

GSK-2269557; GSK 2269557; GSK2269557; Nemiralisib HCl; Nemiralisib hydrochloride

In Vitro

In vitro activity: GSK-2269557 has low oral bioavailability (F=2%) and in vivo clearance of 28 mL/min/kg but has a high volume of distribution of 6.3 L/kg. GSK-2269557 induces concentration-dependent increases in QT interval and Tp-e at 0.3 and 1 μM (1 and 0.5 Hz) and an increase in QRS at 1 μM (2 Hz), however, no treatment-related torsades de pointes (TdP) arrhythmias are observed. In a disease relevant brown Norway rat acute OVA model of Th2 driven lung inflammation, GSK-2269557 is shown to protect against eosinophil recruitment with an ED50 of 67 μg/kg and dose-dependently reduces recruitment of all leukocyte subpopulations and IL-13 in the lungs.

Kinase Assay: Nemiralisib (GSK2269557 free base) is highly selective for PI3Kδ, with>1000-fold selectivity over the closely related isoforms PI3Kα (pIC50=5.3), PI3Kβ (pIC50=5.8) and PI3Kγ (pIC50=5.2). Nemiralisib inhibits IFNγ in the peripheral blood mononuclear (PBMC) assay with an pIC50 of 9.7.

In Vivo

To assess the suitability of the series for inhaled delivery clearance data in rat microsomes and subsequently in vivo pharmacokinetic data from Sprague Dawley male rats is obtained. Compounds (e.g., Nemiralisib) are administered by the oral or intravenous routes, at a dose level of 3 and 1mg/kg respectively (n=2 rats/route). Nemiralisib free base is active in a disease relevant brown norway rat acute OVA model of Type 2 helper T-cells (Th2)-driven lung inflammation.

Animal model

Sprague Dawley male rats

Formulation & Dosage

Formulated in DMSO/PEG200/water (5:45:50 v/v/v); oral:3 mg/kg; IV:1 mg/kg; oral and i.v.

References

J Med Chem. 2015 Sep 24;58(18):7381-99.