PF-04802367 is a highly selective GSK-3 inhibitor with an IC50 of 2.1 nM in the recombinant human GSK-3β enzyme assay and 1.1 nM in the ADP-Glo assay. PF-04802367 inhibits the two known GSK-3 isoforms, GSK-3α and GSK-3β, with identical IC50 values in mobility shift assays. The IC50 values of PF-04802367 were 10.0 and 9.0 nM in the mobility shift assay, respectively. PF-04802367 has reasonable in vitro stability in human liver microsomes (t1/2=78.7 min) and excellent passive permeability. In a stably induced CHO cell line overexpressing GSK-3β and its substrate tau, PF-04802367 inhibited tau phosphorylation with an IC50 of 466 nM[1].PF-04802367 had a significant right-shifting effect on β-catenin translocation in HeLa cells (EC50 of 6.2 μM), gene transcription in U20S cells (EC50 of 20.6 μM) and cell proliferation in HeLa cells (EC50 of 9.0 μM)[1].
PF-04802367 动物研究
Animal study
The inhibition of brain tau phosphorylation by PF-04802367 was dose-dependent when administered as a single subcutaneous injection at doses of 1, 3.2, 10, 32 or 50 mg/kg[1].PF-04802367 has good ADME properties, as well as strong inhibition of CNS/peripheral p-Tau and muscle phosphorylated glycogen synthase (pGS) in vivo[2].
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