AZD1080

AZD1080 is a potent and selective GSK3 inhibitor. AZD1080 inhibits recombinant human GSK3α and GSK3β with pK_i (IC₅₀) of 8.2 (6.9 nM) and 7.5 (31 nM), respectively. IC50 & Target: IC50: 6.9 nM (GSK3α), 31 nM (GSK3β)^[1]
pKi: 8.2 (GSK3α), 7.5 (GSK3β)^[1] In Vitro: AZD1080 shows selectivity against cdk2 (pK_i=5.9; 1150 nM; 37-fold), cdk5 (pK_i=6.4; 429 nM; 14-fold), cdk1 (pK_i=5.7; 1980 nM; 64-fold) and Erk2 (pK_i< 5; >10 μM; >323-fold). AZD1080 (at 10 μM) is also evaluated for pan-kinase selectivity and showed good overall selectivity versus 23 kinases, as well as against 65 different receptors, enzymes and ion channels in MDS Pharma screen (< 50% effect at 10 μM AZD1080). Concentration-dependent inhibition of tau phosphorylation is observed for AZD1080 (IC₅₀=324 nM) and the non-selective reference GSK3 inhibitor LiCl (IC₅₀=1.5 mM) indicating that AZD1080 is several orders of magnitude more potent than LiCl^[1]. In Vivo: The pharmacokinetic analysis in blood after oral administration revealed that AZD1080 has a good oral bioavailability in rats (15-24%) with a half-life of 7.1 h, making AZD1080 attractive for further in vivo testing. The subchronic (3 days) oral treatment with AZD1080 at 4 or 15 μmol/kg significantly blocked the MK-801-induced memory deficit (AZD1080 vs. MK-801, p<0.05 at 4 μmol/kg and p<0.01 at 15 μmol/kg) in mice, raising the hypothesis that longer treatment may be required to prime the synapses to function effectively^[1].