Orally bioavailable and brain-penetrant pyridazine and pyridine-derived γ-secretase modulators reduced amyloidogenic Aβ peptides in vivo

► Two pyridazine- and pyridine-derived GSMs were profiled in vitro and in rats. ► These GSMs are orally bioavailable and brain penetrant. ► These GSMs achieved >100-fold selectivities against Notch. ► These GSMs demonstrated Aβ42-lowering pIC50s as 7.0 and 7.2 in vitro. ► Thirty mg/kg single dose PO, maintained >20% brain Aβ42 reduction over 24 h in rats.