The two isoforms of glycogen synthase kinase 3, GSK3α and GSK3β, constitutively phosphorylate and inactivate glycogen synthase, preventing glycogen synthesis. They also phosphorylate proteins that are relevant to Alzheimer’s disease and osteogenesis. AZD 1080 is a potent, brain permeable inhibitor of GSK3α and GSK3β (Kis = 6.9 and 31 nM, respectively). It shows >14-fold selectivity against several kinases, receptors, enzymes, and ion channels. AZD 1080 inhibits tau phosphorylation in cells. It shows good bioavailability after oral administration in vivo, inhibiting hippocampal tau phosphorylation and reversing cognitive deficits induced by the NMDA receptor antagonist MK-801. In humans, oral AZD 1080 inhibits GSK3 activity in peripheral blood lymphocytes following an initial delay in response.
