612487-72-6

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 (K_is = 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.

AZD1080 is a selective, orally active, brain permeable glycogen synthase kinase-3 (GSK3) inhibitor (1,2). AZD1080 has shown to rescue synaptic plasticity deficits in rodent brain and exhibit peripheral target engagement in humans.

ChEBI: AZD1080 is a member of the class of hydroxyindoles that is 1H-indole substituted by hydroxy, 5-(morpholin-4-ylmethyl)pyridin-2-yl, and cyano groups at positions 2, 3 and 5, respectively. It is a potent, brain permeable inhibitor of human GSK3alpha and GSK3beta with Ki of 6.9 nM and 31 nM, respectively. The drug was being developed by AstraZeneca for the treatment of Alzheimer's disease (clinical trial now discontinued). It has a role as an EC 2.7.11.26 (tau-protein kinase) inhibitor, a tau aggregation inhibitor, an antineoplastic agent and an apoptosis inducer. It is a member of morpholines, a member of pyridines, a member of hydroxyindoles, a nitrile and a tertiary amino compound.

The reaction was carried out in a 10 mL Schlenk tube with 5-bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol (1.00 g, 2.57 mmol), zinc powder (25.5 mg, 0.386 mmol), and bis(dibenzylideneacetone)palladium(0) (37 mg, 0.064 mmol). First, the reaction was added to the Schlenk tube along with a magnetic stirring bar, followed by sealing with a rubber septum, evacuating and displacing twice with nitrogen. Next, degassed dimethylformamide (7 mL) was added via syringe, followed by tri-tert-butylphosphine (65 μL, 20% w/v toluene solution, 0.064 mmol). The reaction mixture was heated to 50 °C with stirring and held for 4 min before zinc cyanide (169 mg, 1.42 mmol) was added under nitrogen protection. The reaction was continued with stirring at 50 °C for 3 h. HPLC analysis showed complete conversion of the reaction. After completion of the reaction, the mixture was cooled to room temperature and filtered through a sintered glass filter. To the filtrate, 3-mercaptopropyl functionalized silica (0.3 g) was added and the mixture was stirred at 40 °C overnight and filtered again. The filtrate was heated to 60 °C and tetrasodium acetate-sodium ethylenediaminetetraacetic acid (25 mL, 0.30 M aqueous solution) was added over 5 min to produce a bright yellow precipitate. The mixture was cooled to room temperature and filtered, the precipitate was washed with water (10 mL) and dried under vacuum at 40 °C to afford the target product 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile (0.63 g, 73% yield). The product characterization data was consistent with Example 5.

This orally active, brain-permeable protein kinase inhibitor (FW = 334.37 g/mol; CAS 612487-72-6), also named 2-hydroxy-3-[5- (4-morpholinyl- methyl) -2-pyridinyl]-1H-indole-5-carbonitrile, selectively targets human GSK3α (Ki = 6.9 nM) and GSK3β (Ki = 31 nM), showing >14x lower inhibitory action against CDK2, CDK5, CDK1 and Erk2. AZD1080 inhibits human tau phosphorylation. The inhibitory pattern on tau phosphorylation reveals a prolonged pharmacodynamic effect predicting less frequent dosing in humans. Subchronic but not acute, administration with AZD1080 reverses MK-801-induced deficits, as measured by long- term potentiation in hippocampal slices and in a cognitive test in mice. Such findings suggest that reversal of synaptic plasticity deficits in dysfunctional systems requires longer term modifications of proteins downstream of GSK3β signaling.

GSK-3α

GSK-3α: 8.2 (pKi); GSK-3β: 7.5 (pKi); cdk5: 6.4 (pKi); cdk2: 5.9 (pKi); cdk1: 5.7 (pKi)

[1] georgievska b1, sandin j, doherty j, m?rtberg a, neelissen j, andersson a, gruber s, nilsson y, sch?tt p, arvidsson pi, hellberg s, osswald g, berg s, f?lting j, bhat rv. azd1080, a novel gsk3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. j neurochem. 2013 may;125(3):446-56.