AZD-6482

• CAT Number: I000619
• CAS Number: 1173900-33-8
• Molecular Formula: C₂₂H₂₄N₄O₄
• Molecular Weight: 408.45
• Purity: ≥95%
• Target: PI3K
• Solubility: DMSO ≥80mg/mL Water <1.2mg/mL Ethanol ≥25mg/mL
• Storage: 3 years -20℃ powder
• IC50: 10 nM
• IUPAC Name: 2-[[(1R)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoic acid
• InChI: InChI=1S/C22H24N4O4/c1-14-11-17(15(2)23-18-6-4-3-5-16(18)22(28)29)21-24-19(12-20(27)26(21)13-14)25-7-9-30-10-8-25/h3-6,11-13,15,23H,7-10H2,1-2H3,(H,28,29)/t15-/m1/s1
• InChIKey: IRTDIKMSKMREGO-OAHLLOKOSA-N
• SMILES: CC1=CN2C(=O)C=C(N=C2C(=C1)C(C)NC3=CC=CC=C3C(=O)O)N4CCOCC4

AZD6482 (Cat.No:I000619) targets a process that is critical to pathological thrombus formation without interfering with normal haemostasis, which avoids the drawbacks of the existing anti-thrombotic therapy. AZD6482 inhibits PI3Kβ/α/γ/δwith IC50 of 0.021, 1.4, 1.2, 0.08μM, respectively. It washed platelet aggregation with concentration at 6 nM.

Reference

[1]. Nylander S, Kull B, Bj?rkman J, Ulvinge JC, Oakes N, Emanuelsson B, Andersson M, Sk?rby T, Inghardt T, Fjellstr?m O, Gustafsson D.Human target validation of phosphoinositide 3-kinase (PI3K)β; effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor.J Thromb Haemost. 2012 Aug 20.
Abstract
Background: Based on in vitro and animal data PI3Kβ is given an important role in platelet adhesion and aggregation but its role in insulin signaling is unclear. Objective: To strengthen the PI3Kβ target validation using the novel, short-acting inhibitor AZD6482. Methods and Results: AZD6482 is a potent, selective and ATP competitive PI3Kβ inhibitor (IC(50) 0.01μM). Maximal anti-platelet effect was achieved at 1μM in the in vitro and ex vivo tests both in dog and in man. In vivo in dog AZD6482 produced a complete anti-thrombotic effect without increased bleeding time or blood loss. AZD6482 was well tolerated in healthy volunteers during a 3h infusion. The ex vivo anti-platelet effect and minimal bleeding time prolongation in the dog model translated well to data obtained in healthy volunteers. AZD6482 inhibited insulin induced human adipocyte glucose uptake in vitro (IC(50) of 4.4μM). In the euglycemic hyperinsulinemic clamp model in rat/’s glucose infusion rate was not affected at 2.3μM but reduced by about 60% at a plasma exposure of 27μM. In man HOMA-index increased by about 10-20% at the highest plasma concentration 5.3μM. Conclusions: This is the first human target validation for PI3Kβ inhibition as anti-platelet therapy showing a mild and generalized antiplatelet effect attenuating but not abolishing multiple signaling pathways with an impressive separation towards primary hemostasis. AZD6482 at /supratherapeutic/ plasma concentrations may attenuate insulin signaling, most likely through PI3Kα inhibition. ? 2012 International Society on Thrombosis and Haemostasis.