AZD2716

AZD2716 is an orally active secretory phospholipase A₂ (sPLA₂) inhibitor. AZD2716 inhibits human GIIA sPLA₂ (IC₅₀=10 nM), human GV sPLA₂ (IC₅₀=40 nM), human GX sPLA₂ (IC₅₀=400 nM), snake venom sPLA₂ (IC₅₀=2 pM), and snake (Bothrops jararacussu) Lys49-PLA2-like toxin (K_d=110 μM). AZD2716 inhibits sPLA₂ isoforms IIa, V, X, snake venom sPLA₂s, and snake venom Lys49-PLA₂-like toxin myotoxic activity via hydrophobic channel binding. AZD2716 suppresses GIIA sPLA₂ production, neutralizes snake venom-induced myotoxicity, and improves survival in envenomed mice. AZD2716 can be used for the research of coronary artery disease, atherosclerosis, and snakebite envenoming^{[1][2][3][4][5]}. In Vitro:AZD2716 potently inhibits plasma sPLA₂ with an IC₅₀ of 0.1 nM^[1].
AZD2716 (266 nM-2.18 mM; 5 min) binds to BthTX-I with a dissociation constant (K_d) of 110 μM, demonstrating micromolar-range affinity^[2].
AZD2716 (6.5 mg/mL; ~15 days, 300 ns) binds to the hydrophobic channels of dimeric PrTX-I (two inhibitor molecules per toxin dimer), preventing fatty acid access and full toxin activation stabilization, with stable binding maintained over 300 ns of molecular dynamics simulation^[2].
AZD2716 (up to 25 μM) does not inhibit OATP1B1-mediated pivastatin uptake in OATP1B1-transfected HEK293 cells at concentrations up to 25 μM^[3].
AZD2716 has an intrinsic clearance of 12 μL/min/10⁶ cells in primary human hepatocytes^[3].
AZD2716 potently inhibits purified human sPLA₂-IIa, sPLA₂-V, and sPLA₂-X enzymes with IC₅₀ values of 0.010 μM, 0.040 μM, and 0.400 μM, respectively, and inhibits human plasma sPLA₂ activity with an IC_u,50 of 0.1 nM^[3].
AZD2716 inhibits sPLA₂ activity in HepG2 cells with an IC₅₀ < 14 nM and suppresses sPLA₂-II production in HepG2 cells with an IC₅₀ of 176 nM^[3].
AZD2716 inhibits sPLA₂ activity in human carotid atherosclerotic plaque homogenates with an IC₅₀ of 56 nM^[3].
AZD2716 potently inhibits multiple sPLA₂ isoforms (GIIA, GV, GX) in cell-free assays, and inhibits sPLA₂ activity in human plasma and atherosclerotic plaque homogenates, with IC₅₀ values ranging from 0.1 nM to 400 nM^[4].
AZD2716 inhibits sPLA₂ activity and suppresses GIIA sPLA₂ production in HepG2 cells, with IC₅₀ values of <14 nM and 176 nM, respectively^[4]. In Vivo:Oral administration of AZD2716 (30 mg; p.o.; single dose) to Macaca fascicularis produces concentration-dependent plasma sPLA₂ activity inhibition with an IC_u,80 of 13 nM^[3].
AZD2716 (5-10 mg/kg; i.v., single dose within 10 minutes of envenoming; p.o., two doses first within 10 minutes second at 6 hours) significantly improves survival in envenomed mice versus venom-only controls, with greater efficacy against viper venoms than elapid venoms, but provides a weaker survival benefit than Varespladib (HY-13402)^[5].