Tovinontrine (IMR-687) 是一种高效的选择性磷酸二酯酶 9 (PDE9)抑制剂，可用于研究镰状细胞病。抑制PDE9A1 和 PDE9A2 的 IC50 分别为 8.19 nM 和 9.99 nM。
Tovinontrine (IMR-687) is a highly potent and selective phosphodiesterase-9 (PDE9) inhibitor specifically for the treatment of sickle cell disease. IC50s are 8.19 nM and 9.99 nM for PDE9A1 and PDE9A2, respectively[1].
IMR-687 inhibits PDE9A with more than 800-fold greater potency than PDE1A3, PDE1B, PDE1C, PDE5A2, with IC50 values of 88.4 μM, 8.48 μM, 12.2 μM, and 81.9 μM, respectively[1]. IMR-687 (0.1-10 μM) treatment in erythroid K562 cells for 72 hours induces hemoglobin (HbF) in a dose-dependent manner[1]. IMR-687 (0.03-10 μM) treatment for 6 hours in erythroid K562 cells increases cGMP in a dose-dependent manner[1].
IMR-687 (30 mg/kg/day; after 30 days of treatment) shows a greater than 3-fold in the percent of HbF+ F-cells (8.4% in vehicle treated and 27.3% in IMR-687 treated) and a corresponding 2-fold decrease in sickled red blood cells (56.3% in vehicle treated and 24.4% in IMR-687 treated)[1].
[1]. James G McArthur, et al. A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease. Haematologica. 2020 Mar;105(3):623-631.
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