Tovinontrine

• CAT Number: I037416
• CAS Number: 2062661-53-2
• Molecular Formula: C21H26N6O2
• Molecular Weight: 394.47
• Purity: ≥95%
• Synonyms: 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-(oxan-4-yl)-7H-imidazo[1,5-a]pyrazin-8-one
• InChI: InChI=1S/C21H26N6O2/c1-14-10-26(13-19-22-5-2-6-23-19)11-16(14)17-12-27-18(21(28)25-17)9-24-20(27)15-3-7-29-8-4-15/h2,5-6,9,12,14-16H,3-4,7-8,10-11,13H2,1H3,(H,25,28)/t14-,16-/m1/s1
• InChIKey: GWGNPYYVGANHRJ-GDBMZVCRSA-N
• SMILES: CC1CN(CC1C2=CN3C(=CN=C3C4CCOCC4)C(=O)N2)CC5=NC=CC=N5

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].

Reference

[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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