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| Targets |
Tovinontrine specifically targets phosphodiesterase-9 (PDE9), an enzyme that catalyzes the hydrolysis of cGMP to GMP. The compound exhibits potent inhibitory activity against PDE9A1 and PDE9A2 with IC50 values of 8.19 nM and 9.99 nM, respectively. PDE9 is a member of the phosphodiesterase superfamily that plays a critical role in regulating intracellular cGMP levels in various tissues, including erythroid cells. Tovinontrine demonstrates approximately 800-fold selectivity for PDE9 over other PDE isoforms including PDE1A3 (IC50 = 88.4 μM), PDE1B (IC50 = 8.48 μM), PDE1C (IC50 = 12.2 μM), and PDE5A2 (IC50 = 81.9 μM). This high selectivity is important for minimizing off-target effects and maximizing the therapeutic benefits of cGMP elevation in target cells.
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| ln Vitro |
IMR-687 has an inhibitory efficacy of about 800 times greater than PDE9A, PDE1A3, PDE1B, PDE1C, and PDE5A2, with IC50 values of 88.4 μM, 8.48 μM, 12.2 μM, and 81.9 μM, in that order [1]. Hemoglobin (HbF) is generated in K562 cells for 72 hours in red blood cells by IMR-687 (0.1–10 μM) in a dose-dependent manner [1]. In erythroid K562 cells, IMR-687 (0.03-10 μM) raises cGMP in a dose-dependent manner over a 6-hour period [1].
In vitro, Tovinontrine (IMR-687) demonstrates potent inhibition of PDE9 with IC50 values of 8.19 nM for PDE9A1 and 9.99 nM for PDE9A2. In erythroid K562 and UT-7 cells, IMR-687 increases intracellular cGMP levels in a dose-dependent manner at concentrations ranging from 0.03 to 10 μM over 6 hours. The compound also induces fetal hemoglobin (HbF) production in K562 cells in a dose-dependent manner at concentrations of 0.1 to 10 μM over 72 hours. In two-phase liquid cultures using CD34+ progenitor cells from sickle cell blood or bone marrow, IMR-687 increases the percentage of HbF-positive erythroid cells generated in vitro. These findings demonstrate that PDE9 inhibition elevates cGMP and promotes HbF production in erythroid progenitor cells. |
| ln Vivo |
IMR-687 (30 mg/kg/day; after 30 days of therapy) demonstrated a more than 3-fold rise in the percentage of HbF+ F cells (vehicle treatment: 8.4%, IMR-687 treatment: 27.3%) and a similar 2-fold reduction in sickle red cells ( Carrier treatment: 56.3% and IMR-687 treatment: 24.4%)[1].
In vivo, Tovinontrine (IMR-687) has been evaluated in the Townes transgenic mouse model of sickle cell disease. Daily oral administration of IMR-687 at 30 mg/kg for 30 days increases the percentage of HbF+ F-cells by more than 3-fold compared to vehicle-treated controls (27.3% vs 8.4%). The compound also reduces sickle erythrocyte frequency by 2-fold (24.4% vs 56.3% in vehicle controls). These findings demonstrate that IMR-687 induces fetal hemoglobin, reduces hemolysis, and decreases reticulocytosis in the SCD mouse model. Additional effects include reduced erythrocyte sickling, decreased immune cell activation, and reduced microvascular stasis. These results support the therapeutic potential of Tovinontrine for treating sickle cell disease. |
| Enzyme Assay |
PDE9 inhibitory activity is assessed using enzymatic assays with recombinant human PDE9 enzymes. The assay typically involves incubating the PDE9 enzyme with a fluorescent or radiolabeled cGMP substrate in the presence of varying concentrations of the test compound. The enzymatic reaction is terminated, and the amount of hydrolysis product (GMP) is quantified using fluorescence polarization, scintillation proximity, or mass spectrometry-based detection methods. IC50 values are calculated from dose-response curves by plotting percent inhibition versus compound concentration. Selectivity profiling against other PDE isoforms (PDE1A3, PDE1B, PDE1C, PDE5A2, etc.) is performed using similar enzymatic assays to confirm the compound's specificity for PDE9.
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| Cell Assay |
Cellular assays for Tovinontrine are performed using erythroid cell lines such as K562 and UT-7, as well as primary CD34+ progenitor cells isolated from sickle cell disease patients. Cells are treated with varying concentrations of the compound (typically 0.03-10 μM) for specified time periods (6-72 hours). Intracellular cGMP levels are quantified using competitive ELISA or HTRF-based detection methods. Fetal hemoglobin (HbF) production is assessed by flow cytometry using anti-HbF antibodies or by HPLC analysis of hemoglobin species. For CD34+ progenitor cell assays, cells are cultured in two-phase liquid culture systems to support erythroid differentiation, and HbF-positive erythroid cells are quantified by flow cytometry.
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| Animal Protocol |
Animal/Disease Models: HbSS-Townes mice (10-12 weeks old) on 129/B6 background [1]
Doses: 30 mg/kg Route of Administration: Dosage daily gavage for 30 days Experimental Results: Caused fetal hemoglobin (HbF) induction, diminished hemolysis, and increased reticulocytosis. In vivo studies of Tovinontrine are conducted using the Townes transgenic mouse model of sickle cell disease (HbSS-Townes mice on a 129/B6 background), typically aged 10-12 weeks. The compound is administered daily by oral gavage at a dose of 30 mg/kg for 30 days. Blood samples are collected at various time points for analysis of HbF levels by flow cytometry or HPLC, assessment of erythrocyte sickling frequency, and measurement of reticulocyte counts. Pharmacodynamic markers including hemoglobin levels, hemolysis parameters, and inflammatory markers are monitored. Immune cell activation and microvascular stasis are evaluated using appropriate assays. Body weight and general health are monitored throughout the study to assess tolerability. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of Tovinontrine have been characterized in preclinical studies. The compound is orally bioavailable and designed for once-daily oral administration. Tovinontrine has a molecular weight of 394.47 and a LogP of 0.4, indicating relatively low lipophilicity that may influence its absorption and distribution characteristics. The compound is formulated as a solid for oral administration. In clinical development, Tovinontrine is being investigated in clinical trial NCT04474314 (A Study of IMR-687 in Subjects With Sickle Cell Disease). Comprehensive pharmacokinetic parameters including Cmax, Tmax, half-life, and oral bioavailability have been evaluated as part of the clinical development program.
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| Toxicity/Toxicokinetics |
Tovinontrine has been evaluated in preclinical toxicology studies as part of its development program for sickle cell disease. The compound is currently under clinical investigation in trial NCT04474314. Standard toxicology assessments conducted during preclinical development would have included acute and repeat-dose toxicity studies in rodents and other species, as well as safety pharmacology evaluations for cardiovascular, respiratory, and central nervous system function. The compound has shown a favorable safety profile in preclinical studies, supporting its advancement to clinical trials. Specific toxicity data is available from the clinical development program but is not detailed in publicly available sources.
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| References | |
| Additional Infomation |
Tovinontrine is an orally administered, highly selective phosphodiesterase 9 (PDE9) small molecule inhibitor. Tovinontrine is being investigated in the clinical trial NCT04474314 (the IMR-687 study in patients with sickle cell disease).
Tovinontrine (IMR-687) is an orally administered, highly selective PDE9 small molecule inhibitor under investigation for the treatment of sickle cell disease. The compound is being studied in clinical trial NCT04474314. By inhibiting PDE9, Tovinontrine elevates cGMP levels in erythroid cells, which in turn promotes fetal hemoglobin (HbF) production through activation of the cGMP-dependent protein kinase (PKG) pathway. HbF induction has been validated as a therapeutic strategy for SCD, as increased HbF levels reduce hemoglobin S polymerization and erythrocyte sickling. The compound's high selectivity for PDE9 over other PDE isoforms minimizes off-target effects and supports its favorable safety profile. Tovinontrine represents a novel approach to SCD therapy targeting the underlying pathophysiology rather than merely managing symptoms. |
| Molecular Formula |
C21H26N6O2
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|---|---|
| Molecular Weight |
394.470143795013
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| Exact Mass |
394.21
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| Elemental Analysis |
C, 63.94; H, 6.64; N, 21.30; O, 8.11
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| CAS # |
2062661-53-2
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| PubChem CID |
124220601
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| Appearance |
White to off-white solid powder
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| LogP |
0.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
631
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@@H]1CN(C[C@H]1C2=CN3C(=CN=C3C4CCOCC4)C(=O)N2)CC5=NC=CC=N5
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| InChi Key |
GWGNPYYVGANHRJ-GDBMZVCRSA-N
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| InChi Code |
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
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| Chemical Name |
6-{(3S,4S)-4-methyl-1-[(pyrimidin-2-yl)methyl]pyrrolidin-3-yl}-3-(oxan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one
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| Synonyms |
Tovinontrine; IMR-687; IMR 687; IMR687;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~253.50 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.34 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.34 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.34 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5350 mL | 12.6752 mL | 25.3505 mL | |
| 5 mM | 0.5070 mL | 2.5350 mL | 5.0701 mL | |
| 10 mM | 0.2535 mL | 1.2675 mL | 2.5350 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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