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| 5mg |
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| 25mg |
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Purity: ≥98%
PF-04447943 (PF04447943) is a novel and potent inhibitor of human recombinant PDE9A with the potential for the treatment of cognitive disorders. It inhibits PDE9A with IC50 of 12 nM and exhibits>78-fold selectivity over other PDE family members (IC50>1000 nM). PF-04447943 was found to have high affinity (Ki of 2.8, 4.5 and 18 nM) for human, rhesus and rat recombinant PDE9 respectively and high selectivity for PDE9 versus PDEs1-8 and 10-11. PF-04447943 significantly increased neurite outgrowth and synapse formation (as indicated by increased synapsin 1 expression) in cultured hippocampal neurons at low (30-100 nM) but not high (300-1000 nM) concentrations. PF-04447943 significantly facilitated hippocampal slice LTP evoked by a weak tetanic stimulus at a concentration of 100 nM but failed to affect response to the weak tetanus at either 30 or 300 nM, or the LTP produced by a theta burst stimulus. Systemic administration of PF-04447943 (1-30 mg/kg p.o.) dose-dependently increased cGMP in the cerebrospinal fluid 30 min after administration indicating target engagement in the CNS of rats. PF-04447943 (1-3 mg/kg p.o.) significantly improved cognitive performance in three rodent cognition assays (mouse Y maze spatial recognition memory model of natural forgetting, mouse social recognition memory model of natural forgetting and rat novel object recognition with a scopolamine deficit). When administered at a dose of 3 mg/kg p.o., which improved performance in novel object recognition, PF-04447943 significantly increased phosphorylated but not total GluR1 expression in rat hippocampal membranes. Collectively these data indicate that PF-04447943 is a potent, selective brain penetrant PDE9 inhibitor that increased indicators of hippocampal synaptic plasticity and improved cognitive function in a variety of cognition models in both rats and mice. Results with PF-04447943 are consistent with previously published findings using a structurally diverse PDE9 inhibitor, BAY73-6199, and further support the suggestion that PDE9 inhibition may represent a novel approach to the palliative remediation of cognitive dysfunction.
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| ln Vitro |
In a cell-free experiment employing recombinant human, rhesus, and rat PDE9A2, Edelinontrine's Ki values are 2.8±0.26, 4.5±0.13, and 18.1±1.9 nM (n=4, 11 and 9 correspondingly). Edelinontrine exhibits a high degree of selectivity when compared to other PDE enzymes (PDE1, Ki=8600±2121 nM, n = 5; PDE2A3, Ki>99,000 nM; PDE3A, Ki>50,000 nM; PDE4A, Ki>29,000 nM; PDE5A, Ki=14,980±5025 nM, n = 5; PDE6C, Ki=5324±2612 nM, n=4; PDE7A2, Ki>75,000 nM; PDE8A, Ki>50,000 nM; PDE10, Ki>51,250±20,056 nM, n = 4; PDE11, Ki>80,000 nM) and exhibits no other notable activity at ~60 other receptors/enzymes. With an IC50 of 375±36.9 nM (n=16) in HEK whole cells expressing rhesus PDE9A2, Edelinontrine suppresses ANP (0.3 μM) induced cGMP[2].
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| ln Vivo |
Pharmacokinetic studies using Edelinontrine in rats show a Tmax of 0.3 h, T1/2 of 4.9 h, Cl of 21.7 mL/min/kg, and an oral bioavailability of 47% based on iv and po doses. After rats were given oral medication (1–30 mg/kg), blood, brain, and cerebrospinal fluid (CSF) concentrations of eldinontrine increased in a dose-dependent manner after thirty minutes. Thirty minutes after dosage, the brain:plasma exposure ratios vary from 0.13 at 1 mg/kg to 0.33 at 30 mg/kg. About 50% of brain levels are represented by CSF levels. The plasma and brain concentrations of Edelinontrine in mice are increased dose-dependently by 3, 10, and 30 mg/kg po. The brain to plasma ratio ranges from 0.26 to 0.7, however this is not totally dosage dependent. At the 30 mg/kg dose, CSF cGMP levels rise in a dose-dependent manner from a basal level of 3 pmol/mL to 13.3 pmol/mL (3.5-fold). Additionally, CSF cGMP levels rise in a dose-dependent way; at the 30 mg/kg dose, they increase by 3.5 times, from a basal level of 3 pmol/mL in animals treated with a vehicle to 13.3 pmol/mL. At all studied doses, CSF cGMP levels are raised, reaching a maximum impact of 3.5 times the increase over controls at 30 mg/kg[2].
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| Cell Assay |
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| References |
[1]. Kleiman RJ, et al. Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo. J Pharmacol Exp Ther. 2012 May;341(2):396-409.
[2]. Hutson, P. H, et al. The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and |
| Molecular Formula |
C20H25N7O2
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| Molecular Weight |
395.458203077316
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| CAS # |
1082744-20-4
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| SMILES |
O=C1C2=C(N(C3CCOCC3)N=C2)N=C([C@@H]4CN(CC5=NC=CC=N5)C[C@H]4C)N1
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| InChi Key |
IWXUVYOOUMLUTQ-CZUORRHYSA-N
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| InChi Code |
InChI=1S/C20H25N7O2/c1-13-10-26(12-17-21-5-2-6-22-17)11-16(13)18-24-19-15(20(28)25-18)9-23-27(19)14-3-7-29-8-4-14/h2,5-6,9,13-14,16H,3-4,7-8,10-12H2,1H3,(H,24,25,28)/t13-,16-/m1/s1
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| Chemical Name |
6-((3S,4S)-4-Methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo(3,4-d)pyrimidin-4-one
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| Synonyms |
PF-04447943; PF-4447943; PF 04447943; PF 4447943; PF04447943; PF4447943.
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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 : ≥ 54.6 mg/mL (~138.07 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.32 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 (6.32 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 (6.32 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 | 2.5287 mL | 12.6435 mL | 25.2870 mL | |
| 5 mM | 0.5057 mL | 2.5287 mL | 5.0574 mL | |
| 10 mM | 0.2529 mL | 1.2644 mL | 2.5287 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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