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Purity: ≥98%
BAY 73-6691 [(R)-BAY 73-6691] is a novel, potent, selective, and brain penetrant PDE9A (Phosphodiesterase 9) inhibitor. Alzheimer's disease (AD) is accompanied by enhanced oxidative stress and excess free radicals. BAY 73-6691 may attenuate the oxidative stress during the development of AD is still unclear. For this purpose, primary cultures of SH-SY5Y cells were incubated with 20μM beta-amyloid25-35 (Aβ25-35), followed by exposure to different concentrations (50, 100, 150 and 200μg/ml) of BAY 73-6691. Furthermore, the antioxidant effect of BAY 73-6691 was evaluated in mice subjected to intracerebroventricular injection of Aβ25-35 (day 0) and treatment with BAY 73-6691 by intraperitoneal injection once daily (days 1-10). Our results elucidated that treatment with BAY 73-6691 attenuated the Aβ25-35-induced cytotoxicity and oxidative stress in SH-SY5Y cells. In vivo, BAY 73-6691 protected Aβ25-35-induced oxidative damage in hippocampus, associated with the attenuation of impairments in hippocampal neurons. Administration of BAY 73-6691 improved learning and memory in the Morris water maze test, and restored several hippocampal memory-associated proteins. This study identified a neuroprotective role for BAY 73-6691 against Aβ25-35-induced oxidative stress in vivo and in vitro, harboring therapeutic potential for the treatment of AD by alleviating the impairments in spatial memory and hippocampal neurons.
| Targets |
Aβ25-35 treatment-induced damage to cell viability is potently attenuated by BAY 73-6691. After being cultivated with Aβ25-35, it was discovered that SH-SY5Y cells were extremely alert; however, the further stimulation of BAY 73-6691 resulted in failed cells. While 200 μg/mL BAY 73-6691 nearly neutralizes the oxidative damage generated by Aβ25-35, BAY 73-6691 cuts off the oxidative damage induced by Aβ25-35 in a wearing manner. The increase in cell trafficking caused by Aβ25-35 is mitigated by BAY 73-6691 [1].
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| ln Vitro |
Aβ25-35 treatment-induced damage to cell viability is potently attenuated by BAY 73-6691. After being cultivated with Aβ25-35, it was discovered that SH-SY5Y cells were extremely alert; however, the further stimulation of BAY 73-6691 resulted in failed cells. While 200 μg/mL BAY 73-6691 nearly neutralizes the oxidative damage generated by Aβ25-35, BAY 73-6691 cuts off the oxidative damage induced by Aβ25-35 in a wearing manner. The increase in cell trafficking caused by Aβ25-35 is mitigated by BAY 73-6691 [1].
In human neuroblastoma SH-SY5Y cells exposed to beta-amyloid₂₅₋₃₅ (Aβ₂₅₋₃₅, 20 µM), treatment with BAY 73-6691 (50, 100, 150, and 200 µg/ml) dose-dependently attenuated the Aβ₂₅₋₃₅-induced loss of cell viability as measured by MTT assay. [1] BAY 73-6691 treatment (at the same concentrations) also reduced Aβ₂₅₋₃₅-induced apoptosis in SH-SY5Y cells, as assessed by Annexin V-FITC/PI double staining and flow cytometry. [1] BAY 73-6691 dose-dependently attenuated Aβ₂₅₋₃₅-induced oxidative stress in SH-SY5Y cells. It decreased the elevated level of malondialdehyde (MDA) and increased the suppressed activities of total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-PX), and catalase (CAT). At 200 µg/ml, it almost neutralized the Aβ₂₅₋₃₅-induced oxidative damage. [1] |
| ln Vivo |
Bayesian analysis 73-6691 From day 7 to day 10 (day 7, F (5, 54) = 65.153; day 8, F (5, 54) = 62.340; day 9, F (5, 54) = 37.529; day 10, F (5, 54) = 38.624; P<0.001). On days 9 and 10, BAY 73-6691 at 3 mg/kg virtually abolished the delayed escape latency. Day 10 following Aβ25-35 injection, BAY 73-6691 significantly increased the Aβ25-35-induced residence time (day 10, F (5,54) = 27.360, P < 0.001). The outcomes demonstrated that swimming speed was unaffected by BAY 73-6691 therapy or Aβ25-35 injection. The sham group did not experience any discernible alterations in clock-spatial memory as a result of BAY 73-6691 therapy. The irregularity of the aforementioned indicators caused by Aβ25-35 is lessened by BAY 73-6691. Mice in the sham operation group's hippocampus neuronal cells are not significantly affected by BAY 73-6691 [1].
In male ICR mice subjected to a single intracerebroventricular injection of Aβ₂₅₋₃₅ (9 nmol per mouse) to induce an Alzheimer's disease model, intraperitoneal administration of BAY 73-6691 (0.3, 1, and 3 mg/kg once daily for 10 days, starting 1 day post Aβ injection) dose-dependently improved spatial learning and memory deficits in the Morris water maze test. The 3 mg/kg dose almost completely abolished the prolongation of escape latency on days 9-10 post-injection and increased the dwell time in the target quadrant, without affecting swimming speed. [1] BAY 73-6691 (3 mg/kg) treatment attenuated Aβ₂₅₋₃₅-induced oxidative stress in the mouse hippocampus. It reduced the elevated MDA level and restored the decreased activities of T-AOC, GSH-PX, and CAT. [1] BAY 73-6691 (3 mg/kg) treatment protected against Aβ₂₅₋₃₅-induced impairments in hippocampal neurons. It reduced the number of apoptotic cells as shown by TUNEL staining, and prevented the Aβ₂₅₋₃₅-induced decrease in hippocampal levels of brain-derived neurotrophic factor (BDNF) and growth-associated protein-43 (GAP-43), as measured by ELISA and Western blotting, respectively. [1] |
| Cell Assay |
For the MTT cell viability assay, SH-SY5Y cells were plated in 96-well plates and treated with Aβ₂₅₋₃₅ (20 µM) with or without BAY 73-6691 (50-200 µg/ml) for 24, 48, or 72 hours. MTT solution was added, incubated, and the formazan product was dissolved for absorbance measurement at 550 nm. [1]
For apoptosis assessment by Annexin V-FITC/PI staining, SH-SY5Y cells were collected after treatment, resuspended in binding buffer, and incubated with Annexin V-FITC and propidium iodide (PI). Apoptotic rates were analyzed by flow cytometry. [1] For oxidative stress marker analysis in cells, supernatants were collected after treatment. Malondialdehyde (MDA) level was measured using the thiobarbituric acid reactive substances (TBARS) method. Total antioxidant capacity (T-AOC) was assessed using the ferric reducing antioxidant power (FRAP) assay. Glutathione peroxidase (GSH-PX) and catalase (CAT) activities were measured using established spectrophotometric methods. [1] |
| Animal Protocol |
Male ICR mice (25-30 g) were anesthetized and given a single intracerebroventricular injection of pre-aggregated Aβ₂₅₋₃₅ peptide (9 nmol in 3 µl) or vehicle (sham group) on day 0. [1]
BAY 73-6691 was administered intraperitoneally once daily at 7:30 AM at doses of 0.3, 1, or 3 mg/kg for 10 consecutive days, starting on day 1 post Aβ injection. The drug formulation/solvent is not specified. [1] Spatial learning and memory were assessed using the Morris water maze task from days 5 to 10 post-injection. [1] On day 10, mice were euthanized. Hippocampi were dissected for measurement of oxidative stress markers (MDA, T-AOC, GSH-PX, CAT), TUNEL staining for apoptosis, and protein analysis (BDNF by ELISA, GAP-43 by Western blot). [1] |
| References | |
| Additional Infomation |
BAY 73-6691 belongs to the pyrazolopyrimidine class of compounds, with the structure 4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine, substituted at positions 1, 4, and 6 with 2-chlorophenyl, oxo, and (2R)-3,3,3-trifluoro-2-methylpropyl groups, respectively. It is a potent and selective phosphodiesterase 9 (PDE9) inhibitor currently in preclinical development for the treatment of Alzheimer's disease. It exhibits nootropic, apoptosis-inducing, neuroprotective, and EC 3.1.4. (phosphodiester hydrolase) inhibitory effects. It belongs to the monochlorobenzene, pyrazolopyrimidine, and organofluorine compounds classes. BAY 73-6691 is described as a selective PDE9A inhibitor with brain penetration. [1]
This study suggests that BAY 73-6691 has neuroprotective effects against Aβ₂₅₋₃₅-induced toxicity both in vitro and in vivo, and that this effect is at least partly achieved by reducing oxidative stress. [1] The results indicate that the inhibitory effect of BAY 73-6691 on PDE9 may represent a promising Alzheimer's disease treatment strategy, with its mechanism of action being the protection of spatial memory and hippocampal neurons from amyloid β-induced damage. [1] |
| Molecular Formula |
C15H12N4OF3CL
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| Molecular Weight |
356.73018
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| Exact Mass |
356.065
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| CAS # |
794568-92-6
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| Related CAS # |
BAY 73-6691 racemate;794568-90-4;(S)-BAY 73-6691;794568-91-5
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| PubChem CID |
135541419
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.503
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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 |
3
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| Heavy Atom Count |
24
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| Complexity |
527
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@H](CC1=NC2=C(C=NN2C3=CC=CC=C3Cl)C(=O)N1)C(F)(F)F
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| InChi Key |
FFPXPXOAFQCNBS-MRVPVSSYSA-N
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| InChi Code |
InChI=1S/C15H12ClF3N4O/c1-8(15(17,18)19)6-12-21-13-9(14(24)22-12)7-20-23(13)11-5-3-2-4-10(11)16/h2-5,7-8H,6H2,1H3,(H,21,22,24)/t8-/m1/s1
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| Chemical Name |
4H-Pyrazolo(3,4-d)pyrimidin-4-one, 1-(2-chlorophenyl)-1,5-dihydro-6-((2R)-3,3,3-trifluoro-2-methylpropyl)-
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| Synonyms |
BAY-73-6691; BAY736691; BAY73-6691; UNII-80ZTV3INTW; (R)-Bay-73-6691;
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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 : ~160 mg/mL (~448.52 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (7.01 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.01 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8032 mL | 14.0162 mL | 28.0324 mL | |
| 5 mM | 0.5606 mL | 2.8032 mL | 5.6065 mL | |
| 10 mM | 0.2803 mL | 1.4016 mL | 2.8032 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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