| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| Other Sizes |
| Targets |
human 5-HT4E ( EC50 = 0.26 nM ); human 5-HT4B ( EC50 = 0.36 nM ); human 5-HT4D ( EC50 = 0.37 nM ); human 5-HT4A ( EC50 = 0.47 nM ); rat 5-HT4S ( EC50 = 0.59 nM )
5-HT4 receptor (5-HT4R). PF-04995274 is a partial agonist of the serotonin 5HT4 receptor with Ki = 0.15 - 0.46 nM for 5-HT4 isoforms a, b, d, and e. It has an EC50 range of 0.26-0.47 nM for human 5-HT4A/4B/4D/4E (Ki range of 0.15-0.46 nM). |
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| ln Vitro |
PF-04995274 has EC50 values for rat 5-HT4S/4L/4E and human 5-HT4A/4B/4D/4E of 0.62 nM and 0.47 nM, 0.36 nM, 0.37 nM, 0.26 nM, 0.59 nM, and 0.65 nM, respectively. For human 5-HT4A/4B/4D/4E and rat 5-HT4S, PF-04995274 has Ki values of 0.36 nM, 0.46 nM, 0.15 nM, 0.32 nM, and 0.3 nM, respectively[3].
PF-04995274 is a potent, high-affinity, and partial 5-HT4R agonist. It has an EC50 range of 0.26-0.47 nM for human 5-HT4A/4B/4D/4E (Ki range of 0.15-0.46 nM), and an EC50 range of 0.59-0.65 nM for rat 5-HT4S/4L/4E (Ki of 0.30 nM for rat 5-HT4S). |
| ln Vivo |
PF-04995274 (3-10 mg/kg; intravenous injection; for 17 days; male 129S6/SvEv mice) treatment is effective as a preventative measure because it reduces learned fear and stress-induced depressive-like behavior[1].
PF-04995274 is an orally active 5-HT4R partial agonist. It is brain penetrant and can be used for cognitive disorders associated with Alzheimer's disease. 5-HT4 agonists modulate cholinergic function and are being studied as possible treatment for cognitive disorders associated with Alzheimer's Disease. |
| Enzyme Assay |
5-HT4 receptor binding assays are performed using membranes prepared from cells expressing recombinant human 5-HT4 receptor isoforms. Radioligand binding studies use [3H]-GR113808 as the labeled ligand. Membrane preparations are incubated with varying concentrations of PF-04995274 and a fixed concentration of radioligand in binding buffer for 60-120 minutes at room temperature. Non-specific binding is determined using excess unlabeled GR113808. Bound radioactivity is measured by scintillation counting after filtration through GF/B filters. IC50 and Ki values are calculated by non-linear regression.
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| Cell Assay |
Cellular 5-HT4 receptor activation is evaluated in cell lines expressing recombinant 5-HT4 receptors (e.g., HEK-293 cells). Cells are cultured in appropriate media at 37°C with 5% CO2 and treated with PF-04995274 at various concentrations. Functional assays measure receptor-mediated cAMP accumulation. The compound's partial agonist activity is assessed by its ability to stimulate cAMP production relative to a full agonist (e.g., 5-HT). Cell viability is assessed using MTT or LDH assays. Each experiment includes known 5-HT4 agonists as positive controls and vehicle controls.
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| Animal Protocol |
Male 129S6/SvEv mice (7-8 weeks) treated with contextual fear conditioning (CFC) and forced swim test (FST)
3 mg/kg, 10 mg/kg Intravenous injection; for 17 day In vivo studies are conducted in rodent models of cognitive impairment or Alzheimer's disease. PF-04995274 is administered orally at doses determined by preclinical studies. Cognitive function is assessed using behavioral tests (Morris water maze, novel object recognition). Brain penetration is confirmed by measuring compound levels in brain tissue by LC-MS/MS. Acetylcholine levels in the brain may be measured by microdialysis. Sample sizes typically range from 8-12 animals per group. |
| ADME/Pharmacokinetics |
Molecular Weight: 432.51. CAS No.: 1331782-27-4. Synonyms: UNII-XI179PG9LV. Purity: Typically ≥98%. For research use only. Brain penetrant.
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| Toxicity/Toxicokinetics |
No comprehensive toxicology data are publicly available. As a 5-HT4 receptor partial agonist, potential adverse effects may include gastrointestinal disturbances (due to 5-HT4 receptor expression in the gut) and cardiac effects. Standard toxicity studies would include acute and subchronic toxicity in rodents, genotoxicity screening, and evaluation of effects on the central nervous system and cardiovascular system. No clinical trials have been reported for this compound. The compound is intended for research use only.
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| References | |
| Additional Infomation |
PF 04995274 is being studied in the clinical trial NCT01193062 (a study evaluating changes in sAPP-α protein in cerebrospinal fluid after a single oral dose of PF-04995274 in healthy subjects).
PF-04995274 is also known as PF04995274. It is a potent, high-affinity, orally active, and partial 5-HT4R agonist. It is brain penetrant and can be used for cognitive disorders associated with Alzheimer's disease. No clinical trials or regulatory approvals have been reported. The compound is for research use only. |
| Molecular Formula |
C23H32N2O6
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|---|---|
| Molecular Weight |
432.52
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| Exact Mass |
432.226
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| Elemental Analysis |
C, 63.87; H, 7.46; N, 6.48; O, 22.19
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| CAS # |
1331782-27-4
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| PubChem CID |
53354764
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| Appearance |
Solid powder
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| LogP |
2.565
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
31
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| Complexity |
566
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| Defined Atom Stereocenter Count |
1
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| SMILES |
OC1(CCOCC1)CN1CCC(COC2C3=C(C=CC=C3O[C@H]3COCC3)ON=2)CC1
|
| InChi Key |
HUJXGQILHAUCCV-MOROJQBDSA-N
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| InChi Code |
InChI=1S/C18H19IN6O4/c1-20-17(28)14-12(26)13(27)18(29-14)25-8-24-11-15(22-7-23-16(11)25)21-6-9-3-2-4-10(19)5-9/h2-5,7-8,12-14,18,26-27H,6H2,1H3,(H,20,28)(H,21,22,23)/t12-,13+,14-,18+/m0/s1
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| Chemical Name |
(2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyloxolane-2-carboxamide
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| Synonyms |
PF04995274; PF 04995274; PF-04995274
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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: 86~100 mg/mL (198.8~231.2 mM)
Ethanol: ~20 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.78 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 (5.78 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 (5.78 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 | 2.3120 mL | 11.5602 mL | 23.1203 mL | |
| 5 mM | 0.4624 mL | 2.3120 mL | 4.6241 mL | |
| 10 mM | 0.2312 mL | 1.1560 mL | 2.3120 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03515733 | Completed | Drug: PF-04995274 Drug: Placebo Oral Tablet |
Depression, Unipolar Treatment Resistant Depression |
University of Oxford | May 31, 2018 | Phase 1 |
| NCT03516604 | Completed | Drug: PF-04995274 Drug: Citalopram |
Depression, Unipolar | Syntrix Biosystems, Inc. | May 16, 2018 | Phase 1 |
| NCT01193062 | Completed | Drug: PF-04995274 | Healthy | Pfizer | September 2010 | Phase 1 |
| NCT01173757 | Completed | Drug: PF-04995274 | Healthy | Pfizer | August 2010 | Phase 1 |
| NCT01091272 | Completed | Drug: PF-04995274 | Healthy | Pfizer | April 2010 | Phase 1 |
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