PF-04995274 (PF04995274) is a novel and potent serotonin 4 receptor (5-HT4) partial agonist, acting centrally as a pro-cognitive agent with the potential to be used for the treatment of Alzheimer's disease (AD).
Physicochemical Properties
| Molecular Formula | C23H32N2O6 |
| Molecular Weight | 432.52 |
| Exact Mass | 432.226 |
| Elemental Analysis | C, 63.87; H, 7.46; N, 6.48; O, 22.19 |
| CAS # | 1331782-27-4 |
| PubChem CID | 53354764 |
| Appearance | Solid powder |
| LogP | 2.565 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 31 |
| Complexity | 566 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | OC1(CCOCC1)CN1CCC(COC2C3=C(C=CC=C3O[C@H]3COCC3)ON=2)CC1 |
| InChi Key | HUJXGQILHAUCCV-MOROJQBDSA-N |
| 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 |
| Chemical Name | (2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyloxolane-2-carboxamide |
| Synonyms | PF04995274; PF 04995274; PF-04995274 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| 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 ) |
| 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]. |
| 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]. |
| 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 |
| References |
[1]. Prophylactic efficacy of 5-HT4R agonists against stress. Neuropsychopharmacology. 2019 Oct 10. [2]. Translational receptor occupancy for the 5-HT4 partial agonist PF-04995274 in rats, non-human primates and healthy volunteers. Alzheimer’s Dement: J Alzheimer’s Assoc. 2011;7:S653. [3]. Systems pharmacology modeling in neuroscience: Prediction and outcome of PF-04995274, a 5-HT4 partial agonist, in a clinical scopolamine impairment trial. Advances in Alzheimer's Disease. Vol.2 No.3(2013). |
| Additional Infomation | Pf 04995274 is under investigation in clinical trial NCT01193062 (Study In Healthy Subjects To Evaluate The Changes In The Protein sAPP-Alpha In Cerebrospinal Fluid Following A Single Oral Dose Of PF-04995274). |
Solubility Data
| Solubility (In Vitro) |
DMSO: 86~100 mg/mL (198.8~231.2 mM) Ethanol: ~20 mg/mL |
| 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. 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. 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 | 2.3120 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 |