| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
H3 receptor (histamine H3): in vitro human H3 Ki = 2.3 nM [1]
H3 receptor (rat): in vitro rat H3 Ki = 37 nM [1] PF-03654746 targets the histamine H3 receptor, a presynaptic G protein-coupled receptor that regulates the release of histamine and other neurotransmitters. As an antagonist, it blocks the receptor, preventing the auto-inhibitory feedback of histamine release. This leads to increased release of histamine, acetylcholine, noradrenaline, and dopamine, which are involved in cognition, arousal, and attention. |
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| ln Vitro |
In vitro binding affinity: PF-03654746 exhibited human H3 Ki = 2.3 nM and rat H3 Ki = 37 nM. [1]
Plasma protein binding: unbound fraction (fu,p) in rat, NHP, and human plasma was 70% ± 3.5%, 70% ± 2.4%, and 66% ± 0.7%, respectively. Brain homogenate unbound fraction (fu,b) in rat was 70% ± 0.7%. [1] Permeability and transporter assessment: PF-03654746 had MDCK-MDR1 efflux ratio (ER) of 1.1, mouse BCRP ER of 1.6, and high passive permeability (Papp A-B = 17 × 10⁻⁶ cm/s²). [1] In vitro, PF-03654746 is a potent and selective H3 receptor antagonist. It demonstrates high affinity for the H3 receptor and is selective over other histamine receptors and other targets. In functional assays, it increases the release of histamine and other neurotransmitters from neuronal preparations. Its effects are consistent with H3 receptor blockade. |
| ln Vivo |
In rat: after subcutaneous administration (1 or 3.2 mg/kg), PF-03654746 achieved net BBB equilibrium with mean Cb,u:Cp,u = 2.11, mean CCSF:Cp,u = 0.95, and mean Cb,u:CCSF = 2.2. [1]
In NHP: PET-derived H3 receptor occupancy using [11C]GSK189254 gave a Cp,u-based IC50 of 0.99 nM (after NTCO correction). Using the rat-derived Cb,u:Cp,u (2.11), the calculated unbound brain nIC50 was 2.1 nM, which correlated well with the human in vitro Ki (2.3 nM). [1] In human: PET-derived H3 receptor occupancy gave a Cp,u IC50 of 0.313 nM. Applying the rat Cb,u:Cp,u (2.11) gave a human nIC50 of 0.66 nM. [1] CSF penetration: rat CCSF:Cp,u = 0.95, NHP CCSF:Cp,u = 0.94, human CCSF:Cp,u = 0.86. [1] In vivo, PF-03654746 has been studied in clinical trials for various indications, including ADHD, Tourette syndrome, allergic rhinitis, narcolepsy, and schizophrenia. It reduces allergen-induced nasal symptoms, suggesting potential for allergic rhinitis. It also improves cognitive efficacy in Alzheimer's disease models. However, clinical development may have been discontinued. |
| Enzyme Assay |
In vitro H3 receptor binding assays for PF-03654746 are performed using membrane preparations from cells expressing recombinant human H3 receptors. Radioligand binding studies employ [³H]-N-alpha-methylhistamine or other suitable tracers. Membranes are incubated with varying concentrations of PF-03654746, and bound and free ligands are separated by filtration. Ki values are calculated from competition binding curves.
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| Cell Assay |
MDCK-MDR1 efflux assay: PF-03654746 was tested in MDCK cells overexpressing human MDR1 (P-gp) to determine the efflux ratio (ER = 1.1). [1]
Mouse BCRP efflux assay: PF-03654746 was tested in mouse Bcrp1-overexpressing cells, giving ER = 1.6. [1] Permeability assay: Apparent permeability (Papp A-B) was measured in control LLC-PK1 cells, yielding > 17 × 10⁻⁶ cm/s². [1] In vitro cell-based assays for PF-03654746 are performed using cells expressing recombinant H3 receptors. Cells are cultured in appropriate media and treated with PF-03654746 at various concentrations. Receptor activation is assessed by measuring the inhibition of forskolin-stimulated cAMP accumulation. The EC₅₀ or IC₅₀ values are calculated from dose-response curves. |
| Animal Protocol |
Rat pharmacokinetic study: Male Sprague-Dawley rats (n=4 per time point per dose) received subcutaneous PF-03654746 at 1 or 3.2 mg/kg. Blood, CSF, and brain were collected at 0.5, 1, 2, and 4 h post-dose. Brain samples were homogenized with three volumes of water. Plasma, brain homogenate, and CSF were analyzed by LC-MS/MS. [1]
NHP pharmacokinetic and PET study: Male cynomolgus monkeys (n=5) received intravenous bolus of PF-03654746 at 0.167 or 0.5 mg/kg. Blood and CSF collected up to 30 h. For PET imaging, rhesus monkeys (n=3) received IV infusion of PF-03654746 at 0.25, 0.7, 2.0, and 7.0 μg/kg/h over 4 h. [11C]GSK189254 was administered as a 1-min infusion (2.64±0.97 mCi). Dynamic PET scans (120-150 min) were acquired on an HRRT scanner. Arterial and venous blood samples were collected for plasma input function and drug concentration. Occupancy was calculated using the Cunningham occupancy plot with NTCO correction. [1] Human study: Healthy volunteers (n=14) received oral PF-03654746 3 mg once daily for 12 days. On day 12, serial CSF and blood samples were collected from pre-dose to 6 h post-dose. CSF was flash-frozen, serum harvested. PET imaging in humans was reported separately (Gallezot et al., 2016). [1] In vivo animal studies for PF-03654746 were conducted in rodent models of cognitive impairment, ADHD, and allergic rhinitis. The compound is administered orally or intraperitoneally. Cognitive performance is assessed using behavioral tests. In allergic rhinitis models, nasal symptoms are assessed after allergen challenge. Neurotransmitter levels in the brain are measured by microdialysis. |
| ADME/Pharmacokinetics |
Rat: After SC administration (1 or 3.2 mg/kg), PF-03654746 showed rapid absorption (tmax 0.25 h) and elimination (t1/2 0.5-0.6 h) in plasma, brain, and CSF. Linear dose-exposure relationship. [1]
NHP: After IV bolus (0.167 or 0.5 mg/kg), PF-03654746 had t1/2 of 0.5 h in plasma and CSF. [1] Human: After multiple oral doses (1.25 to 12 mg QD for 14 days), PF-03654746 showed plasma tmax at 3±0.5 h, long t1/2 of 13.6±2.9 h, and low CL/F of 4.0±0.3 mL/min/kg. Following 3 mg QD for 12 days, plasma and CSF profiles were parallel with tmax at 3 h and 4 h respectively. [1] Specific pharmacokinetic properties of PF-03654746, such as half-life and oral bioavailability, were characterized in preclinical and clinical studies. As a small molecule with a molecular weight of 322.4 g/mol, it is expected to have good oral bioavailability and high brain penetration. Its pharmacokinetic profile supports once or twice daily dosing. |
| Toxicity/Toxicokinetics |
PF-03654746 is generally well-tolerated. Common adverse effects may include headache, somnolence, and gastrointestinal disturbances. As a research compound, it is intended for laboratory use only and is not for human therapeutic use outside approved clinical trials. Standard safety precautions should be followed when handling this compound.
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| References |
Xenobiotica.2017 Feb;47(2):119-126.
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| Additional Infomation |
PF-03654746 has been studied for the treatment of narcolepsy, schizophrenia, Tourette syndrome, and excessive daytime sleepiness.
PF-03654746 is a histamine H3 receptor antagonist that demonstrates net BBB equilibrium in rats (Cb,u:Cp,u = 2.11) and is not a substrate for P-gp or BCRP. PET receptor occupancy studies in NHP and humans allowed quantitative estimation of unbound brain concentrations. The integrated parameter nIC50 (calculated as rat Cb,u:Cp,u × Cp,u IC50) gave values (NHP 2.1 nM, human 0.66 nM) that correlated with the human in vitro Ki (2.3 nM), supporting the translation of rat-derived brain partitioning to higher species. [1] PF-03654746 is a potent and selective histamine H3 receptor antagonist. It has high brain penetration and has been studied in clinical trials for ADHD, Tourette syndrome, allergic rhinitis, and other indications. It reduces allergen-induced nasal symptoms. This product is for research use only. |
| Molecular Formula |
C18H24N2OF2
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|---|---|
| Molecular Weight |
322.39276
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| Exact Mass |
322.186
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| CAS # |
935840-31-6
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| Related CAS # |
PF-03654746 Tosylate;1039399-17-1
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| PubChem CID |
16119086
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
3.91
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
23
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| Complexity |
419
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCNC([C@H]1C[C@](C2=CC(F)=C(CN3CCCC3)C=C2)(F)C1)=O
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| InChi Key |
SXMBKHYDZOCBMT-PPUGGXLSSA-N
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| InChi Code |
InChI=1S/C18H24F2N2O/c1-2-21-17(23)14-10-18(20,11-14)15-6-5-13(16(19)9-15)12-22-7-3-4-8-22/h5-6,9,14H,2-4,7-8,10-12H2,1H3,(H,21,23)/t14-,18-
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| Chemical Name |
(1R,3R)-N-Ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)cyclobutane-1-carboxamide
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| Synonyms |
PF-03654746; PF 03654746; PF03654746.
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1018 mL | 15.5092 mL | 31.0183 mL | |
| 5 mM | 0.6204 mL | 3.1018 mL | 6.2037 mL | |
| 10 mM | 0.3102 mL | 1.5509 mL | 3.1018 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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