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| 25mg |
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| 50mg |
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Purity: ≥98%
PF-05089771 Tosylate, the tosylate salt of PF05089771, is a potent and subtype selective NaV1.7 inhibitor with IC50 of 11 nM. It is also a Nav1.8 voltage-gated sodium channel blocker with the potential to be used in the treatment of chronic neuropathic pain.
| Targets |
hNav1.7: (IC50 =11 nM); cynNav1.7 (IC50 =12 nM); dogNav1.7 (IC50 =13 nM); ratNav1.7 (IC50 = 171 nM), musNav1.7 (IC50 = 8 nM)
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| ln Vitro |
It has been found that PF-05089771 exhibits a range of selectivity over TTX-sensitive (TTX-S) channels (10-fold for Nav1.2 to 900-fold for Nav1.3 and Nav1.4) and is more than 1000-fold selective over tetrodotoxin-resistant (TTX-R) Nav1.5 and Nav1.8 channels (IC50s >10 μM)[1]. PF-05089771 (30 nM) inhibits the majority of TTX-S current (75.5 ± 10.5%, n = 5) and 100 nM resulted in total block[1].
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| ln Vivo |
Compared to vehicle, peroral or inhaled PF-05089771 administration caused about 50–60 % inhibition of cough at the doses that did not alter respiratory rate [3].
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| Enzyme Assay |
The inhibitory profile of PF-05089771 suggests that a conformational change in the domain IV VSD after depolarization is necessary and sufficient to reveal a high-affinity binding site with which PF-05089771 interacts, stabilizing the channel in a nonconducting conformation from which recovery is slow [2].
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| Cell Assay |
Voltage clamp HEK cells or mouse DRG neurons were continuously superfused with extracellular solution (ECS) containing (in mM): 30 NaCl, 110 Choline Cl, 3 KCl, 0.8 MgCl2, 1.8 CaCl2, 0.05 CdCl2, 10 Glucose, 10 HEPES, 5 Sucrose (300–310 mOsm, titrated to pH 7.4 with TEA-OH). The patch pipette (intracellular) solution (ICS) contained (in mM): 5 NaCl, 135 CsF, 10 CsCl, 2 MgATP, 10 HEPES, 5 EGTA (290–300 mOsm, titrated to pH 7.2 with KOH). For human DRG recordings the following solutions were used (ECS in mM):150 NaCl, 4 BaCl, 2 CaCl2, 1 MgCl2, 0.1 CdCl2, 10 Glucose, 10 HEPES, (300–310 mOsm titrated to pH 7.3 with Na-OH). ICS in mM: 140 CsF, 10 NaCl, 1 EGTA, 1 MgCl2, 10 HEPES, 10 glucose, (290–300 mOsm, titrated to pH 7.3 with Cs-OH). Series resistance compensation was routinely applied to at least 75%. Before acquisition, 20 ms pulses to 0 mV were repeatedly applied (0.05 Hz) from Vm = -120 mV until stable current responses were obtained. All experiments were carried out at room temperature (21–24°C). IC50 values were generated in HEK 293 cell lines by voltage clamping at -120 mV before stepping to the V0.5 of inactivation for 5 seconds in order to accumulate compound binding. This was followed by a 100 ms return to -120 mV preceding a 20 ms test step to 0 mV. Cells with large TTX-S currents (>5 nA mouse, >8 nA human) and cells with series resistance values greater than 15 MΩ, or variable series resistance were omitted from analysis [2].
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| Animal Protocol |
The guinea pigs were randomly divided into several groups. The animals in the first group received systemic peroral (p.o.) injection of NaV1.7 inhibitor PF-05089771 (15 mg/kg, in 1 ml water) or vehicle (DMSO) 2.5 h prior to inhalation challenge by aerosolized capsaicin (25 μM) for 5 min. The drug solution or vehicle was injected randomly by p.o. administration in the dose of 1 mL in guinea pig weighing about 350 g. The drug solution as a mixture was always vortexed before each use. The application of the substance was slow to ensure that the animal swallowed the whole volume of the tested drug solution. Because of the unpaired design of this experiment, capsaicin-induced cough without any intervention was compared between the groups 10 days later and no significant difference was observed (data not shown). The animals in the second design inhaled aerosol of PF-05089771 (100 μM) or vehicle for 10 min before inhalation of capsaicin (25 μM) containing PF-05089771 (100 μM) or vehicle for 5 min. The experiment had paired design in which two cough challenges were separated by 10 days. The animals received randomly PF-05089771 first or the vehicle first. We also created a third smaller group of animals that underwent a similar protocol with PF-05089771 in the lower concentration of 10 μM. To find out the potential effect of NaV1.7 inhibitor on respiratory rate, respiratory cycles were counted during a 1 min period. The respiratory rate was determined within the last minute of the PF-05089771 inhalation. In the experiment with systemic p.o. administration of PF-05089771, respiratory rate was determined during the first minute of capsaicin inhalation because in the first minute no cough was detected in 16 animals and only one cough was detected in 4 animals [3].
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| References |
[1]. Alexandrou AJ, et al. Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLoS One. 2016 Apr 6;11(4):e0152405.
[2]. Theile JW, et al. The Selective Nav1.7 Inhibitor, PF-05089771, Interacts Equivalently with Fast and Slow Inactivated Nav1.7 Channels. Mol Pharmacol. 2016 Nov;90(5):540-548. [3]. The effect of the voltage-gated sodium channel NaV1.7 blocker PF-05089771 on cough in the guinea pig. Respir Physiol Neurobiol. 2022 May:299:103856. |
| Molecular Formula |
C25H20CL2FN5O6S3
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| Molecular Weight |
672.54
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| CAS # |
1430806-04-4
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| Related CAS # |
PF 05089771;1235403-62-9
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| SMILES |
O=S(C1=CC(Cl)=C(OC2=CC=C(Cl)C=C2C3=CNN=C3N)C=C1F)(NC4=CSC=N4)=O.OS(=O)(C5=CC=C(C) C=C5)=O
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| InChi Key |
NVKBPDYKPNYMDR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H12Cl2FN5O3S2.C7H8O3S/c19-9-1-2-14(10(3-9)11-6-24-25-18(11)22)29-15-5-13(21)16(4-12(15)20)31(27,28)26-17-7-30-8-23-17;1-6-2-4-7(5-3-6)11(8,9)10/h1-8,26H,(H3,22,24,25);2-5H,1H3,(H,8,9,10)
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| Chemical Name |
4-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide;4-methylbenzenesulfonic acid
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| Synonyms |
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| 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) |
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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 | 1.4869 mL | 7.4345 mL | 14.8690 mL | |
| 5 mM | 0.2974 mL | 1.4869 mL | 2.9738 mL | |
| 10 mM | 0.1487 mL | 0.7435 mL | 1.4869 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.
 Inhibition of human Nav1.7 by PF-05089771 develops and recovers slowly.Mol Pharmacol.2016 Nov;90(5):540-548. |
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 Time course of block by PF-05089771 is independent of the availability of kinetically defined inactivated states.Mol Pharmacol.2016 Nov;90(5):540-548. |
 Onset of inhibition develops over similar time course using different conditioning trains with equal time at 0 mV.Mol Pharmacol.2016 Nov;90(5):540-548. |
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