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Purity: ≥98%
PF-05089771 (PF05089771) is a potent and subtype selective NaV1.7 inhibitor (IC50 = 11 nM) and Nav1.8 voltage-gated sodium channel blocker with the potential to be used in the treatment of chronic neuropathic pain. As of June 2014, it has completed phase II clinical trials for wisdom tooth removal and primary erythromelalgia. PF-05089771 binds to a site in the voltage sensing domain and interacts with the voltage-sensor domain (VSD) of domain IV. PF-05089771 exhibits a slow onset of block that is depolarization and concentration dependent, with a similarly slow recovery from block. Furthermore, the onset of block by PF-05089771 develops with similar rates using protocols that bias channels into predominantly fast- or slow-inactivated states, suggesting that channel inhibition is less dependent on the availability of a particular inactivated state than the relative time that the channel is depolarized.
| 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]. The majority of TTX-S current (75.5 ± 10.5%, n = 5, Fig. 5D) is blocked by PF-05089771 (30 nM), while a full block was achieved at 100 nM[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 |
C18H12CL2FN5O3S2
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| Molecular Weight |
500.34
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| Exact Mass |
498.97426
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| Elemental Analysis |
C, 43.21; H, 2.42; Cl, 14.17; F, 3.80; N, 14.00; O, 9.59; S, 12.82
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| CAS # |
1235403-62-9
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| Related CAS # |
PF 05089771 tosylate;1430806-04-4
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| Appearance |
White to off-white solid
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| LogP |
4.3
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| tPSA |
160Ų
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| SMILES |
O=S(C1=CC(Cl)=C(OC2=CC=C(Cl)C=C2C3=C(N)NN=C3)C=C1F)(NC4=CSC=N4)=O
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| InChi Key |
ZYSCOUXLBXGGIM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H12Cl2FN5O3S2/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/h1-8,26H,(H3,22,24,25)
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| Chemical Name |
4-(2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide
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| Synonyms |
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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 |
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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) |
Solubility in Formulation 1: 2.5 mg/mL (5.00 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: ≥ 2.25 mg/mL (4.50 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 22.5 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. View More
Solubility in Formulation 3: ≥ 2.25 mg/mL (4.50 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 | 1.9986 mL | 9.9932 mL | 19.9864 mL | |
| 5 mM | 0.3997 mL | 1.9986 mL | 3.9973 mL | |
| 10 mM | 0.1999 mL | 0.9993 mL | 1.9986 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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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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