| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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Purity: ≥98%
PF-06305591 is a novel, potent and highly selective blocker of voltage gated sodium channel NaV1.8 with an IC50 of 15 nM and with excellent ADME and safety profiles. The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.
| Targets |
Human Voltage-Gated Sodium Channel 1.8 (hNaV1.8) (IC50 = 15 ± 2 nM). [1]
Other human NaV isoforms (hNaV1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7) (IC50 > 30 µM). [1] |
|---|---|
| ln Vitro |
PF-06305591 (compound 9) has favorable attributes such as passive permeability, hERG activity, NaV selectivity, and in vitro metabolic stability [1].
PF-06305591 potently inhibits hNaV1.8 with an IC50 of 15 ± 2 nM. [1] It shows exquisite selectivity (>2000-fold) over other human NaV isoforms (hNaV1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7), with IC50 values >30 µM for each. [1] PF-06305591 shows no significant activity (IC50 >30 µM) against a panel of other ion channels including: KVLQT1 (KCNQ1, KV7.1), KV1.5, KV1.1/1.2, SK2 (KCNN2), T-type and L-type calcium channels, and GABA-A (α1β2). [1] PF-06305591 exhibits no significant inhibition of the hERG potassium channel (IC50 >30 µM). [1] Wide ligand profiling (CEREP™ panel) at 10 µM showed no significant off-target activity (<20% activity). [1] PF-06305591 displays excellent passive permeability (Papp AB = 3.5 x 10^-6 cm/sec in RRCK cell line). [1] PF-06305591 exhibits low in vitro metabolic clearance in human liver microsomes (HLM < 11 µL/min/mg protein) and human hepatocytes (hHep < 2 µL/min/million cells). [1] PF-06305591 has good solubility (2 mg/mL at pH 7.4). [1] |
| ln Vivo |
PF-06305591 (compound 9) exhibits high bioavailability in rats. PF-06305591 offers the option to explore higher fold IC50 of Nav1.8 blockage in the clinic, allowing for a more full assessment of the role of NaV1.8 in pain therapy [1].
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| Animal Protocol |
Rat Pharmacokinetic Study: Rats were administered PF-06305591 intravenously (i.v.) at a dose of 1 mg/kg and orally (p.o.) at a dose of 3 mg/kg. [1]
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| ADME/Pharmacokinetics |
In rats, after intravenous injection of PF-06305591 at a dose of 1 mg/kg, the plasma clearance (Clp) was 39 mL/min/kg, the steady-state volume of distribution (Vss) was 2.7 L/kg, and the terminal half-life (T1/2) was 1.5 hours. [1] In rats, after oral administration of PF-06305591 at a dose of 3 mg/kg, the oral bioavailability (F) was 49%. [1]
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| Toxicity/Toxicokinetics |
PF-06305591 showed no significant inhibitory effect on hERG potassium channels in vitro (IC50 >30 µM), indicating that it is unlikely to cause arrhythmias through this mechanism. [1]
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| References | |
| Additional Infomation |
PF-06305591 is currently undergoing clinical trial NCT01776619 (PF-06305591 Multiple-Dose Safety and Tolerability Study). PF-06305591 is a potent, highly selective small-molecule NaV1.8 sodium channel blocker based on benzimidazole. [1] It was identified as a candidate clinical drug for the previously reported PF-04531083. [1] Due to its superior solubility compared to PF-04531083, the development of PF-06305591 aims to investigate its higher NaV1.8 blocking IC50 in clinical applications. [1] Its molecular weight is 274, calculated logP (clogP) is 1.5, measured LogD is 2.1, topological polar surface area (TPSA) is 98, and pKa is 5.9. [1]
The ligand efficiency (LipE) value is 6.3. [1] A multigram-scale synthetic route was developed for further analysis. [1] |
| Molecular Formula |
C15H22N4O
|
|---|---|
| Molecular Weight |
274.361382961273
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| Exact Mass |
274.179
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| CAS # |
1449473-97-5
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| Related CAS # |
PF-06305591 dihydrate;2703582-76-5
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| PubChem CID |
71666749
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| Appearance |
White to off-white solid powder
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| LogP |
1.5
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
20
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| Complexity |
365
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
O=C([C@H](C)[C@@H](C1=NC2=CC=C(C=C2N1)C(C)(C)C)N)N
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| InChi Key |
APWZIFIAVVFPNT-PELKAZGASA-N
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| InChi Code |
InChI=1S/C15H22N4O/c1-8(13(17)20)12(16)14-18-10-6-5-9(15(2,3)4)7-11(10)19-14/h5-8,12H,16H2,1-4H3,(H2,17,20)(H,18,19)/t8-,12+/m1/s1
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| Chemical Name |
(2R,3S)-3-amino-3-(6-tert-butyl-1H-benzimidazol-2-yl)-2-methylpropanamide
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| Synonyms |
PF-06305591; PF 06305591; PF06305591
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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 : ~140 mg/mL (~510.28 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.11 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 (9.11 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 (9.11 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 | 3.6448 mL | 18.2242 mL | 36.4485 mL | |
| 5 mM | 0.7290 mL | 3.6448 mL | 7.2897 mL | |
| 10 mM | 0.3645 mL | 1.8224 mL | 3.6448 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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