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| Targets |
Nav1.7-IN-2 targets the voltage-gated sodium channel Nav1.7, a member of the Nav1.x family of sodium channels. Nav1.7 is preferentially expressed in peripheral sensory neurons and sympathetic ganglia, where it plays a critical role in the initiation and propagation of action potentials. Gain-of-function mutations in the SCN9A gene encoding Nav1.7 cause inherited pain syndromes such as primary erythermalgia and paroxysmal extreme pain disorder, while loss-of-function mutations result in congenital insensitivity to pain. This genetic validation makes Nav1.7 a highly attractive target for the development of non-opioid analgesics. By inhibiting Nav1.7, Nav1.7-IN-2 blocks sodium influx into nociceptive neurons, thereby suppressing neuronal signaling and reducing pain perception. The compound's selectivity for Nav1.7 over other sodium channel isoforms is critical for minimizing off-target effects.
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| ln Vitro |
Nav1.7-IN-2 demonstrates potent in vitro activity against Nav1.7 channels. The compound inhibits Nav1.7 with an IC50 of 80 nM, as determined in electrophysiological assays. In patch-clamp studies using cells expressing recombinant Nav1.7 channels, Nav1.7-IN-2 blocks sodium currents in a concentration-dependent manner. The compound's potency against Nav1.7 is consistent with its utility for studying pain pathways. Selectivity profiling against other voltage-gated sodium channel isoforms (Nav1.1, Nav1.2, Nav1.3, Nav1.5, Nav1.6, and Nav1.8) is typically performed to assess the compound's specificity. The compound's in vitro activity has been characterized in published patent literature. Its potency and selectivity make it a valuable tool for studying the role of Nav1.7 in pain and nociception.
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| ln Vivo |
In vivo activity of Nav1.7-IN-2 has been evaluated in animal models of pain. By blocking Nav1.7-mediated sodium influx, the compound suppresses neuronal signaling and produces analgesic effects. Nav1.7-IN-2 is useful for the treatment of diseases treatable by inhibition of voltage-gated sodium channels, particularly chronic pain disorders. In preclinical models, Nav1.7 inhibitors have demonstrated efficacy in reducing pain behaviors in models of inflammatory pain, neuropathic pain, and postoperative pain. The compound's ability to block Nav1.7 in vivo is expected to translate to analgesic efficacy. Comprehensive in vivo efficacy data for Nav1.7-IN-2 specifically are available in the patent literature. The compound's favorable profile supports its use as a research tool for studying pain mechanisms and developing new analgesics.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for Nav1.7-IN-2 are performed using electrophysiological techniques, as sodium channels are ion channels rather than enzymes or traditional receptors. The most common method is the patch-clamp technique, which measures the flow of sodium ions through the channel. Cells expressing recombinant Nav1.7 channels are voltage-clamped, and sodium currents are elicited by depolarizing voltage steps. Varying concentrations of the test compound are applied, and the inhibition of sodium current is measured. IC50 values are calculated by plotting percent inhibition against compound concentration using non-linear regression analysis. Alternatively, fluorescent-based membrane potential assays or ion flux assays using radioactive tracers can be used for higher-throughput screening. Selectivity assays compare the compound's activity against other Nav isoforms expressed in similar systems. Each concentration is typically tested in multiple cells to ensure reproducibility.
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| Cell Assay |
In vitro cellular assays for Nav1.7-IN-2 are performed using cells expressing recombinant Nav1.7 channels or primary sensory neurons. The most physiologically relevant assay is the patch-clamp electrophysiology assay using cells (typically HEK293 or CHO cells) stably expressing human Nav1.7. Sodium currents are elicited and measured in the presence of varying concentrations of the test compound. Alternatively, high-content screening assays using fluorescent dyes sensitive to membrane potential or intracellular sodium concentration can be used. For primary neurons, dorsal root ganglion (DRG) neurons are isolated and cultured, and compound effects on action potential firing are assessed using multi-electrode arrays or patch-clamp recordings. Cytotoxicity is assessed in parallel using standard viability assays to ensure that observed effects are not due to cell death. The cellular IC50 is determined from dose-response curves.
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| Animal Protocol |
In vivo animal studies for Nav1.7-IN-2 are conducted using rodent models of pain. Commonly used models include the formalin test (inflammatory pain), the complete Freund's adjuvant (CFA) model (inflammatory pain), the spared nerve injury (SNI) model (neuropathic pain), and the von Frey test for mechanical allodynia. Animals are administered the compound via oral gavage, intraperitoneal injection, or subcutaneous injection at various doses and schedules. Pain behaviors are assessed by measuring paw withdrawal thresholds (mechanical allodynia) using von Frey filaments or paw withdrawal latencies (thermal hyperalgesia) using a Hargreaves apparatus. Efficacy is expressed as the percent reversal of pain behavior compared to vehicle-treated controls. Pharmacokinetic studies assess drug concentrations in plasma and target tissues. Motor function is assessed using the rotarod test to rule out nonspecific effects on motor coordination. Body weight and clinical observations are monitored as safety indicators.
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| ADME/Pharmacokinetics |
Nav1.7-IN-2 has a molecular formula of C22H22FN5O2 and a molecular weight of 407.44 g/mol. Its chemical name is 3-[[4-[3-(4-fluoro-2-methylphenoxy)azetidin-1-yl]pyrimidin-2-yl]amino]-N-methylbenzamide. The compound is soluble in DMSO and other organic solvents. Comprehensive pharmacokinetic parameters including half-life, volume of distribution, clearance, and oral bioavailability have been characterized in preclinical studies. The compound's ability to cross the blood-brain barrier is a key consideration for targeting Nav1.7 in the central nervous system. Pharmacokinetic studies in animal models have characterized the compound's exposure and distribution. The compound's pharmacokinetic profile supports its use in preclinical pain models. Detailed pharmacokinetic data are available in the patent literature.
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| Toxicity/Toxicokinetics |
Nav1.7-IN-2 is intended for laboratory research use only and has not undergone comprehensive clinical toxicology testing. As a sodium channel blocker, the compound would be expected to have cardiovascular effects if it inhibits cardiac sodium channels (Nav1.5), but selectivity for Nav1.7 over Nav1.5 is a key consideration in compound design. Standard in vitro cytotoxicity assays in cell lines are typically performed alongside efficacy studies to rule out nonspecific toxicity. In vivo, animals are monitored for signs of toxicity including body weight changes, behavioral abnormalities, and clinical observations. Motor function is assessed using the rotarod test to rule out effects on motor coordination, which could indicate off-target sodium channel inhibition in the central nervous system. Comprehensive toxicological characterization including genotoxicity, cardiotoxicity (hERG assay), and repeated-dose toxicity studies has not been reported in the public domain. The compound is not approved for human use and is strictly intended for research purposes.
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| References | |
| Additional Infomation |
Nav1.7-IN-2 is a potent and selective inhibitor of voltage-gated sodium channel Nav1.7 with an IC50 of 80 nM. It is extracted from patent WO/2011103196 A1, compound example J. The compound has a molecular formula of C22H22FN5O2 and a molecular weight of 407.44 g/mol. Its chemical name is 3-[[4-[3-(4-fluoro-2-methylphenoxy)azetidin-1-yl]pyrimidin-2-yl]amino]-N-methylbenzamide. By blocking Nav1.7-mediated sodium influx, the compound suppresses neuronal signaling and produces analgesic effects. Nav1.7 is a genetically validated pain target, and inhibitors of this channel are being pursued as non-opioid analgesics. Nav1.7-IN-2 is useful for the treatment of chronic pain disorders. The compound is not in clinical trials and has not received regulatory approval. It is available from research chemical suppliers for non-clinical research purposes only. Nav1.7-IN-2 is a valuable research tool for studying pain mechanisms and developing new analgesics.
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| Molecular Formula |
C22H22FN5O2
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| Molecular Weight |
407.440787792206
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| Exact Mass |
407.175
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| CAS # |
1332295-35-8
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| PubChem CID |
53348208
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.646
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| LogP |
2.32
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
576
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=C(C=CC(=C1)F)OC2CN(C2)C3=NC(=NC=C3)NC4=CC=CC(=C4)C(=O)NC
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| InChi Key |
MFAKJGXMORSMIX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H22FN5O2/c1-14-10-16(23)6-7-19(14)30-18-12-28(13-18)20-8-9-25-22(27-20)26-17-5-3-4-15(11-17)21(29)24-2/h3-11,18H,12-13H2,1-2H3,(H,24,29)(H,25,26,27)
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| Chemical Name |
3-[[4-[3-(4-fluoro-2-methylphenoxy)azetidin-1-yl]pyrimidin-2-yl]amino]-N-methylbenzamide
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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 : ~50 mg/mL (~122.72 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.14 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 (6.14 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 | 2.4543 mL | 12.2717 mL | 24.5435 mL | |
| 5 mM | 0.4909 mL | 2.4543 mL | 4.9087 mL | |
| 10 mM | 0.2454 mL | 1.2272 mL | 2.4543 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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