| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
|
| Targets |
Nav1.7
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|---|---|
| ln Vitro |
AMG8379 exhibits a selectivity that is 100–1000 times greater than that of other members of the NaV family, such as TTX-resistant NaV channels in DRG neurons and NaV1.4 and 1.5 expressed in muscle and the heart, respectively [1]. Based on firing levels in NaV1.7 KO mice, the IC50 for AMG8379's suppression of C-fiber spikes was computed. This value indicates total pharmacological blockage of the NaV1.7 component of the experiment. Accordingly, the IC50 of the AMG8379 module is 47.0 ± 8.1 nM[1].
|
| ln Vivo |
AMG8379 (30-100 mg/kg; oral) reduces capsaicin-induced nociceptive responses [1]. In vivo target engagement of AMG8379 in mice was evaluated in multiple NaV1.7-dependent behavioral endpoints. AMG8379 dose-dependently inhibited intradermal histamine-induced scratching and intraplantar capsaicin-induced licking, and reversed UVB radiation skin burn-induced thermal hyperalgesia; notably, behavioral effects were not observed with AMG8380 at similar plasma exposure levels[1].
|
| Enzyme Assay |
AMG8379 Antagonist Activity [1]
AMG8379 and AMG8380 represent a pair of atropisomeric quinolone sulfonamides discovered in our efforts to identify an isoform-selective NaV1.7 inhibitor (Fig. 1A). Discovery and optimization of drug-like properties for this chemical class is described in a separate report (Graceffa et al., 2017). AMG8379 potently inhibited recombinant human and mouse, but not rat, NaV1.7 channels expressed in heterologous HEK293 cells when evaluated by automated patch-clamp electrophysiology on a PatchXpress... |
| Animal Protocol |
Animal/Disease Models: CD-1 male mice [1]
Doses: 30 or 100 mg/kg body weight Route of Administration: Oral Experimental Results: There was a dose-dependent reduction in overall nociceptive behavior. |
| References | |
| Additional Infomation |
Potent and selective antagonists of the voltage-gated sodium channel NaV1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human NaV1.7 channels with an IC50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC50 of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state. AMG8379 was 100- to 1000-fold selective over other NaV family members, including NaV1.4 expressed in muscle and NaV1.5 expressed in the heart, as well as TTX-resistant NaV channels in DRG neurons. Using an ex vivo mouse skin-nerve preparation, AMG8379 blocked mechanically induced action potential firing in C-fibers in both a time-dependent and dose-dependent manner. AMG8379 similarly reduced the frequency of thermally induced C-fiber spiking, whereas AMG8380 affected neither mechanical nor thermal responses. In vivo target engagement of AMG8379 in mice was evaluated in multiple NaV1.7-dependent behavioral endpoints. AMG8379 dose-dependently inhibited intradermal histamine-induced scratching and intraplantar capsaicin-induced licking, and reversed UVB radiation skin burn-induced thermal hyperalgesia; notably, behavioral effects were not observed with AMG8380 at similar plasma exposure levels. AMG8379 is a potent and selective NaV1.7 inhibitor that blocks sodium current in heterologous cells as well as DRG neurons, inhibits action potential firing in peripheral nerve fibers, and exhibits pharmacodynamic effects in translatable models of both itch and pain.[1]
|
| Molecular Formula |
C25H16CLF2N3O5S
|
|---|---|
| Molecular Weight |
543.93
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| Exact Mass |
543.046
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| Elemental Analysis |
C, 71.23; H, 4.83; F, 13.00; O, 10.95
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| CAS # |
1641574-26-6
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| Related CAS # |
AMG8379;1642112-31-9;AMG8380;1642112-32-0
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| PubChem CID |
117737142
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| Appearance |
Typically exists as solid at room temperature
|
| LogP |
4.8
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
9
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
37
|
| Complexity |
969
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O1N=C(C=C1)NS(C1C=C2C=CC(=O)N(C3C=C(F)C(C4C=C(F)C=C(Cl)C=4)=CC=3OC)C2=CC=1)(=O)=O
|
| InChi Key |
HXQNEKJQBGXFAG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H16ClF2N3O5S/c1-35-23-12-19(15-8-16(26)11-17(27)9-15)20(28)13-22(23)31-21-4-3-18(10-14(21)2-5-25(31)32)37(33,34)30-24-6-7-36-29-24/h2-13H,1H3,(H,29,30)
|
| Chemical Name |
1-[4-(3-chloro-5-fluorophenyl)-5-fluoro-2-methoxyphenyl]-N-(1,2-oxazol-3-yl)-2-oxoquinoline-6-sulfonamide
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| Synonyms |
(Rac)AMG8379; AMG8380; (Rac)-AMG8379; AMG8379; 1642112-31-9; 1641574-26-6; AMG 8379; 1-[4-(3-chloro-5-fluorophenyl)-5-fluoro-2-methoxyphenyl]-N-(1,2-oxazol-3-yl)-2-oxoquinoline-6-sulfonamide; 1642112-32-0; (Rac) AMG8379
|
| 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)
|
| 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 | 1.8385 mL | 9.1924 mL | 18.3847 mL | |
| 5 mM | 0.3677 mL | 1.8385 mL | 3.6769 mL | |
| 10 mM | 0.1838 mL | 0.9192 mL | 1.8385 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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