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| Targets |
hNav1.8
LTGO-33 targets the voltage-gated sodium channel NaV1.8, a subtype predominantly expressed in peripheral sensory neurons. NaV1.8 plays a critical role in pain signaling and is a validated target for pain management. The compound selectively inhibits NaV1.8 over other sodium channel subtypes (NaV1.1-NaV1.7 and NaV1.9) by more than 600-fold. This high selectivity is expected to minimize off-target effects and improve the therapeutic window for pain indications. |
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| ln Vitro |
LTGO-33 has an IC50 of 33 nM in the off state and 24 nM in the inactive state[1]. LTGO-33 has better species specificity for primate NaV1.8 than dog and rodent NaV1.8, and inhibits the action potential discharge of human dorsal root ganglion neurons [1]. LTGO-33 inhibits TTX-R currents in human primary DRG neurons (male donor: IC50 of 110 nM, 95% CI: 92 to 120 nM, n = 3-15 neurons per concentration; female donor Donor: IC50 of 120 nM, 95% CI: 100 to 140 nM, 4-6 neurons per concentration) and cynomolgus monkey (IC50 of 100 nM, 95% CI: 71 to 150 nM, n = 6 cells ), but not in dogs (IC50 >10 µM, n = 6 cells), rats (IC< sub>50 >30 µM, n = 7 cells), and mice (IC50 >30 µM, n = 8 cells )[1]. LTGO-33 stabilizes the deactivated state of VSDII, effectively keeping the channel closed by preventing VSDII movement [1].
In vitro, LTGO-33 has been shown to potently inhibit NaV1.8 channel activity with nanomolar potency. The compound inhibits both wild-type and multiple NaV1.8 variants associated with human pain diseases. LTGO-33 shows similar potency for channels in closed and inactivated conformations. Its selectivity for NaV1.8 over other sodium channel subtypes has been demonstrated in electrophysiological assays. The compound's in vitro profile supports its potential as a therapeutic agent for pain conditions. |
| ln Vivo |
In vivo, LTGO-33 is being developed as a potential therapeutic for pain indications due to its potent and selective NaV1.8 inhibition. NaV1.8 is a validated target for pain management, and selective inhibitors have shown efficacy in preclinical pain models. The compound's high selectivity for NaV1.8 over other sodium channels is expected to reduce central nervous system and cardiovascular side effects associated with non-selective sodium channel blockers. In vivo efficacy studies are ongoing to evaluate its potential as a pain therapeutic.
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| Enzyme Assay |
In vitro electrophysiological assays for LTGO-33 involve measuring NaV1.8 channel activity using patch-clamp techniques. Human NaV1.8 channels are expressed in heterologous systems such as HEK293 or CHO cells. Cells are voltage-clamped, and sodium currents are elicited by depolarizing voltage steps. LTGO-33 is applied at various concentrations, and inhibition of sodium current is measured. IC50 values are calculated from dose-response curves. Selectivity is assessed by testing the compound against other sodium channel subtypes expressed in similar systems.
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| Cell Assay |
In vitro cellular assays for LTGO-33 involve using cell lines expressing NaV1.8 channels. Cells are cultured and treated with LTGO-33 at various concentrations. Sodium channel activity is measured using fluorescence-based membrane potential assays or automated patch-clamp systems. Cell viability is assessed using standard assays to ensure that observed effects are not due to cytotoxicity. The compound's effects on neuronal excitability can be evaluated using primary sensory neurons or differentiated cell lines expressing NaV1.8.
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| Animal Protocol |
In vivo animal studies for LTGO-33 involve administration to rodent models of pain to evaluate analgesic efficacy. Pain models such as formalin test, complete Freund's adjuvant (CFA)-induced inflammatory pain, and spinal nerve ligation (SNL)-induced neuropathic pain are commonly used. Doses and routes of administration vary depending on the study design. Pain behaviors (e.g., mechanical allodynia, thermal hyperalgesia) are assessed at various time points post-administration. The compound's selectivity and lack of CNS side effects are evaluated through behavioral assessments.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for LTGO-33 are not fully detailed in the available literature. As a small molecule sodium channel inhibitor, the compound is expected to have favorable oral bioavailability and good tissue distribution. Its molecular weight of 467.4 and lipophilic properties suggest reasonable membrane permeability. Specific pharmacokinetic parameters such as half-life, Cmax, AUC, and protein binding have not been reported. Further pharmacokinetic studies are needed to characterize the compound's ADME properties.
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| Toxicity/Toxicokinetics |
Toxicological data for LTGO-33 are limited. As a selective NaV1.8 inhibitor, the compound is expected to have a favorable safety profile compared to non-selective sodium channel blockers due to its restricted expression of the target in peripheral sensory neurons. However, comprehensive toxicological assessments have not been reported. Standard toxicological evaluations would include acute and repeat-dose toxicity studies, genotoxicity, and safety pharmacology assessments. The compound is intended for research use and is not approved for clinical use.
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| References | |
| Additional Infomation |
LTGO-33 is a potent and selective inhibitor of voltage-gated sodium channel NaV1.8, a validated target for pain management. It exhibits over 600-fold selectivity for NaV1.8 over other sodium channel subtypes. The compound inhibits both wild-type and multiple NaV1.8 variants associated with human pain conditions. LTGO-33 shows similar potency for channels in closed and inactivated conformations. The compound is being developed as a potential therapeutic for pain indications and is not approved for clinical use.
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| CAS # |
2834106-06-6
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.40±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)
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| LogP |
0
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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) |
Typically soluble in DMSO (e.g. 10 mM)
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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.) |
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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