| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 50mg |
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| Targets |
Transient Receptor Potential Melastatin 8 (TRPM8) - antagonist [1]
- Human TRPM8 IC50: 8.3 nM (in menthol-induced calcium influx assay) [1] - Rat TRPM8 IC50: 5.8 nM (in menthol-induced calcium influx assay) [1] |
|---|---|
| ln Vitro |
Menthol causes intracellular Ca2+ release and calcium storage accumulation of Ca2+ entrance, as seen by intracellular Ca2+ visual display; RQ-00203078 blocks each of these effects. In vitro and here, RQ-00203078 (1-10 μM) inhibits the polarized migration of HSC3 and HSC4 in the oral squamous [2].
In a functional assay measuring menthol (30 μM)-induced calcium influx in HEK293 cells expressing human TRPM8, RQ-00203078 demonstrated potent antagonistic activity with an IC50 of 8.3 nM. [1] - In the same assay using rat TRPM8, RQ-00203078 showed an IC50 of 5.8 nM. [1] - RQ-00203078 exhibited high selectivity for TRPM8 over other TRP channels. It showed no significant inhibition (IC50 > 10 μM) of human or rat TRPA1 (activated by allyl isothiocyanate, 100 μM). It also showed no significant inhibition of human TRPV4 (IC50 > 3 μM, hypotonic solution-induced) and human/rat TRPV1 (IC50 > 10 μM / > 3 μM, capsaicin-induced). [1] - In human liver microsome (HLM) stability assays, RQ-00203078 demonstrated low intrinsic clearance, with a Clint value of < 7 mL/min/kg. [1] - The equilibrium solubility of RQ-00203078 was measured and found to be 185 μM in a high throughput automated method. [1] |
| ln Vivo |
RQ-00203078 (Compound 36) exhibited dose-dependent external in vivo activity following isicillin-induced toxicity in the humidity dog shaking paradigm, with an ED50 value of 0.65 mg/kg [1]. Pharmacokinetic studies at a dose of 3 mg/kg (po), a Cmax value of 2300 ng/mL, and a bioavailability of 86% effectively proved the significant risks of RQ-00203078 (compound) 36].
In the icilin-induced wet-dog shakes (WDS) model in rats, oral administration of RQ-00203078 dose-dependently attenuated the shaking behavior. The compound exhibited an ED50 of 0.65 mg/kg. [1] - In rat pharmacokinetic studies, oral administration of RQ-00203078 at 3 mg/kg resulted in a Cmax of 2300 ng/mL and a bioavailability of 86%. [1] |
| Cell Assay |
TRPM8 Antagonism Assay (Calcium Influx): HEK293 cells stably expressing human or rat TRPM8 were used. Cells were loaded with a calcium-sensitive dye. The test compound, RQ-00203078, was pre-incubated with the cells for a set period. TRPM8 activation was then stimulated by the addition of the agonist menthol (30 μM). The resulting increase in intracellular calcium was measured by fluorescence. The IC50 value, the concentration of compound required to inhibit 50% of the menthol-induced calcium influx, was calculated from the dose-response curve. [1]
- Selectivity Assays (TRPA1, TRPV1, TRPV4): Similar calcium influx assays were performed using HEK293 cells expressing the respective TRP channels (human or rat TRPA1, TRPV1, TRPV4). Channels were activated by their specific agonists (e.g., allyl isothiocyanate for TRPA1, capsaicin for TRPV1, hypotonic solution for TRPV4). The inhibitory effect of RQ-00203078 was tested to assess its selectivity. [1] |
| Animal Protocol |
Wet-Dog Shakes (WDS) Model:** Male rats were fasted and then orally administered either vehicle (0.5% methyl cellulose) or RQ-00203078 at doses of 0.3, 1, 3, and 10 mg/kg. One hour after drug administration, icilin (1 mg/kg) was injected intraperitoneally to induce shaking behavior. The number of wet-dog shakes was counted over a 30-minute period immediately following the icilin injection. The ED50 value was calculated based on the dose-dependent inhibition of WDS. Each group consisted of 6 animals. [1]
- **Rat Pharmacokinetic (PK) Study:** Rats were administered RQ-00203078 orally at a dose of 3 mg/kg. Plasma samples were collected at various time points, and drug concentrations were measured to determine Cmax and bioavailability. [1] Wet-Dog Shakes (WDS) Model: Male rats were fasted and then orally administered either vehicle (0.5% methyl cellulose) or RQ-00203078 at doses of 0.3, 1, 3, and 10 mg/kg. One hour after drug administration, icilin (1 mg/kg) was injected intraperitoneally to induce shaking behavior. The number of wet-dog shakes was counted over a 30-minute period immediately following the icilin injection. The ED50 value was calculated based on the dose-dependent inhibition of WDS. Each group consisted of 6 animals. [1] - Rat Pharmacokinetic (PK) Study: Rats were administered RQ-00203078 orally at a dose of 3 mg/kg. Plasma samples were collected at various time points, and drug concentrations were measured to determine Cmax and bioavailability. [1] |
| ADME/Pharmacokinetics |
Metabolic Stability (in vitro): In human liver microsome (HLM) assays, RQ-00203078 had a low intrinsic clearance (Clint) of less than 7 mL/min/kg, indicating good metabolic stability. [1]
- Oral Bioavailability (in vivo): In rats, RQ-00203078 demonstrated excellent oral bioavailability of 86% at a 3 mg/kg oral dose. [1] - Cmax (in vivo): In the same rat PK study, the maximum plasma concentration (Cmax) achieved was 2300 ng/mL after a 3 mg/kg oral dose. [1] - Solubility (in vitro): The equilibrium solubility of RQ-00203078 was measured as 185 μM using a high throughput automated method. [1] |
| References |
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| Additional Infomation |
RQ-00203078 (compound 36) is a novel 2-pyridyl-benzensulfonamide derivative identified through high-throughput screening and subsequent structure-activity relationship (SAR) optimization from a hit compound. [1]
- The compound was designed with the introduction of a carboxylic acid group to improve liver microsome stability and equilibrium solubility. [1] - TRPM8 is a calcium-permeable, non-selective cation channel expressed on primary sensory neurons and is activated by cold temperatures and chemical agonists like menthol and icilin. It is a therapeutic target for conditions involving cold hypersensitivity, such as chemotherapy-induced peripheral neuropathy, diabetic neuropathy, migraine, and overactive bladder. [1] - RQ-00203078 is a highly potent, selective, and orally active TRPM8 antagonist. Its excellent in vivo efficacy and oral bioavailability make it a valuable pharmacological tool for investigating the therapeutic potential of TRPM8 blockade in various disease models. [1] |
| Molecular Formula |
C21H13CLF6N2O5S
|
|---|---|
| Molecular Weight |
554.84
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| Exact Mass |
554.013
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| Elemental Analysis |
C, 45.46; H, 2.36; Cl, 6.39; F, 20.54; N, 5.05; O, 14.42; S, 5.78
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| CAS # |
1254205-52-1
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| PubChem CID |
49783953
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| Appearance |
White to off-white solid powder
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| Density |
1.6±0.1 g/cm3
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| Boiling Point |
602.0±65.0 °C at 760 mmHg
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| Flash Point |
317.9±34.3 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.567
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| LogP |
6.04
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
852
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C(C(F)(F)F)C([H])=NC=1N(C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])OC(F)(F)F)S(C1C([H])=C([H])C(C(=O)O[H])=C([H])C=1[H])(=O)=O
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| InChi Key |
IJGQFZYYEHCCIZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H13ClF6N2O5S/c22-17-9-14(20(23,24)25)10-29-18(17)30(11-12-1-5-15(6-2-12)35-21(26,27)28)36(33,34)16-7-3-13(4-8-16)19(31)32/h1-10H,11H2,(H,31,32)
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| Chemical Name |
4-[[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-[[4-(trifluoromethoxy)phenyl]methyl]sulfamoyl]benzoic acid
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| Synonyms |
RQ-00203078 RQ00203078 RQ 00203078
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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 : ~100 mg/mL (~180.23 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.51 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 (4.51 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 | 1.8023 mL | 9.0116 mL | 18.0232 mL | |
| 5 mM | 0.3605 mL | 1.8023 mL | 3.6046 mL | |
| 10 mM | 0.1802 mL | 0.9012 mL | 1.8023 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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