RQ-00203078

Selective and orally active TRPM8 antagonist CAS# 1254205-52-1

RQ-00203078

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Chemical structure

RQ-00203078

3D structure

Chemical Properties of RQ-00203078

Cas No. 1254205-52-1 SDF Download SDF
PubChem ID 49783953 Appearance Powder
Formula C21H13ClF6N2O5S M.Wt 554.85
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 38 mg/mL (68.49 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 4-[[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-[[4-(trifluoromethoxy)phenyl]methyl]sulfamoyl]benzoic acid
SMILES C1=CC(=CC=C1CN(C2=C(C=C(C=N2)C(F)(F)F)Cl)S(=O)(=O)C3=CC=C(C=C3)C(=O)O)OC(F)(F)F
Standard InChIKey IJGQFZYYEHCCIZ-UHFFFAOYSA-N
Standard InChI 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)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of RQ-00203078

DescriptionPotent TRPM8 antagonist (IC50 values are 5.3 and 8.3 nM for rat and human channels respectively). Exhibits >350-fold selectivity for TRPM8 over TRPV4, TRPV1 and TRPA1. Reduces HSC3 and HSC4 oral squamous carcinoma cell migration and invasion in vitro. Also attenuates icilin-induced wet dog shakes in rats. Orally active.

RQ-00203078 Dilution Calculator

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Preparing Stock Solutions of RQ-00203078

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.8023 mL 9.0114 mL 18.0229 mL 36.0458 mL 45.0572 mL
5 mM 0.3605 mL 1.8023 mL 3.6046 mL 7.2092 mL 9.0114 mL
10 mM 0.1802 mL 0.9011 mL 1.8023 mL 3.6046 mL 4.5057 mL
50 mM 0.036 mL 0.1802 mL 0.3605 mL 0.7209 mL 0.9011 mL
100 mM 0.018 mL 0.0901 mL 0.1802 mL 0.3605 mL 0.4506 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on RQ-00203078

Description:

IC50: 8.3 and 5.8 nM for hTRPM8 and rTRPM8, respectively

The transient receptor potential melastatin 8 (TRPM8), a member of the TRP melastatin sub-group, is known to play a role in cold hyperalgesia and cold allodynia caused by disease conditions such as chemotherapy-induced peripheral neuropathy (CIPN, using the agents oxaliplatin, vincristine, or paclitaxel), diabetic neuropathy, migraine and overactive bladder (OAB). RQ-00203078 is identified as a selective and orally active TRPM8 antagonist.

In vitro: In the menthol-induced calcium influx assay, RQ-00203078 is a novel and highly potent TRPM8 antagonist with human and rat IC50 values of 8.3 nM and 5.8 nM, respectively. RQ-00203078 was highly selective over other TRP channels [1].

In vivo: RQ-00203078 demonstrated excellent activity in vivo in a dose dependent manner with an ED50 value of 0.65 mg/kg in the icilin-induced wet-dog shakes model in rats after oral administration [1].

Clinical trial: Up to now, RQ-00203078 is still in the preclinical development stage.

Reference:
[1] Ohmi M, Shishido Y, Inoue T, Ando K, Fujiuchi A, Yamada A, Watanabe S, Kawamura K.  Identification of a novel 2-pyridyl-benzensulfonamide derivative, RQ-00203078, as a selective and orally active TRPM8 antagonist. Bioorg Med Chem Lett. 2014 Dec 1;24(23):5364-8.

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References on RQ-00203078

Identification of a novel 2-pyridyl-benzensulfonamide derivative, RQ-00203078, as a selective and orally active TRPM8 antagonist.[Pubmed:25455182]

Bioorg Med Chem Lett. 2014 Dec 1;24(23):5364-8.

A novel series of 2-pyridyl-benzensulfonamide derivatives have been identified as selective and orally active TRPM8 antagonists via high throughput screening (HTS). Exploration of the structure-activity relationships of compound 1 has led to the identification of RQ-00203078 (compound 36) as a highly selective, potent and orally available TRPM8 antagonist. RQ-00203078 demonstrated excellent in vivo activity in a dose dependent manner with an ED50 value of 0.65 mg/kg in the icilin-induced wet-dog shakes model in rats after oral administration and may become an important pharmacological tool for fully assessing the potential therapeutic use of the targets activated by cold stimulation.

Blockade of TRPM8 activity reduces the invasion potential of oral squamous carcinoma cell lines.[Pubmed:22267123]

Int J Oncol. 2012 May;40(5):1431-40.

Several members of the transient receptor potential (TRP)-channel family are expressed in cancer cells. One, cold/menthol-sensitive TRPM8, is reportedly an important player in carcinogenesis in human prostate cancer, although its involvement in oral squamous cell carcinoma (SCC) remains unclear. The present immunohistochemistry and RT-PCR results revealed intense TRPM8 expression in two SCC cell lines, HSC3 and HSC4, derived from the human tongue. Menthol, icilin, and a more specific TRPM8 agonist (WS-12) induced non-specific cation currents, with Ca2+ permeability being greater than that of Na+ or K+. The novel TRPM8 antagonist RQ-00203078 (RQ) profoundly reduced such agonist-induced cation currents. Intracellular Ca2+ imaging revealed that menthol induced both intracellular Ca2+ release and store-operated Ca2+ entry, with RQ inhibiting each effect. To assess the possible pathophysiological role of TRPM8 in oral SCC, we performed motility and invasion assays, and gelatin zymography. Menthol augmented the migration and invasion abilities of both HSC3 and HSC4 cells by potentiating MMP-9 activity. RQ suppressed all of these effects. These results may aid understanding of the pathophysiological implications of TRPM8 channels in the oral SCC cells, support TRP proteins as valuable targets for pharmaceutical intervention, and inform the targeting of oral SCC in which the prognosis is poor.

Description

RQ-00203078 is a highly selective, potent and orally available TRPM8 antagonist (IC50 values are 5.3 and 8.3 nM for rat and human channels respectively), exhibits >350-fold selectivity for TRPM8 over TRPV4, TRPV1 and TRPA1.

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