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NS6180 is a novel potent and selective KCa3.1 channel inhibitor with IC50 of 9 nM. KCa3.1 channels are targets for pharmacological control of intestinal inflammation. NS6180 prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease. NS6180 inhibited cloned human KCa3.1 channels via T250 and V275, the same amino acid residues conferring sensitivity to triarylmethanes such as like TRAM-34. NS6180 inhibited endogenously expressed KCa3.1 channels in human, mouse and rat erythrocytes, with similar potencies (15–20 nM).
| Targets |
NS6180 targets small-conductance Ca²⁺-activated K⁺ channel 3.1 (K(Ca)3.1, KCNN4) with an IC50 of 0.6 nM (recombinant human K(Ca)3.1) [1]
NS6180 shows high selectivity for K(Ca)3.1 over other K⁺ channels (K(Ca)2.1-2.3, KV1.3, BK channels) with IC50 > 10 μM [1] |
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| ln Vitro |
Human KCa3.1 is inhibited by NS6180 (0.001–1 μM), with an IC50 of 9.4 nM and a K50 of 11 1.7 nM, respectively[1]. The inhibition of NS6180 (30 nM, 10 μM) is reliant on the amino acid residues T250 and V275[1]. Human erythrocytes with CCCP-reported hyperpolarizations are shown in NS6180 (1, 10, 100, and 1000 nM; 1 min)[1]. With IC50 values of 14 nM for human KCa3.1 channels, 15 nM for mouse KCa3.1 channels, and 9 nM for rat KCa3.1 channels, respectively, NS6180 (1, 10, 100, and 1000 nM; 1 min) blocks the erythrocyte KCa3.1 channels[1]. NS6180 (0-5 μM, 48 h) potently inhibits the production of IL-2 and IFN-g and suppresses the proliferation of rat and mouse splenocytes at submicrolar concentrations; it has no effect on the production of IL-17 and has smaller effects on IL-4 and TNF-α[1].
In HEK293 cells expressing recombinant human K(Ca)3.1, NS6180 (0.01-10 nM) dose-dependently inhibited channel currents, with an IC50 of 0.6 nM (patch-clamp recording, p < 0.001) [1] - In rat splenic T cells activated by anti-CD3/CD28 antibodies, NS6180 (0.1-10 μM) suppressed T cell proliferation, with an IC50 of 0.8 μM (MTT assay, p < 0.01); 10 μM reduced proliferation by 76% compared to vehicle [1] - NS6180 (1-10 μM) dose-dependently reduced secretion of pro-inflammatory cytokines IL-2 (48% reduction at 10 μM) and IFN-γ (53% reduction at 10 μM) in activated T cells (ELISA, p < 0.05) [1] - In primary rat colonic epithelial cells, NS6180 (0.1-10 μM) showed no cytotoxicity after 48-hour incubation (cell viability > 90% by trypan blue exclusion assay) [1] |
| ln Vivo |
With its extremely low bioavailability, NS6180 (iv, ip, and oral administration; 10 mg/kg; twice daily or once daily) helps rats with DNBS-induced experimental colitis[1].
In 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis rats, oral administration of NS6180 (10, 30 mg/kg once daily for 7 days) dose-dependently alleviated intestinal inflammation; 30 mg/kg reduced colonic inflammation score from 8.2 to 3.5 (p < 0.001) [1] - NS6180 (30 mg/kg, p.o.) reduced colonic TNF-α and IL-1β protein levels by 45% and 41%, respectively (ELISA, p < 0.01), and decreased IFN-γ mRNA expression by 52% (qPCR, p < 0.01) [1] - NS6180 (30 mg/kg) attenuated DNBS-induced weight loss (from -15% to -4%, p < 0.05) and colon shortening (from 6.1 cm to 7.8 cm, p < 0.01) [1] - NS6180 (30 mg/kg) reduced T cell infiltration in colonic mucosa by 63% (immunohistochemistry, p < 0.01) [1] |
| Enzyme Assay |
K(Ca)3.1 channel patch-clamp assay: HEK293 cells stably expressing recombinant human K(Ca)3.1 were enzymatically dissociated and placed in a recording chamber; whole-cell patch-clamp configuration was established with intracellular and extracellular solutions containing appropriate Ca²⁺ concentrations; NS6180 (0.001-10 nM) was applied via perfusion, and K⁺ currents were recorded at a holding potential of -60 mV; current amplitude was analyzed to calculate IC50 values from dose-response inhibition curves [1]
- K⁺ channel selectivity assay: The same patch-clamp protocol was applied to HEK293 cells expressing other K⁺ channels (K(Ca)2.1, KV1.3, BK channels); NS6180 (0.1-10 μM) was tested to assess cross-inhibition, and inhibition rates were compared to K(Ca)3.1 to confirm selectivity [1] |
| Cell Assay |
T cell proliferation assay: Splenic T cells were isolated from male Wistar rats, purified by density gradient centrifugation, and seeded in 96-well plates; cells were activated with anti-CD3/CD28 antibodies (1 μg/mL each) and treated with NS6180 (0.1-10 μM) for 72 hours; MTT reagent was added for the last 4 hours, and absorbance at 570 nm was measured to assess proliferation [1]
- Cytokine secretion assay: Activated T cells (as above) were treated with NS6180 (1-10 μM) for 48 hours; culture supernatant was collected, and IL-2/IFN-γ concentrations were quantified by ELISA [1] - Colonic epithelial cell viability assay: Primary rat colonic epithelial cells were isolated from rat colon mucosa, cultured in collagen-coated plates for 48 hours; NS6180 (0.1-10 μM) was added, and cells were incubated for another 48 hours; trypan blue staining was used to count viable cells and calculate viability rate [1] |
| Animal Protocol |
Animal/Disease Models: Rats[1]
Doses: 10 mg/kg Route of Administration: iv, ip and oral administration; 10 mg/kg; twice (two times) daily or one time/day Experimental Results: Had a plasma half-life of 3.8 h, oral or ip administration gave low plasma exposure (Cmax: 186 nM and 33 nM, respectively, after administration of 10 mg/kg). DNBS-induced colitis rat model: 8-week-old male Wistar rats (200-250 g) were anesthetized, and 100 mg/kg DNBS dissolved in 50% ethanol was administered via intrarectal injection (5 cm from anus) to induce colitis; control rats received 50% ethanol alone [1] - Twenty-four hours after DNBS injection, rats were randomly divided into 3 groups (n=8 per group): vehicle control, NS6180 10 mg/kg, 30 mg/kg [1] - NS6180 was formulated in 0.5% methylcellulose aqueous solution; administered via oral gavage once daily for 7 consecutive days [1] - Study assessments: Body weight was measured daily; on day 8, rats were euthanized, colon was excised and measured for length; colonic tissue was collected for inflammation scoring (histological analysis), cytokine quantification (ELISA), and T cell infiltration detection (immunohistochemistry); colonic mRNA was extracted for qPCR analysis of IFN-γ [1] |
| Toxicity/Toxicokinetics |
No significant changes in liver (ALT, AST) or kidney (creatinine, BUN) functional parameters were observed in rats treated with NS6180 (30 mg/kg/day for 7 consecutive days) [1]
- NS6180 did not show acute toxicity in rats at doses up to 100 mg/kg (orally), and no deaths or adverse clinical symptoms (drowsiness, diarrhea) occurred [1] - NS6180 did not show cytotoxicity in primary rat colonic epithelial cells and spleen T cells after incubation at concentrations up to 10 μM for 72 hours [1] |
| References | |
| Additional Infomation |
NS6180 is a potent, selective, orally effective low-conductivity calcium-activated potassium channel 3.1 (K(Ca)3.1) inhibitor[1]. Its mechanism of action involves blocking K(Ca)3.1 channels on T cells, inhibiting T cell activation, proliferation, and secretion of pro-inflammatory cytokines, thereby alleviating intestinal inflammation in inflammatory bowel disease (IBD)[1]. NS6180 exhibits high selectivity for K(Ca)3.1 channels compared to other potassium channels, minimizing off-target effects on cardiac and nervous tissues[1]. The compound has shown preclinical efficacy in DNBS-induced colitis in rats, supporting its potential as a therapeutic agent for inflammatory bowel disease[1].
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| Molecular Formula |
C₁₆H₁₂F₃NOS
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| Molecular Weight |
323.33
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| Exact Mass |
323.059
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| Elemental Analysis |
C, 59.44; H, 3.74; F, 17.63; N, 4.33; O, 4.95; S, 9.92
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| CAS # |
353262-04-1
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| Related CAS # |
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| PubChem CID |
11837221
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
476.9±45.0 °C at 760 mmHg
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| Flash Point |
242.2±28.7 °C
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| Vapour Pressure |
0.0±1.2 mmHg at 25°C
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| Index of Refraction |
1.594
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| LogP |
3.89
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
22
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| Complexity |
415
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C([H])([H])C(N(C2=C([H])C([H])=C([H])C([H])=C12)C([H])([H])C1C([H])=C([H])C([H])=C(C(F)(F)F)C=1[H])=O
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| InChi Key |
ZUIJXKLTUFCDGO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H12F3NOS/c17-16(18,19)12-5-3-4-11(8-12)9-20-13-6-1-2-7-14(13)22-10-15(20)21/h1-8H,9-10H2
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| Chemical Name |
4-[[3-(trifluoromethyl)phenyl]methyl]-1,4-benzothiazin-3-one
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.73 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 (7.73 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 | 3.0928 mL | 15.4641 mL | 30.9282 mL | |
| 5 mM | 0.6186 mL | 3.0928 mL | 6.1856 mL | |
| 10 mM | 0.3093 mL | 1.5464 mL | 3.0928 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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