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| Targets |
The primary target of NS 2028 is soluble guanylyl cyclase (sGC), a heterodimeric enzyme composed of α and β subunits that catalyzes the conversion of GTP to the second messenger cyclic GMP (cGMP). sGC is the primary receptor for nitric oxide (NO) and is activated by NO binding to its heme moiety, leading to a conformational change that stimulates cGMP production. NS 2028 acts as a specific and irreversible inhibitor of sGC, blocking both basal and NO-stimulated enzyme activity. The compound inhibits basal sGC with an IC50 of 30 nM and NO-stimulated sGC with an IC50 of 200 nM. It also inhibits S-nitrosoglutathione-enhanced sGC activity in mouse cerebellum homogenates with an IC50 of 17 nM. The compound's irreversible mechanism of action distinguishes it from reversible sGC inhibitors and makes it particularly useful for studying the long-term effects of sGC inhibition. NS 2028 does not compete with ATP, indicating that its mechanism of inhibition is distinct from ATP-competitive kinase inhibitors.
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| ln Vitro |
When compared to cells cultured in a vehicle, NS -2028 (10 μM) suppresses cell number growth by 25% [2]. By preventing p38 MAPK activation, NS -2028 (10 μM; 30 min) stimulates cell proliferation test in the presence of VEGF [2].
In vitro, NS 2028 is a potent and specific inhibitor of sGC. It inhibits purified bovine lung guanylyl cyclase in a concentration-dependent and irreversible manner. The compound has an IC50 of 30 nM for the basal enzyme and 200 nM for the NO-stimulated enzyme. In mouse cerebellum homogenates, NS 2028 inhibits S-nitrosoglutathione-enhanced sGC activity with an IC50 of 17 nM, demonstrating 4.7-fold greater potency than ODQ (IC50 = 80 nM). NS 2028 (10 μM; 30 mins) decreases VEGF-induced endothelial cell (EC) migration by inhibiting p38 MAPK activation, indicating that sGC inhibition can modulate angiogenesis-related signaling pathways. The compound inhibits NO-dependent relaxant responses in non-vascular smooth muscle, confirming its functional activity in tissue preparations. These in vitro studies establish NS 2028 as a highly effective tool for investigating the role of sGC in NO-mediated signaling and its downstream effects on vascular tone, platelet function, and neurotransmission. |
| ln Vivo |
After VEGF particles were ingested, NS-2028 (a powder medication; 1 g/L; 8 days) dramatically decreased the formation of new blood vessels in avascular rabbits [2].
In vivo, NS 2028 is used as a pharmacological tool to inhibit sGC activity and block NO-cGMP signaling. By inhibiting sGC, NS 2028 prevents the production of cGMP in response to NO, thereby blocking the downstream effects of NO-mediated signaling, including vasodilation, inhibition of platelet aggregation, and neurotransmission. The compound's irreversible mechanism of action ensures sustained inhibition of sGC activity, making it particularly useful for studying the long-term consequences of sGC blockade in vivo. While specific in vivo efficacy data for NS 2028 are not extensively detailed in the available literature, its mechanism of action suggests that it would be effective in animal models of cardiovascular disease, neurological disorders, and inflammation where NO-cGMP signaling is implicated. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for NS 2028 involve sGC enzyme assays using purified bovine lung sGC or tissue homogenates. The compound's inhibitory activity is measured by monitoring the conversion of GTP to cGMP in the presence of the enzyme. IC50 values are determined from dose-response curves generated by plotting inhibitor concentration against residual sGC activity. The irreversible nature of NS 2028 inhibition can be confirmed by pre-incubation experiments, where the enzyme is incubated with the compound and then diluted or dialyzed to remove unbound inhibitor, followed by measurement of residual activity. These assays provide quantitative measures of the compound's potency and confirm its mechanism of action as an irreversible sGC inhibitor.
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| Cell Assay |
Cell Proliferation Assay[2]
Cell Types: HUVEC Cell Tested Concentrations: 10 μM Incubation Duration: 24 hrs (hours) Experimental Results: diminished number of cells in culture. EC migration[2]. Western Blot Analysis[2] Cell Types: HUVEC Cell Tested Concentrations: 10 μM Incubation Duration: 30 minutes Experimental Results: VEGF-enhanced p38 phosphorylation is attenuated. In vitro cellular assays for NS 2028 are conducted in endothelial cells, smooth muscle cells, or other cell types that express sGC. Cells are treated with the compound, and cGMP levels are measured using immunoassays or other methods to assess sGC activity. NS 2028 (10 μM; 30 mins) decreases VEGF-induced endothelial cell migration by inhibiting p38 MAPK activation. This demonstrates that NS 2028 can modulate cellular responses downstream of sGC inhibition. The compound's effects on NO-mediated signaling pathways, including vasodilation and inhibition of platelet aggregation, can be assessed using appropriate functional assays. These cellular assays confirm that NS 2028 engages its target in a cellular context and produces the expected downstream effects on sGC signaling. |
| Animal Protocol |
Animal/Disease Models: Rabbit[2]
Doses: 1 g/L Route of Administration: Oral administration; 1 g/L; 8 days Experimental Results: Inhibits VEGF-induced angiogenesis in vivo. In vivo animal studies for NS 2028 are typically conducted in rodent models to investigate the role of NO-cGMP signaling in various physiological and pathological processes. The compound can be administered via various routes, including intraperitoneal injection or local application, to achieve sGC inhibition in specific tissues or systemic effects. Outcome measures may include blood pressure measurements to assess vasodilation, platelet aggregation assays to evaluate thrombus formation, and behavioral tests to study the role of NO-cGMP signaling in learning and memory. The compound's irreversible mechanism of action ensures sustained inhibition, making it suitable for long-term studies. Pharmacokinetic studies would be required to determine the compound's bioavailability, half-life, and tissue distribution. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of NS 2028 indicate that it has a molecular weight of 269.1 and a molecular formula of C9H5BrN2O3. The compound is soluble in DMSO at a concentration of 10 mM, facilitating its use in in vitro assays and formulation for in vivo administration. The compound is typically stored as a powder at appropriate conditions to maintain stability. Its molecular weight and physicochemical properties suggest that it has reasonable drug-like characteristics, although its irreversible mechanism of action would require careful consideration for therapeutic development. NS 2028 displays 4.7-fold more potency than ODQ, another commonly used sGC inhibitor, making it a preferred tool for many applications.
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| Toxicity/Toxicokinetics |
The toxicological profile of NS 2028 is primarily derived from its use as a research compound in preclinical studies. As an irreversible sGC inhibitor, potential on-target toxicities could include hypertension, platelet hyperaggregability, and impaired neurotransmission, given the physiological roles of NO-cGMP signaling in regulating vascular tone, platelet function, and synaptic plasticity. The compound's irreversible mechanism of action would require careful consideration for in vivo use, as it would result in sustained inhibition that could lead to cumulative effects. Comprehensive toxicology studies would be required for therapeutic development, including assessments of cardiovascular, hematological, and neurological safety. However, NS 2028 is primarily used as a research tool rather than a therapeutic candidate.
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| References |
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| Additional Infomation |
NS 2028 is a highly potent and specific irreversible inhibitor of soluble guanylyl cyclase (sGC). It is also known as NS-2028. The compound has IC50 values of 30 nM for basal sGC and 200 nM for NO-stimulated sGC. NS 2028 inhibits S-nitrosoglutathione-enhanced sGC activity with an IC50 of 17 nM, displaying 4.7-fold more potency than ODQ. The compound is commonly used in nitric oxide signaling pathway research. It inhibits NO-dependent relaxant responses in non-vascular smooth muscle. NS 2028 is not approved for clinical use and is available from research chemical suppliers for preclinical studies.
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| Molecular Formula |
C9H5BRN2O3
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| Molecular Weight |
269.05
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| Exact Mass |
267.948
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| CAS # |
204326-43-2
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| PubChem CID |
4551
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| Appearance |
White to off-white solid powder
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| Density |
2.1±0.1 g/cm3
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| Boiling Point |
353.8±52.0 °C at 760 mmHg
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| Melting Point |
161-162ºC
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| Flash Point |
167.8±30.7 °C
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| Vapour Pressure |
0.0±0.8 mmHg at 25°C
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| Index of Refraction |
1.778
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| LogP |
0.27
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
15
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| Complexity |
333
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
MUDRLQRJCGJJTB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C9H5BrN2O3/c10-5-1-2-7-6(3-5)12-8(4-14-7)11-15-9(12)13/h1-3H,4H2
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| Chemical Name |
8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one
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| Synonyms |
NS2028 NS-2028 NS 2028
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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 : ~250 mg/mL (~929.20 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (8.07 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 21.7 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: ≥ 2.17 mg/mL (8.07 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 21.7 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 | 3.7168 mL | 18.5839 mL | 37.1678 mL | |
| 5 mM | 0.7434 mL | 3.7168 mL | 7.4336 mL | |
| 10 mM | 0.3717 mL | 1.8584 mL | 3.7168 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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