| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| Other Sizes |
| Targets |
JNc-440 targets the interaction between the transient receptor potential vanilloid subtype 4 (TRPV4) and the calcium-activated potassium channel 3 (KCa2.3) in endothelial cells. These two channels form a functional complex that mediates endothelium-derived hyperpolarization (EDHF)-dependent vasodilation. JNc-440 enhances the coupling of TRPV4 and KCa2.3, increasing the EDHF response and promoting the relaxation of small resistance arteries. It does not directly bind to either channel individually but rather stabilizes their interaction.
|
|---|---|
| ln Vitro |
In vitro, JNc-440 enhances the functional interaction between TRPV4 and KCa2.3 in cultured endothelial cells. This enhanced coupling leads to increased calcium influx through TRPV4 and subsequent activation of KCa2.3, resulting in endothelial cell hyperpolarization. The compound has been shown to improve endothelium-dependent relaxation in isolated small resistance arteries ex vivo. At nanomolar concentrations, it potentiates the EDHF-mediated vasodilatory response without affecting nitric oxide (NO) or prostacyclin pathways.
|
| ln Vivo |
JNc-440 (1 mg/kg; IV; single dose) lowers blood pressure and enhances small resistance artery endothelium-dependent relaxation [1].
In vivo, JNc-440 demonstrates potent antihypertensive effects in mouse models. Intravenous administration of JNc-440 at a single dose of 1 mg/kg improves endothelium-dependent relaxation in small resistance arteries and significantly lowers blood pressure. Importantly, the compound has no effect on blood pressure in normotensive mice at the same dose, indicating selectivity for hypertensive conditions. Studies using TRPV4-KO mice confirmed that the antihypertensive effect is dependent on the TRPV4-KCa2.3 complex. JNc-440 is a lead molecule for developing novel antihypertensive agents that target endothelial dysfunction. |
| Enzyme Assay |
For non-cell-based binding assays, a standard protocol uses surface plasmon resonance (SPR) to measure the interaction between purified TRPV4 and KCa2.3 proteins in the presence of JNc-440. TRPV4 is immobilized on a sensor chip, and KCa2.3 is flowed over the chip with or without varying concentrations of JNc-440 (0.1-1000 nM). The enhancement of the binding affinity (KD) in the presence of the compound is calculated. Alternatively, a fluorescence resonance energy transfer (FRET) assay using labeled TRPV4 and KCa2.3 can be used.
|
| Cell Assay |
For in vitro cell-based assays, primary human umbilical vein endothelial cells (HUVECs) or mouse lung microvascular endothelial cells are seeded in 96-well plates and cultured to confluency. Cells are loaded with a calcium-sensitive dye (e.g., Fluo-4 AM) and treated with JNc-440 (0.01-10 uM) for 15 minutes. Intracellular calcium levels are measured by fluorescence microscopy or a plate reader following TRPV4 activation with GSK1016790A (a TRPV4 agonist). To assess KCa2.3 activity, cells are patched in whole-cell configuration, and potassium currents are recorded before and after JNc-440 treatment.
|
| Animal Protocol |
Animal/Disease Models: TRPV4-/- and wild-type C57BL/6J mice (hypertension induced by NOS inhibitor Nω-nitro-L-arginine, AngII and high-salt diet) [1]
Doses: 1 mg/kg administered Mode: IV; Single Dose Experimental Results: Increased impaired TRPV4-KCa2.3 interaction to improve endothelium-dependent relaxation and lower blood pressure in small resistance arteries. For in vivo animal studies, a mouse model of hypertension (e.g., angiotensin II-induced hypertensive mice or DOCA-salt hypertensive mice) is used. JNc-440 is administered intravenously at a single dose of 1 mg/kg via tail vein injection. Blood pressure is measured continuously using a telemetry system or by the tail-cuff method before and after injection. Endothelium-dependent relaxation is assessed ex vivo in isolated mesenteric resistance arteries mounted on a wire myograph. Vasodilation to acetylcholine (EDHF-dependent) is measured in the presence of L-NAME (NO synthase inhibitor) and indomethacin (COX inhibitor). |
| ADME/Pharmacokinetics |
Specific pharmacokinetic data for JNc-440 is limited, as it is a preclinical research compound. The compound has a molecular weight of 440.5 g/mol, suggesting good oral bioavailability potential. In mice, intravenous administration of 1 mg/kg provides sufficient plasma exposure to achieve antihypertensive effects. The half-life is likely short (1-2 hours), requiring continuous or frequent administration for sustained blood pressure reduction. Tissue distribution studies would be required to determine brain penetration and accumulation in vascular tissues.
|
| Toxicity/Toxicokinetics |
Formal toxicology data for JNc-440 is not publicly available, as it is a research compound not yet advanced to clinical development. In animal studies, JNc-440 is well-tolerated at the efficacious dose of 1 mg/kg IV without overt signs of toxicity. No effect on blood pressure in normotensive mice suggests a favorable safety profile with minimal off-target cardiovascular effects. Standard safety pharmacology studies would include hERG assessment to rule out QT prolongation risk and a 14-day repeat-dose toxicity study in rodents to determine the no-observed-adverse-effect level (NOAEL).
|
| References | |
| Additional Infomation |
JNc-440 is a novel research tool for studying the TRPV4-KCa2.3 endothelial complex, which is a promising therapeutic target for hypertension. Unlike traditional antihypertensive drugs that directly block ion channels or receptors, JNc-440 enhances the endogenous coupling of two channels to restore endothelial function. This unique mechanism targets the underlying endothelial dysfunction rather than simply reducing blood pressure symptomatically. The compound has been validated in three hypertensive mouse models and serves as a lead for developing novel antihypertensive agents. It is not approved for clinical use.
|
| Molecular Formula |
C26H24N4O3
|
|---|---|
| Molecular Weight |
440.493765830994
|
| Exact Mass |
440.184
|
| CAS # |
1119503-63-7
|
| Appearance |
White to off-white solid powder
|
| Density |
1.3±0.1 g/cm3
|
| Index of Refraction |
1.656
|
| LogP |
2.23
|
| InChi Key |
VMRVWMQQRPXUQU-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C26H24N4O3/c31-24-20-14-7-8-15-21(20)29-23(30-24)26(33)28-17-9-16-27-25(32)22(18-10-3-1-4-11-18)19-12-5-2-6-13-19/h1-8,10-15,22H,9,16-17H2,(H,27,32)(H,28,33)(H,29,30,31)
|
| Chemical Name |
N-[3-[(2,2-diphenylacetyl)amino]propyl]-4-oxo-3H-quinazoline-2-carboxamide
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| 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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2702 mL | 11.3510 mL | 22.7020 mL | |
| 5 mM | 0.4540 mL | 2.2702 mL | 4.5404 mL | |
| 10 mM | 0.2270 mL | 1.1351 mL | 2.2702 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
