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| Targets |
The primary target of JNJ303 is the potassium channel KCNQ1 (Kv7.1) in complex with its ancillary subunit KCNE1, which generates the slow delayed rectifier potassium current (IKs). IKs is a voltage-gated potassium current that plays a critical role in cardiac repolarization. JNJ303 is a potent and specific IKs blocker with an IC50 value of 64 nM. It does not have any effects on other cardiac channels at concentrations of 3.3 µM for INa, ICa, Ito, and IK.
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| ln Vitro |
JNJ 303's IC50 value of 64 nM allows it to block IK[1]. Other cardiac channels are unaffected by JNJ 303 (3.3 μM) [1]. Unprovoked torsade de pointes (TdP) and QT prolongation are brought on by JNJ 303 [1].
In vitro, JNJ303 is a potent IKs blocker with an IC50 value of 64 nM. It inhibits heteromeric Kv7.1/KCNE1 channel complexes in a concentration- and time-dependent manner. JNJ303 does not have any effects on other cardiac channels at concentrations of 3.3 µM for INa, ICa, Ito, and IK. The compound's specificity for IKs over other cardiac channels makes it a valuable tool for studying IKs function. |
| ln Vivo |
JNJ 303 mimics the decrease in mice's fasting blood glucose levels caused by Exn4 [2].
In vivo, JNJ303 induces QT-prolongations and causes unprovoked torsades de pointes (TdP). As a potent IKs blocker, it would be expected to prolong cardiac repolarization and increase the risk of arrhythmias. JNJ303 can be used for the research of diabetes, obesity and central nervous system. However, specific in vivo efficacy data from animal models is not detailed in the available sources. The compound is for research use only and not for therapeutic applications. |
| Enzyme Assay |
For IKs channel inhibitors, standard cell-free assays involve electrophysiological techniques (patch-clamp) using cells expressing recombinant KCNQ1/KCNE1 channels. The compound is applied at various concentrations, and channel activity is measured to determine IC50 values. Selectivity for IKs over other cardiac channels is assessed using cells expressing other ion channels.
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| Cell Assay |
For IKs channel inhibitors, standard cellular assays involve treatment of cardiomyocytes or cells expressing KCNQ1/KCNE1 channels with the test compound. IKs current is measured by patch-clamp electrophysiology. Action potential duration and QT interval can be assessed in cardiomyocyte models to evaluate the compound's effects on cardiac repolarization.
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| Animal Protocol |
For in vivo evaluation of IKs blockers, standard animal models include guinea pig or rabbit models where QT interval and arrhythmia incidence can be measured. The compound is typically administered intravenously or orally, and electrocardiogram (ECG) parameters and arrhythmia events are monitored. JNJ303 induces QT-prolongations and causes unprovoked torsades de pointes (TdP).
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| ADME/Pharmacokinetics |
JNJ303 has a molecular weight of 440.98 and formula C21H29ClN2O4S. It is soluble in DMSO at 10 mM. As a small molecule with moderate lipophilicity, it would be expected to have reasonable cell permeability. Comprehensive pharmacokinetic studies would be required for therapeutic development.
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| Toxicity/Toxicokinetics |
JNJ303 induces QT-prolongations and causes unprovoked torsades de pointes (TdP), indicating significant cardiac safety concerns. As a research compound targeting IKs, standard preclinical toxicology would be required for therapeutic development. The compound is for research use only and not for therapeutic applications.
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| References | |
| Additional Infomation |
JNJ303 is a potent and specific inhibitor of the delayed rectifier potassium current (IKs) with an IC50 value of 64 nM. It is a potent blocker of the voltage-dependent IKs-channel encoded by KCNQ1/KCNE1. JNJ303 induces QT-prolongations and causes unprovoked torsades de pointes (TdP). No regulatory approval for therapeutic use has been identified.
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| Molecular Formula |
C21H29CLN2O4S
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|---|---|
| Molecular Weight |
440.98
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| Exact Mass |
440.154
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| CAS # |
878489-28-2
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| Related CAS # |
878489-28-2;
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| PubChem CID |
11575823
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
5.422
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
726
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC(C)(C(=O)NC1[C@@H]2CC3C[C@H]1CC(C2)(C3)NS(=O)(=O)C)OC4=CC=C(C=C4)Cl
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| InChi Key |
OSGIRCJRKSAODN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H29ClN2O4S/c1-20(2,28-17-6-4-16(22)5-7-17)19(25)23-18-14-8-13-9-15(18)12-21(10-13,11-14)24-29(3,26)27/h4-7,13-15,18,24H,8-12H2,1-3H3,(H,23,25)
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| Chemical Name |
2-(4-Chloro-phenoxy)-N-(5-methanesulfonylamino-adamantan-2-yl)-2-methyl-propionamide
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| Synonyms |
JNJ303 JNJ-303 JNJ 303 AC-1 AC 1 AC1
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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 : ~62.5 mg/mL (~141.73 mM)
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| 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 | 2.2677 mL | 11.3384 mL | 22.6768 mL | |
| 5 mM | 0.4535 mL | 2.2677 mL | 4.5354 mL | |
| 10 mM | 0.2268 mL | 1.1338 mL | 2.2677 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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