Details
Stereochemistry | ACHIRAL |
Molecular Formula | C25H32N2O2S |
Molecular Weight | 424.599 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
COC1=CC=C2SCCN(CC2=C1)C(=O)CCN3CCC(CC4=CC=CC=C4)CC3
InChI
InChIKey=KCWGETCFOVJEPI-UHFFFAOYSA-N
InChI=1S/C25H32N2O2S/c1-29-23-7-8-24-22(18-23)19-27(15-16-30-24)25(28)11-14-26-12-9-21(10-13-26)17-20-5-3-2-4-6-20/h2-8,18,21H,9-17,19H2,1H3
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/19442077
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19442077
Japan Tobacco developed JTV-519 (known also as K201) as an antiarrhythmic agent. This drug was in Phase II trials for the potential treatment of Atrial Fibrillation, but study was terminated. In experimental myofibrillar overcontraction models, JTV-519 demonstrated greater cardioprotectant effects than propranolol, also, this drug investigated against heart failure, but then these researches have been discontinued. In addition, K201 was in phase II clinical trial for investigation its topical implementation for Atopic Dermatitis. The mechanism of its action is both complex and controversial, known that it is a non-specific blocker of sodium, potassium and calcium channels (multiple-channel blocker). It is believed to stabilize the closed state of the RyR2 (cardiac ryanodine receptor) by increasing its affinity for the FKBP12.6 (12.6 kDa FK506 binding protein), in addition was suggested, that suppression of spontaneous Ca2 release and the activity of RyR2 contributes, at least in part, to the anti-arrhythmic properties of K201.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: multiple-channel blocker Sources: https://www.ncbi.nlm.nih.gov/pubmed/19442077 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
inconclusive [IC50 21.3174 uM] | ||||
inconclusive [IC50 23.9185 uM] | ||||
likely | ||||
moderate [IC50 6.3209 uM] | ||||
no | ||||
no | ||||
yes [IC50 0.5355 uM] |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
JTV-519 Japan Tobacco. | 2001 Jul |
|
Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. | 2004 Apr 9 |
|
K201 (JTV519) suppresses spontaneous Ca2+ release and [3H]ryanodine binding to RyR2 irrespective of FKBP12.6 association. | 2007 Jun 15 |
|
K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum. | 2010 Mar |
Sample Use Guides
Atrial Fibrillation: oral tablet, x28 days or single intravenous infusionAtopic Dermatitis: Cream
Route of Administration:
Other
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22509897
JTV519 was effective in reducing sarcoplasmic reticulum (SR) Ca²⁺ leak by specifically regulating ryanodine receptors (RyR2) opening at diastolic [Ca²⁺](i) in the absence of increased RyR2 phosphorylation at Ser(2814) , extending the potential use of JTV519 to conditions of acute cellular Ca²⁺ overload. SR Ca²⁺ leak was induced by ouabain in murine cardiomyocytes. [Ca²⁺]-transients, SR Ca²⁺ load and RyR2-mediated Ca²⁺ leak (sparks/waves) were quantified, with or without JTV519 (1 µmol·L⁻¹). Contribution of Ca²⁺ -/calmodulin-dependent kinase II (CaMKII) was assessed by KN-93 and Western blot (RyR2-Ser(2814) phosphorylation). Effects of JTV519 on contractile force were investigated in non-failing human ventricular trabeculae.
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ACTIVE MOIETY
SALT/SOLVATE (PARENT)