JTV-519

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C25H32N2O2S.ClH
Molecular Weight	461.06
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.COC1=CC=C2SCCN(CC2=C1)C(=O)CCN3CCC(CC4=CC=CC=C4)CC3

InChI

InChIKey=DKKLXCRMAXNIJF-UHFFFAOYSA-N

InChI=1S/C25H32N2O2S.ClH/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;1H

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C25H32N2O2S
Molecular Weight	424.599
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
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
multiple-channel blocker 2 Target ID: multiple-channel blocker Sources: https://www.ncbi.nlm.nih.gov/pubmed/19442077	Blocker 537

Conditions

Condition	Modality	Highest Phase	Product
Atrial fibrillation 131 Sources: https://clinicaltrials.gov/ct2/show/NCT01259622	Primary	Phase II 1132	Unknown Approved Use Unknown
Atopic dermatitis 43 Sources: https://clinicaltrials.gov/ct2/show/NCT00863005	Primary	Phase II 1132	Unknown Approved Use Unknown
heart failure 2 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15972811	Primary	Preclinical	Unknown Approved Use Unknown

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 P-gp 1461 MRP2 383 MRP1 106

Drug as perpetrator

Target	Modality	Activity
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=440681637	inconclusive [IC50 21.3174 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=440681637	inconclusive [IC50 23.9185 uM]
MRP1 172	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/12359358/	likely
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/12359358/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363679204	moderate [IC50 6.3209 uM]
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/12359358/	no
MRP2 475	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/12359358/	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=440681637	yes [IC50 0.5355 uM]

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.sciencedirect.com/science/article/pii/S1740677305000628 \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1340326#sid=174509615

PubMed

Title	Date	PubMed
JTV-519 Japan Tobacco.	2001 Jul	11757794
Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2.	2004 Apr 9	15073377
K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum.	2010 Mar	19718543

Sample Use Guides

In Vivo Use Guide

Atrial Fibrillation: oral tablet, x28 days or single intravenous infusionAtopic Dermatitis: Cream

Route of Administration: Other

In Vitro Use Guide

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.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 16:49:56 GMT 2023` Edited by `admin` on `Fri Dec 15 16:49:56 GMT 2023`
Record UNII	0I621Y6R4Q
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

JTV-519

Common Name

English

JTV 519

Code

English

1-PROPANONE, 1-(2,3-DIHYDRO-7-METHOXY-1,4-BENZOTHIAZEPIN-4(5H)-YL)-3-(4-(PHENYLMETHYL)-1-PIPERIDINYL)-, HYDROCHLORIDE (1:1)

Systematic Name

English

K-201

Code

English

K201

Common Name

English

K 201

Code

English

Code System Code Type Description

SMS_ID

300000041391