JTV-519(JTV-519) - 药物靶点：Potassium channel x RYR2 x Sodium channels x calcium channel_在研适应症：心房颤动，心律失常，肾病综合征_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [1]

靶点

Potassium channel x RYR2 x Sodium channels x calcium channel

作用方式

阻滞剂、调节剂、抑制剂

作用机制

钾离子通道阻滞剂、RYR2调节剂(兰尼碱受体-2调节剂)、钠通道阻滞剂

+ [1]

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

Washington University School of Medicine

AETAS Pharma Co., Ltd.

Columbia University

非在研机构

Sequel Pharmaceuticals, Inc.日本烟草（香港）有限公司

Moberg Pharma AB

权益机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C25H33ClN2O2S

InChIKeyDKKLXCRMAXNIJF-UHFFFAOYSA-N

CAS号1038410-88-6

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关联

6

项与 JTV-519 相关的临床试验

EUCTR2010-023101-35-DK

/ Not yet recruiting临床2期

TUNDRA-AF: A mulTi-center, randomized, doUble-bliNded, placebo-controlled Dose-escalating study of the effects of K201 on the RestorAtion of sinus rhythm in subjects with symptomatic Atrial Fibrillation of recent onset - TUNDRA-AF

开始日期2011-02-11

申办/合作机构

Sequel Pharmaceuticals, Inc.

NCT01259622

/ Terminated临床2期

A mulTi-center, Randomized, doUble-bliNded, Placebo-controlled Dose-escalating Study of the Effects of K201 on the RestorAtion of Sinus Rhythm in Subjects With Symptomatic Atrial Fibrillation of Recent Onset

The purpose of this study is to evaluate the effects of a single intravenous infusion of K201 compared to placebo in a dose escalating manner on conversion to sinus rhythm, reduction of subject's symptom score, and safety.

开始日期2011-02-01

申办/合作机构

Sequel Pharmaceuticals, Inc.

EUCTR2009-017838-44-DK

/ Not yet recruitingN/A

A Pilot Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Centered Safety, Tolerability and Preliminary Efficacy Study of K201 Oral for the Prevention of Atrial Fibrillation (AF) Recurrence in Subjects Post-Conversion from AF - ARCTIC-AF

开始日期2010-04-09

申办/合作机构

Sequel Pharmaceuticals, Inc.

100 项与 JTV-519 相关的临床结果

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100 项与 JTV-519 相关的转化医学

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100 项与 JTV-519 相关的专利（医药）

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115

项与 JTV-519 相关的文献（医药）

2024-12-01·Molecular Diversity

First report on chemometrics-driven multilayered lead prioritization in addressing oxysterol-mediated overexpression of G protein-coupled receptor 183

Article

作者: Kar, Supratik ; Ojha, Probir Kumar ; Bhattacharjee, Arnab

Contemporary research has convincingly demonstrated that upregulation of G protein-coupled receptor 183 (GPR183), orchestrated by its endogenous agonist, 7α,25-dihydroxyxcholesterol (7α,25-OHC), leads to the development of cancer, diabetes, multiple sclerosis, infectious, and inflammatory diseases. A recent study unveiled the cryo-EM structure of 7α,25-OHC bound GPR183 complex, presenting an untapped opportunity for computational exploration of potential GPR183 inhibitors, which served as our inspiration for the current work. A predictive and validated two-dimensional QSAR model using genetic algorithm (GA) and multiple linear regression (MLR) on experimental GPR183 inhibition data was developed. QSAR study highlighted that structural features like dissimilar electronegative atoms, quaternary carbon atoms, and CH₂RX fragment (X: heteroatoms) influence positively, while the existence of oxygen atoms with a topological separation of 3, negatively affects GPR183 inhibitory activity. Post assessment of true external set prediction capability, the MLR model was deployed to screen 12,449 DrugBank compounds, followed by a screening pipeline involving molecular docking, druglikeness, ADMET, protein-ligand stability assessment using deep learning algorithm, molecular dynamics, and molecular mechanics. The current findings strongly evidenced DB05790 as a potential lead for prospective interference of oxysterol-mediated GPR183 overexpression, warranting further in vitro and in vivo validation.

2024-09-01·British Journal of Pharmacology

A novel ryanodine receptor 2 inhibitor, M201‐A, enhances natriuresis, renal function and lusi‐inotropic actions: Preclinical and phase I study

Article

作者: Hasunuma, Tomoko ; Nakamura, Masahiko ; Taguchi, Isao ; Sugiyama, Atsushi ; Kambayashi, Ryuichi ; McCarroll, Charlotte S ; Dobi, Sara ; Kikuchi, Migaku ; Otani, Naoyuki ; Mitsuhisa, Yamano ; Kusano, Kengo ; Riddell, Alexandra ; Matsuda, Ryuko ; Smith, Godfrey ; Kaneko, Noboru ; Kayley, Scott ; Loughrey, Christopher M ; Martin, Tamara P ; Ishikawa, Tetsuya ; Inoue, Yuko ; Kumagai, Yuji ; Fujiwara, Toshihiko ; Hirano, Sayuri ; Shimamoto, Ken ; Da Silva Costa, Ana ; Toda, Masashi ; Toyoda, Shigeru ; Shinozaki, Makoto ; Mark, Patric B ; Sakai, Toshiya ; Saxena, Priyanka ; Elliott, Elspeth B ; Kitai, Takeshi ; Iwata, Kunio

AbstractBackground and PurposeThe ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201‐A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies.Experimental ApproachFollowing the administration of M201‐A (1,4‐benzothiazepine‐1‐oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201‐A was administered intravenously at doses of 0.2 and 0.4 mg·kg−1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses.Key ResultsIn rat heart cells, M201‐A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi‐inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201‐A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability.Conclusions and ImplicationsThe novel drug M201‐A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi‐inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

2024-03-01·Journal of Molecular and Cellular Cardiology

Dual effect of cardiac FKBP12.6 overexpression on excitation-contraction coupling and the incidence of ventricular arrhythmia depending on its expression level

Article

作者: Gandon-Renard, Marine ; Gómez, Ana Maria ; Courilleau, Delphine ; Val-Blasco, Almudena ; Gomez, Susana ; Mercadier, Jean-Jacques ; Benitah, Jean-Pierre ; Oughlis, Célia ; Gerbaud, Pascale ; Lefebvre, Florence ; Pereira, Laetitia ; Mercier-Nomé, Françoise ; Journé, Clément

FKBP12.6, a binding protein to the immunosuppressant FK506, which also binds the ryanodine receptor (RyR2) in the heart, has been proposed to regulate RyR2 function and to have antiarrhythmic properties. However, the level of FKBP12.6 expression in normal hearts remains elusive and some controversies still persist regarding its effects, both in basal conditions and during β-adrenergic stimulation. We quantified FKBP12.6 in the left ventricles (LV) of WT (wild-type) mice and in two novel transgenic models expressing distinct levels of FKBP12.6, using a custom-made specific anti-FKBP12.6 antibody and a recombinant protein. FKBP12.6 level in WT LV was very low (0.16 ± 0.02 nmol/g of LV), indicating that <15% RyR2 monomers are bound to the protein. Mice with 14.1 ± 0.2 nmol of FKBP12.6 per g of LV (TG1) had mild cardiac hypertrophy and normal function and were protected against epinephrine/caffeine-evoked arrhythmias. The ventricular myocytes showed higher [Ca²⁺]_i transient amplitudes than WT myocytes and normal SR-Ca²⁺ load, while fewer myocytes showed Ca²⁺ sparks. TG1 cardiomyocytes responded to 50 nM Isoproterenol increasing these [Ca²⁺]_i parameters and producing RyR2-Ser2808 phosphorylation. Mice with more than twice the TG1 FKBP12.6 value (TG2) showed marked cardiac hypertrophy with calcineurin activation and more arrhythmias than WT mice during β-adrenergic stimulation, challenging the protective potential of high FKBP12.6. RyR2^R420Q CPVT mice overexpressing FKBP12.6 showed fewer proarrhythmic events and decreased incidence and duration of stress-induced bidirectional ventricular tachycardia. Our study, therefore, quantifies for the first time endogenous FKBP12.6 in the mouse heart, questioning its physiological relevance, at least at rest due its low level. By contrast, our work demonstrates that with caution FKBP12.6 remains an interesting target for the development of new antiarrhythmic therapies.

100 项与 JTV-519 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	JTV-519	-	DB02929

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
心律失常	临床2期	欧洲	AETAS Pharma Co., Ltd.	-
心律失常	临床2期	美国	AETAS Pharma Co., Ltd.	-
心房颤动	临床1期	俄罗斯	Sequel Pharmaceuticals, Inc.	2008-03-01
心房颤动	临床1期	以色列	Sequel Pharmaceuticals, Inc.	2008-03-01
心肌梗塞	临床1期	-	日本烟草（香港）有限公司	-
心肌梗塞	临床1期	-	AETAS Pharma Co., Ltd.	-
心肌梗塞	临床1期	日本	-	-
心肌梗塞	临床1期	-	Sequel Pharmaceuticals, Inc.	-
心房颤动	药物发现	以色列	Sequel Pharmaceuticals, Inc.	2008-03-01
心房颤动	药物发现	俄罗斯	Sequel Pharmaceuticals, Inc.	2008-03-01