Delving into the Latest Updates on JTV-519 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

Potassium channel x RYR2 x Sodium channels x calcium channel

Mechanism

Potassium channel blockers, RYR2 modulators(Ryanodine receptor 2 modulators), Sodium channels blockers

+ [1]

Therapeutic Areas

Cardiovascular DiseasesUrogenital Diseases

Active Indication

Atrial FibrillationArrhythmias, CardiacNephrotic Syndrome+ [1]

Inactive Indication

Dermatitis, AtopicHeart FailureMyocardial Infarction+ [1]

Originator Organization

Japan Tobacco (Hong Kong) Ltd.

Active Organization

Washington University School of Medicine

AETAS Pharma Co., Ltd.

Columbia University

Inactive Organization

Moberg Pharma AB

Sequel Pharmaceuticals, Inc.Japan Tobacco (Hong Kong) Ltd.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC25H33ClN2O2S

InChIKeyDKKLXCRMAXNIJF-UHFFFAOYSA-N

CAS Registry1038410-88-6

View All Structures (2)

BACKGROUNDHuman-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) created from patients with catecholaminergic polymorphic ventricular tachycardia 1 (CPVT1) have been used to study CPVT1 arrhythmia.OBJECTIVEThe purpose of this study was to evaluate the Ca²⁺ signaling aberrancies and pharmacological sensitivities of 3 CRISPR/Cas9-introduced CPVT1 mutations located in different molecular domains of ryanodine receptor 2 (RyR2).METHODSCRISPR/Cas9-engineered hiPSC-CMs carrying RyR2 mutations-R420Q, Q4201R, and F2483I-were voltage clamped, and their electrophysiology, pharmacology, and Ca²⁺ signaling phenotypes measured using total internal reflection fluorescence microscopy.RESULTSR420Q and Q4201R mutant hiPSC-CMs exhibit irregular, long-lasting, spatially wandering Ca²⁺ sparks and aberrant Ca²⁺ releases similar to F2483I unlike the wild-type myocytes. Large sarcoplasmic reticulum (SR) Ca²⁺ leaks and smaller SR Ca²⁺ contents were detected in cells expressing Q4201R and F2483I, but not R420Q. Fractional Ca²⁺ release and calcium-induced calcium release gain were higher in Q4201R than in R420Q and F2483I hiPSC-CMs. JTV519 was equally effective in suppressing Ca²⁺ sparks, waves, and SR Ca²⁺ leaks in hiPSC-CMs derived from all 3 mutant lines. Flecainide and dantrolene similarly suppressed SR Ca²⁺ leaks, but were less effective in decreasing spark frequency and durations.CONCLUSIONCRISPR/Cas9 gene editing of hiPSCs provides a novel approach in studying CPVT1-associated RyR2 mutations and suggests that Ca²⁺-signaling aberrancies and drug sensitivities may vary depending on the mutation site.

01 Dec 2020·British Journal of PharmacologyQ2 · MEDICINE

Nicotine stimulates ion transport via metabotropic β4 subunit containing nicotinic ACh receptors

Q2 · MEDICINE

Article

Author: Fronius, Martin ; Hollenhorst, Monika I. ; Kumar, Praveen ; Scholze, Petra ; Krasteva‐Christ, Gabriela

Background and PurposeMucociliary clearance is an innate immune process of the airways, essential for removal of respiratory pathogens. It depends on ciliary beat and ion and fluid homeostasis of the epithelium. We have shown that nicotinic ACh receptors (nAChRs) activate ion transport in mouse tracheal epithelium. Yet the receptor subtypes and signalling pathways involved remained unknown.Experimental ApproachTransepithelial short circuit currents (ISC) of freshly isolated mouse tracheae were recorded using the Ussing chamber technique. Changes in [Ca2+]i were studied on freshly dissociated mouse tracheal epithelial cells.Key ResultsApical application of the nAChR agonist nicotine transiently increased ISC. The nicotine effect was abolished by the nAChR antagonist mecamylamine. α‐Bungarotoxin (α7 antagonist) had no effect. The agonists epibatidine (α3β2, α4β2, α4β4 and α3β4) and A‐85380 (α4β2 and α3β4) increased ISC. The antagonists dihydro‐β‐erythroidine (α4β2, α3β2, α4β4 and α3β4), α‐conotoxin MII (α3β2) and α‐conotoxin PnIA (α3β2) reduced the nicotine effect. Nicotine‐ and epibatidine‐induced currents were unaltered in β2−/−mice, but in β4−/− mice no increase was observed. In the presence of thapsigargin (endoplasmatic reticulum Ca2+‐ATPase inhibitor) or the ryanodine receptor antagonists JTV‐519 and dantrolene there was a reduction in the nicotine‐effect, indicating involvement of Ca2+ release from intracellular stores. Additionally, the PKA inhibitor H‐89 and the TMEM16A (Ca2+‐activated chloride channel) inhibitor T16Ainh‐A01 significantly reduced the nicotine‐effect.Conclusion and Implicationsα3β4 nAChRs are responsible for the nicotine‐induced current changes via Ca2+ release from intracellular stores, PKA and ryanodine receptor activation. These nAChRs might be possible targets to stimulate chloride transport via TMEM16A.

01 Nov 2020·Cardiology in ReviewQ4 · MEDICINE

Catecholaminergic Polymorphic Ventricular Tachycardia

Q4 · MEDICINE

Review

Author: Frishman, William H. ; Kim, Chan W. ; Dutta, Tanya ; Aronow, Wilbert S. ; Frenkel, Daniel

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare congenital arrhythmogenic disorder induced by physical or emotional stress. It mainly affects children and younger adults and is characterized by rapid polymorphic and bidirectional ventricular tachycardia. Symptoms can include dizziness, palpitations, and presyncope, which may progress to syncope, hypotonia, convulsive movements, and sudden cardiac death. CPVT is the result of perturbations in Ca2+ ion handling in the sarcoplasmic reticulum of cardiac myocytes. Mutations in the cardiac ryanodine receptor gene and the calsequestrin isoform 2 gene are most commonly seen in familial CPVT patients. Under catecholaminergic stimulation, either mutation can result in an excess Ca2+ load during diastole resulting in delayed after depolarization and subsequent arrhythmogenesis. The current first-line treatment for CPVT is β-blocker therapy. Other therapeutic interventions that can be used in conjunction with β-blockers include moderate exercise training, flecainide, left cardiac sympathetic denervation, and implantable cardioverter-defibrillators. Several potential therapeutic interventions, including verapamil, dantrolene, JTV519, and gene therapy, are also discussed.

100 Deals associated with JTV-519

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External Link

KEGG	Wiki	ATC	Drug Bank
-	JTV-519	-	DB02929

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Atrial Fibrillation	Phase 3	IL	Sequel Pharmaceuticals, Inc.	01 Mar 2008
Atrial Fibrillation	Phase 2	RU	Sequel Pharmaceuticals, Inc.	01 Mar 2008
Arrhythmias, Cardiac	Phase 2	US	AETAS Pharma Co., Ltd.	-
Arrhythmias, Cardiac	Phase 2	-	AETAS Pharma Co., Ltd.	-
Myocardial Infarction	Phase 2	-	AETAS Pharma Co., Ltd.	-
Myocardial Infarction	Phase 2	-	Japan Tobacco (Hong Kong) Ltd.	-
Myocardial Infarction	Phase 2	-	Sequel Pharmaceuticals, Inc.	-
Atrial Fibrillation	Discovery	IL	Sequel Pharmaceuticals, Inc.	01 Mar 2008
Atrial Fibrillation	Discovery	RU	Sequel Pharmaceuticals, Inc.	01 Mar 2008
Myocardial Infarction	Discovery	JP	-	-