Delving into the Latest Updates on Tonabersat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

GJA1

Mechanism

GJA1 inhibitors(Gap junction alpha-1 protein inhibitors)

Therapeutic Areas

Cardiovascular DiseasesEndocrinology and Metabolic DiseaseEye Diseases+ [1]

Active Indication

Diabetic macular oedemaEpilepsy

Inactive Indication

Migraine DisordersMigraine With AuraMigraine Without Aura

Originator Organization

GSK Plc

Active Organization

Jaeb Center For Health Research Foundation, Inc.

Upsher-Smith Laboratories LLC

Inactive Organization

Minster Research LtdProximagen Group Plc

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC20H19ClFNO4

InChIKeyXLIIRNOPGJTBJD-ROUUACIJSA-N

CAS Registry175013-84-0

A stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed to assay tonabersat and assess its stability in pharmaceutical formulations. Chromatographic separation was achieved using a Kinetex® C18 column (2.6 µm, 150 x 3 mm, 100 Å) at 50 °C, with a 20 µL injection volume. A linear gradient of acetonitrile in water (5 - 33.5 %) was applied for 1 min, followed by a gradual increase to 100 % over 26 min at a flow rate of 0.5 mL/min. Tonabersat and its degradation products were detected at 275 nm and 210 nm, respectively. The optimized method was used to evaluate the stability of tonabersat in lipid-based pharmaceutical formulations at 5 ± 3 °C, 25 ± 2°C/60 ± 5 % RH, and 40 ± 2 °C/75 ± 5 % RH over 3 months. The method was validated as per ICH guidelines and demonstrated linearity in the range of 5 - 200 µg/mL (R² = 0.99994) with good accuracy (98.25 - 101.58 % recovery) and precision (% RSD < 2.5 %). The limits of detection and quantitation were 0.8 µg/mL and 5 µg/mL, respectively. Forced degradation studies showed significant degradation on exposure to alkaline (90.33 ± 0.80 %), acidic (70.60 ± 1.57 %), and oxidative stress (33.95 ± 0.69 %) at 70 °C, but no degradation was observed on exposure to thermal or photolytic stress. No chemical degradation was observed in either formulation on storage. Thus, the method was sensitive, specific, and suitable for stability testing of tonabersat in pharmaceutical formulations.

01 Jan 2024·Experimental Neurology

Blockade of connexin hemichannels with tonabersat protects against mild hypoxic ischemic brain injury in neonatal rats

Article

Author: Dean, Justin M ; Zhou, Kelly Q ; Wassink, Guido ; Ranasinghe, Sumudu ; Davidson, Joanne O ; McDouall, Alice ; Karunasinghe, Rashika N

BACKGROUND AND PURPOSEThere is growing evidence that infants with mild hypoxic-ischemic (HI) encephalopathy have increased risk of brain injury and adverse neurodevelopmental outcomes. Currently, there is no approved treatment for these infants. It was previously shown that blocking connexin 43 hemichannels is neuroprotective in models of moderate to severe HI injury. However, it is yet to be established whether these channels play a role in the evolution of mild HI brain injury, and whether blocking these channels after mild HI is neuroprotective.METHODSHI was induced in postnatal day 10 rats of both sexes by right carotid artery ligation followed by 80 min of hypoxia in 8% oxygen. Pups receiving HI were randomised to receive intraperitoneal injections of either saline, vehicle (2-hydroxypropyl-beta-cyclodextrin polyethylene glycol-400), or tonabersat (2 mg/kg), at 60 min, 24 h, and 48 h after hypoxia. Seven days after HI, brains were harvested for measurement of volume loss and histological analysis.RESULTSHI resulted in a significant reduction in hemispheric, hippocampal, and white matter volumes, which were significantly attenuated after treatment with tonabersat. HI was also associated with a significant reduction in numbers of neurons in the CA1 and CA3 hippocampal regions, a reduction in the numbers of oligodendrocytes in the corpus callosum, and an increase in the number of astrocytes in both regions, which were significantly attenuated by tonabersat treatment. There were no differences in rectal temperatures between tonabersat- and vehicle-treated rat pups.CONCLUSIONSBlockade of connexin hemichannels with tonabersat significantly reduced mild HI injury in the hippocampus and white matter, without causing hypothermia.

01 Dec 2022·Diabetic Medicine

Blocking connexin 43 hemichannel‐mediated ATP release reduces communication within and between tubular epithelial cells and medullary fibroblasts in a model of diabetic nephropathy

Article

Author: Hills, Claire E. ; Williams, Bethany M. ; Squires, Paul E. ; Demirel, Isak ; Cliff, Chelsy L.

AbstractIntroductionFibrosis of renal tubules is the final common pathway in diabetic nephropathy and develops in the face of tubular injury and fibroblast activation. Aberrant connexin 43 (Cx43) hemichannel activity has been linked to this damage under euglycaemic conditions, however, its role in glycaemic injury is unknown. This study investigated the effect of a Cx43 blocker (Tonabersat) on hemichannel activity and cell–cell interactions within and between tubular epithelial cells and fibroblasts in an in vitro model of diabetic nephropathy.MethodsHuman kidney (HK2) proximal tubule epithelial cells and medullary fibroblasts (TK173) were treated in low (5 mM) or high (25 mM) glucose ± transforming growth factor beta‐1 (TGFβ1) ± Tonabersat in high glucose. Carboxyfluorescein dye uptake and ATPlite luminescence assessed changes in hemichannel‐mediated ATP release, while immunoblotting determined protein expression. Co‐incubation with the ATP‐diphosphohydrolase apyrase or a P2X7R inhibitor (A438079) assessed ATP‐P2X7R signalling. Indirect co‐culture with conditioned media from the alternate cell type evaluated paracrine‐mediated heterotypic interactions.ResultsTonabersat partially negated glucose/TGFβ1‐induced increases in Cx43 hemichannel‐mediated ATP release and downstream changes in adherens junction and extracellular matrix (ECM) protein expression in HK2 and TK173 cells. Apyrase and A438079 highlighted the role for ATP‐P2X7R in driving changes in protein expression in TK173 fibroblasts. Indirect co‐culture studies suggest that epithelial cell secretome increases Tonabersat‐sensitive hemichannel‐mediated dye uptake in fibroblasts and downstream protein expression.ConclusionTonabersat‐sensitive hemichannel‐mediated ATP release enhances TGFβ1‐driven heterotypic cell–cell interaction and favours myofibroblast activation. The data supports the potential benefit of Cx43 inhibition in reducing tubulointerstitial fibrosis in late‐stage diabetic nephropathy.

100 Deals associated with Tonabersat

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06578

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetic macular oedema	Phase 2	US	Jaeb Center For Health Research Foundation, Inc.	02 May 2023
Migraine With Aura	Phase 1	GB	Minster Research Ltd	01 Apr 2006
Migraine With Aura	Phase 1	DK	Minster Research Ltd	01 Apr 2006
Migraine With Aura	Phase 1	HU	Minster Research Ltd	01 Apr 2006
Migraine With Aura	Phase 1	ZA	Minster Research Ltd	01 Apr 2006
Migraine Without Aura	Phase 1	GB	Minster Research Ltd	01 Apr 2006
Migraine Without Aura	Phase 1	DK	Minster Research Ltd	01 Apr 2006
Migraine Without Aura	Phase 1	ZA	Minster Research Ltd	01 Apr 2006
Migraine Without Aura	Phase 1	HU	Minster Research Ltd	01 Apr 2006
Migraine Disorders	Preclinical	-	Upsher-Smith Laboratories LLC	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00332007 (Pubmed \| Lancet Neurol)	Phase 2	Migraine With Aura	39	Tonabersat 40 mg	(sqfqzaplbf) = Tonabersat was well tolerated but overall had more side-effects than placebo tlejyhiiqc (pcawwplvtb )	Positive	01 Aug 2009
				Placebo
NCT00311662 (Pubmed \| Cephalalgia)	Phase 2	Migraine Disorders	124	Tonabersat 20 mg	(fqoyxwqgtm) = chfkdkamxm niplcaxscq (mkpizbzbdq )	-	01 Jul 2009
				Placebo	(fqoyxwqgtm) = uvcqocpnmn niplcaxscq (mkpizbzbdq )