Delving into the Latest Updates on Carisbamate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Carisbamate (USAN), Comfyde

+ [3]

Target

Neurotransmitter receptor

Mechanism

Neurotransmitter receptor modulators

Therapeutic Areas

Nervous System DiseasesCongenital DisordersSkin and Musculoskeletal Diseases+ [1]

Active Indication

Langer-Giedion SyndromeLennox Gastaut SyndromeSeizures

Inactive Indication

Diabetic NeuropathiesDiabetic peripheral neuropathyDrug Resistant Epilepsy+ [7]

Originator Organization

SK Biopharmaceuticals Co., Ltd.

Active Organization

SK Life Science, Inc.

SK Biopharmaceuticals Co., Ltd.

Johnson & Johnson

Inactive Organization

Janssen Research & Development LLCJohnson & Johnson Pharmaceutical Research & Development LLC

ALZA Corp.

+ [1]

Drug Highest PhasePhase 3

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC9H10ClNO3

InChIKeyOLBWFRRUHYQABZ-MRVPVSSYSA-N

CAS Registry194085-75-1

The hyperpolarization-activated cation current (I_h) exhibits a slowly activating time course of the current (I_h) when the cell membrane is hyperpolarized for an extended duration. It is involved in generating electrical activity in various excitable cells. Numerous structurally distinct compounds or herbal drugs have the potential to impact both the magnitude and gating kinetics of this current. Brivaracetam, a chemical analog of levetiracetam known to be a ligand for synaptic vesicle protein 2A, could directly suppress the I_h magnitude. Carisbamate, an anticonvulsant agent, not only inhibited the I_h amplitude but also reduced the strength of voltage-dependent hysteresis (Hys_(V)) associated with I_h. Cilobradine, similar to ivabradine, inhibited the amplitude of I_h; however, it also suppressed the amplitude of delayed-rectifier K⁺ currents. Dexmedetomidine, an agonist of α2-adrenergic receptor, exerted a depressant action on I_h in a concentration-dependent fashion. Suppression of I_h amplitude was observed when GAL-021, a breathing control modulator, was present at a concentration exceeding 30 μM. Lutein, one of the few xanthophyll carotenoids, was able to suppress the I_h amplitude as well as to depress Hys_(V)'s strength of I_h. Pirfenidone, a pyridine derivative known to be an anti-fibrotic agent, depressed the I_h magnitude in a concentration- and voltage-dependent fashion. Tramadol, a synthetic centrally active analgesic, was shown to reduce the I_h magnitude, independent of its interaction with opioid receptors. Various herbal drugs, including ent-kaurane-type diterpenoids from Croton tonkinensis, Ganoderma triterpenoids, honokiol, and pterostilbene, demonstrated efficacy in reducing the magnitude of I_h. Conversely, oxaliplatin, a platinum-based chemotherapeutic compound, was observed to effectively increase the I_h amplitude. Collectively, the regulatory effects of these compounds or herbal drugs on cellular function can be partly attributed to their perturbations on I_h.

01 Jan 2023·Frontiers in cellular neuroscience

Concerted suppressive effects of carisbamate, an anti-epileptic alkyl-carbamate drug, on voltage-gated Na⁺ and hyperpolarization-activated cation currents.

Article

Author: Wu, Sheng-Nan ; Hung, Te-Yu ; Huang, Chin-Wei

Carisbamate (CRS, RWJ-333369) is a new anti-seizure medication. It remains unclear whether and how CRS can perturb the magnitude and/or gating kinetics of membrane ionic currents, despite a few reports demonstrating its ability to suppress voltage-gated Na⁺ currents. In this study, we observed a set of whole-cell current recordings and found that CRS effectively suppressed the voltage-gated Na⁺ (I_Na) and hyperpolarization-activated cation currents (I_h) intrinsically in electrically excitable cells (GH₃ cells). The effective IC₅₀ values of CRS for the differential suppression of transient (I_Na(T)) and late I_Na (I_Na(L)) were 56.4 and 11.4 μM, respectively. However, CRS strongly decreased the strength (i.e., Δarea) of the nonlinear window component of I_Na (I_Na(W)), which was activated by a short ascending ramp voltage (V_ramp); the subsequent addition of deltamethrin (DLT, 10 μM) counteracted the ability of CRS (100 μM, continuous exposure) to suppress I_Na(W). CRS strikingly decreased the decay time constant of I_Na(T) evoked during pulse train stimulation; however, the addition of telmisartan (10 μM) effectively attenuated the CRS (30 μM, continuous exposure)-mediated decrease in the decay time constant of the current. During continued exposure to deltamethrin (10 μM), known to be a pyrethroid insecticide, the addition of CRS resulted in differential suppression of the amplitudes of I_Na(T) and I_Na(L). The amplitude of I_h activated by a 2-s membrane hyperpolarization was diminished by CRS in a concentration-dependent manner, with an IC₅₀ value of 38 μM. For I_h, CRS altered the steady-state I-V relationship and attenuated the strength of voltage-dependent hysteresis (Hys_(V)) activated by an inverted isosceles-triangular V_ramp. Moreover, the addition of oxaliplatin effectively reversed the CRS-mediated suppression of Hys_(V). The predicted docking interaction between CRS and with a model of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel or between CRS and the hNa_V1.7 channel reflects the ability of CRS to bind to amino acid residues in HCN or hNa_V1.7 channel via hydrogen bonds and hydrophobic interactions. These findings reveal the propensity of CRS to modify I_Na(T) and I_Na(L) differentially and to effectively suppress the magnitude of I_h. I_Na and I_h are thus potential targets of the actions of CRS in terms of modulating cellular excitability.

01 Jan 2023·Therapeutic Advances in Neurological Disorders

Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies

Review

Author: Sills, Graeme J.

Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset and often intractable seizures and developmental delay/regression, and include Dravet syndrome and Lennox–Gastaut syndrome (LGS). Rufinamide, fenfluramine, stiripentol, cannabidiol and ganaxolone are antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs. Rufinamide is thought to suppress neuronal hyperexcitability by preventing the functional recycling of voltage-gated sodium channels from the inactivated to resting state. It is licensed for adjunctive treatment of seizures associated with LGS. Fenfluramine increases extracellular serotonin levels and may reduce seizures via activation of specific serotonin receptors and positive modulation of the sigma-1 receptor. Fenfluramine is licensed for adjunctive treatment of seizures associated with Dravet syndrome and LGS. Stiripentol is a positive allosteric modulator of type-A gamma-aminobutyric acid (GABAA) receptors. As a broad-spectrum inhibitor of cytochrome P450 enzymes, its antiseizure effects may additionally arise through pharmacokinetic interactions with co-administered ASMs. Stiripentol is licensed for treating seizures associated with Dravet syndrome in patients taking clobazam and/or valproate. The mechanism(s) of action of cannabidiol remains largely unclear although multiple targets have been proposed, including transient receptor potential vanilloid 1, G protein-coupled receptor 55 and equilibrative nucleoside transporter 1. Cannabidiol is licensed as adjunctive treatment in conjunction with clobazam for seizures associated with Dravet syndrome and LGS, and as adjunctive treatment of seizures associated with tuberous sclerosis complex. Like stiripentol, ganaxolone is a positive allosteric modulator at GABAA receptors. It has recently been licensed in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder. Greater understanding of the causes of DEEs has driven research into the potential use of other novel and repurposed agents. Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin.

100 Deals associated with Carisbamate

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External Link

KEGG	Wiki	ATC	Drug Bank
D06573	Carisbamate	N03AX19	DB12338

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Seizures	Phase 3	TW	SK Life Science, Inc.	28 Apr 2022
Seizures	Phase 3	RS	SK Life Science, Inc.	28 Apr 2022
Seizures	Phase 3	PL	SK Life Science, Inc.	28 Apr 2022
Seizures	Phase 3	AR	SK Life Science, Inc.	28 Apr 2022
Lennox Gastaut Syndrome	Phase 3	-	SK Biopharmaceuticals Co., Ltd.	-
Epilepsy, Partial, Motor	Preclinical	-	SK Life Science, Inc.	01 Jan 2009
Status Epilepticus	Preclinical	-	SK Life Science, Inc.	01 Jan 2009
Epilepsy, Complex Partial	Preclinical	-	SK Life Science, Inc.	01 Nov 2006
Epilepsy	Preclinical	EU	Johnson & Johnson Pharmaceutical Research & Development LLC	-
Epilepsy	Preclinical	US	Johnson & Johnson Pharmaceutical Research & Development LLC	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02435381 (CTgov)	Phase 1/2	Alcoholism	11	Placebo (Placebo)	fhomditaxe(ehczmnlltd) = lzeagexucg upopqzssbp (bpfzglshvp, rhadrcvpmm - odvduydeom) View more	-	02 Mar 2021
				Carisbamate (Carisbamate)	fhomditaxe(ehczmnlltd) = tcsdlodfhn upopqzssbp (bpfzglshvp, mvogiwyrjz - wmhfphoyyc) View more
NCT00740623 (Pubmed \| Turk J Pediatr)	Phase 3	Epilepsies, Partial	547	Carisbamate 800 mg/day	(eulhosjayg) = Dizziness was the most common treatment-emergent adverse event, with a higher incidence (≥ 5% difference) in the combined carisbamate group (31%) than placebo (9%); the incidence was higher with carisbamate 1,200 mg (32%, n = 58) than with carisbamate 800 mg (30%, n = 53) wnyxtwjazd (yybateqmzk )	Negative	01 Apr 2011
				Carisbamate 1,200 mg/day
IEC2009	Not Applicable	Epilepsies, Partial	419	Carisbamate 400-800 mg/day	amxzhbzsig(gmghhhoapl) = low behavioral/psychiatric adverse event rates puuetxhpik (esexawoelj ) View more	Positive	02 Jul 2009
IEC2009	Not Applicable	Epilepsies, Partial	-	Carisbamate 400mg/day	bfgmpyzfkc(qxaayddntf) = low behavioral/psychiatric adverse event rates jwpjbfcrko (kujlyyipvq ) View more	Positive	02 Jul 2009