Cav2.2 blockers(Voltage-gated N-type calcium channel alpha-1B subunit blockers), Nav1.2 blockers(Sodium channel protein type II alpha subunit blockers)

Therapeutic Areas

Nervous System DiseasesCardiovascular Diseases

Active Indication-

Inactive Indication

Brain Ischemia

Originator Organization

GSK Plc

Active Organization-

Inactive Organization

GSK Plc

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC15H16Cl3N5

InChIKeyPDOCBJADCWMDGL-UHFFFAOYSA-N

CAS Registry130800-90-7

100 Clinical Results associated with Sipatrigine

100 Translational Medicine associated with Sipatrigine

100 Patents (Medical) associated with Sipatrigine

Literatures (Medical) associated with Sipatrigine

01 Jul 2021·Biochemistry and Biophysics Reports

Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092

Article

Author: Walsh, Yvonne ; Veale, Emma L ; Leach, Michael ; Mathie, Alistair

TREK and TRESK K2P channels are widely expressed in the nervous system, particularly in sensory neurons, where they regulate neuronal excitability. In this study, using whole-cell patch-clamp electrophysiology, we characterise the inhibitory effect of the anticonvulsant lamotrigine and two derivatives, sipatrigine and 3,5-diamino-6-(3,5-bistrifluoromethylphenyl)-1,2,4-triazine (CEN-092) on these channels. Sipatrigine was found to be a more effective inhibitor than lamotrigine of TREK-1, TREK-2 and TRESK channels. Sipatrigine was slightly more potent on TREK-1 channels (EC₅₀ = 16 μM) than TRESK (EC₅₀ = 34 μM) whereas lamotrigine was equally effective on TREK-1 and TRESK. Sipatrigine was less effective on a short isoform of TREK-2, suggesting the N terminus of the channel is important for both inhibition and subsequent over-recovery. Inhibition of TREK-1 and TREK-2 channels by sipatrigine was reduced by mutation of a leucine residue associated with the norfluoxetine binding site on these channels (L289A and L320A on TREK-1 and TREK-2, respectively) but these did not affect inhibition by lamotrigine. Inhibition of TRESK by sipatrigine and lamotrigine was attenuated by mutation of bulky phenylalanine residues (F145A and F352A) in the inner pore helix. However, phosphorylation mutations did not alter the effect of sipatrigine. CEN-092 was a more effective inhibitor of TRESK channels than TREK-1 channels. It is concluded that lamotrigine, sipatrigine and CEN-092 are all inhibitors of TREK and TRESK channels but do not greatly discriminate between them. The actions of these compounds may contribute to their current and potential use in the treatment of pain and depression.

03 Apr 2017·Journal of General PhysiologyQ2 · MEDICINE

Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants

Q2 · MEDICINE

Article

Author: Zhorov, Boris S. ; Tikhonov, Denis B.

Local anesthetics, antiarrhythmics, and anticonvulsants include both charged and electroneutral compounds that block voltage-gated sodium channels. Prior studies have revealed a common drug-binding region within the pore, but details about the binding sites and mechanism of block remain unclear. Here, we use the x-ray structure of a prokaryotic sodium channel, NavMs, to model a eukaryotic channel and dock representative ligands. These include lidocaine, QX-314, cocaine, quinidine, lamotrigine, carbamazepine (CMZ), phenytoin, lacosamide, sipatrigine, and bisphenol A. Preliminary calculations demonstrated that a sodium ion near the selectivity filter attracts electroneutral CMZ but repels cationic lidocaine. Therefore, we further docked electroneutral and cationic drugs with and without a sodium ion, respectively. In our models, all the drugs interact with a phenylalanine in helix IVS6. Electroneutral drugs trap a sodium ion in the proximity of the selectivity filter, and this same site attracts the charged group of cationic ligands. At this position, even small drugs can block the permeation pathway by an electrostatic or steric mechanism. Our study proposes a common pharmacophore for these diverse drugs. It includes a cationic moiety and an aromatic moiety, which are usually linked by four bonds.

14 May 2009·Journal of Medicinal ChemistryQ1 · MEDICINE

Oxadiazolylindazole Sodium Channel Modulators are Neuroprotective toward Hippocampal Neurones

Q1 · MEDICINE

Article

Author: Garthwaite, John ; Visintin, Cristina ; Lancaster, Barrie ; Gane, Paul J. ; Riddall, Dieter R. ; Clutterbuck, Lisa A. ; Selwood, David L. ; Posada, Cristina Garcia

We report the discovery of a new class of neuroprotective voltage-dependent sodium channel modulators exemplified by (5-(1-benzyl-1H-indazol-3-yl)-1,2,4-oxadiazol-3-yl)methanamine 11 (CFM1178). The compounds were inhibitors of [(14)C]guanidinium ion flux in rat forebrain synaptosomes and displaced binding of the sodium channel ligand [(3)H]BW202W92. 11 and the corresponding N(2)-benzyl isomer, 38 (CFM6058), demonstrated neuroprotective activity in hippocampal slices comparable to sipatrigine. CYP450 enzyme inhibition observed with 11 was reduced with 38. In electrophysiological experiments on dissociated hippocampal neurons, these two compounds caused use- and voltage-dependent block of sodium currents. Sodium channel isoform profiling against Na(v)1.1-1.8 demonstrated that the standard sodium channel blocker lamotrigine had modest activity against Na(v)1.1, while sipatrigine was generally more potent and less selective. 11 and 38 showed potent activity against Na(v)1.6, pointing to pharmacological block of this isoform being consistent with the neuroprotective effect. 38 also showed use dependent block of Na(v)1.6 in HEK cells.

100 Deals associated with Sipatrigine

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Ischemia	Preclinical	GB	GSK Plc	-

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