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Chemical Compound Review

Sipatrigine     2-(4-methylpiperazin-1-yl)-5- (2,3,5...

Synonyms: CHEMBL28854, SureCN135888, CHEBI:140243, AC1L1TYB, AC1Q3LMC, ...
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Disease relevance of BW 619C89


Psychiatry related information on BW 619C89

  • Neuropsychiatric effects (reduced consciousness, agitation, confusion, visual perceptual disturbance, or frank hallucinations) occurred in 16 of 21 patients receiving sipatrigine and in no placebo patients [6].

High impact information on BW 619C89

  • When administered intravenously to Fischer 344 rats 5 minutes after permanent middle cerebral artery occlusion, BW619C89 produced marked reductions of both total (cortex and basal ganglia) and cortical infarct volumes [1].
  • RESULTS: In the in vitro studies, BW619C89 inhibited veratrine- (but not potassium-) evoked release of both endogenous glutamate and aspartate from rat cerebral cortex slices with IC50 values of approximately 5 microM [1].
  • CONCLUSIONS: These results suggest that glutamate release inhibitors such as BW619C89 may provide an alternative to excitatory amino acid receptor antagonists in the treatment of focal cerebral ischemia and stroke [1].
  • In the endothelin-1 (ET-1) model of middle cerebral artery occlusion (MCAo) in conscious rats, both AM-36 (6 mg/kg i.p.) and sipatrigine (10 mg/kg i.p.) 30 min post-MCAo significantly reduced cortical, but not striatal infarct volume [7].
  • Effects of extracellular pH on the interaction of sipatrigine and lamotrigine with high-voltage-activated (HVA) calcium channels in dissociated neurones of rat cortex [8].

Biological context of BW 619C89


Anatomical context of BW 619C89


Associations of BW 619C89 with other chemical compounds

  • Drugs such as Ifenprodil, Cerestat and Selfotel, that have failed in clinical trials, were found to have very low therapeutic ratios of < or = 1, whereas compounds with more tolerable clinical side-effect profiles were found to have higher therapeutic ratios (2, 10 and 10 for Sipatrigine, Remacemide and sPBN, respectively) [14].

Gene context of BW 619C89

  • The neuroprotective agent sipatrigine (10 microM) inhibited both hTREK-1 (73.3+/-4.4%) and hTRAAK (45.1+/-11.2%) in a reversible, voltage-independent manner [15].

Analytical, diagnostic and therapeutic context of BW 619C89

  • These findings suggest that BW619C89 has long-lasting cerebroprotective effects with advantageous functional consequences after single oral administration in a rodent model of stroke [16].
  • Administration of 50 mg/kg of 619C89 30 and 60 min after the onset of ischemia reduced cortical infarction volume (P < 0.05), but there was no effect when the drug was given 5 min after reperfusion [5].
  • METHODS: Patients within 12 h of clinically diagnosed stroke were randomized to placebo or sipatrigine at total doses of 10, 18, 27, or 36 mg/kg by continuous intravenous infusion over 65 h [6].
  • Although associated with cardiovascular effects in animal models in vivo, there is no published information concerning the effects of sipatrigine on cardiac ion currents and action potentials (AP) [17].


  1. BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage. Leach, M.J., Swan, J.H., Eisenthal, D., Dopson, M., Nobbs, M. Stroke (1993) [Pubmed]
  2. Clinical experience with excitatory amino acid antagonist drugs. Muir, K.W., Lees, K.R. Stroke (1995) [Pubmed]
  3. Neuroprotective effects of a use-dependent blocker of voltage-dependent sodium channels, BW619C89, in rat middle cerebral artery occlusion. Graham, S.H., Chen, J., Lan, J., Leach, M.J., Simon, R.P. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  4. Pharmacokinetics of 619C89, a novel neuronal sodium channel inhibitor, in acute stroke patients after loading and discrete maintenance infusions. Hussein, Z., Fraser, I.J., Lees, K.R., Muir, K.W., Lunnon, M.W., Hobbiger, S.F., Posner, J. British journal of clinical pharmacology. (1996) [Pubmed]
  5. Neuroprotective effects of the glutamate release inhibitor 619C89 in temporary middle cerebral artery occlusion. Kawaguchi, K., Graham, S.H. Brain Res. (1997) [Pubmed]
  6. Phase II clinical trial of sipatrigine (619C89) by continuous infusion in acute stroke. Muir, K.W., Holzapfel, L., Lees, K.R. Cerebrovasc. Dis. (2000) [Pubmed]
  7. Sodium channel blocking activity of AM-36 and sipatrigine (BW619C89): in vitro and in vivo evidence. Callaway, J.K., Castillo-Melendez, M., Giardina, S.F., Krstew, E.K., Beart, P.M., Jarrott, B. Neuropharmacology (2004) [Pubmed]
  8. Effects of extracellular pH on the interaction of sipatrigine and lamotrigine with high-voltage-activated (HVA) calcium channels in dissociated neurones of rat cortex. Hainsworth, A.H., Spadoni, F., Lavaroni, F., Bernardi, G., Stefani, A. Neuropharmacology (2001) [Pubmed]
  9. Electrophysiology of sipatrigine: a lamotrigine derivative exhibiting neuroprotective effects. Calabresi, P., Stefani, A., Marfia, G.A., Hainsworth, A.H., Centonze, D., Saulle, E., Spadoni, F., Leach, M.J., Giacomini, P., Bernardi, G. Exp. Neurol. (2000) [Pubmed]
  10. Inhibition of human N-type voltage-gated Ca2+ channels by the neuroprotective agent BW619C89. McNaughton, N.C., Leach, M.J., Hainsworth, A.H., Randall, A.D. Neuropharmacology (1997) [Pubmed]
  11. On the inhibition of voltage activated calcium currents in rat cortical neurones by the neuroprotective agent 619C89. Stefani, A., Hainsworth, A.H., Spadoni, F., Bernardi, G. Br. J. Pharmacol. (1998) [Pubmed]
  12. State-dependent inhibition of Na+ currents by the neuroprotective agent 619C89 in rat hippocampal neurons and in a mammalian cell line expressing rat brain type IIA Na+ channels. Xie, X.M., Garthwaite, J. Neuroscience (1996) [Pubmed]
  13. Mechanisms of ischaemic damage to central white matter axons: a quantitative histological analysis using rat optic nerve. Garthwaite, G., Brown, G., Batchelor, A.M., Goodwin, D.A., Garthwaite, J. Neuroscience (1999) [Pubmed]
  14. A comparative assessment of the efficacy and side-effect liability of neuroprotective compounds in experimental stroke. Dawson, D.A., Wadsworth, G., Palmer, A.M. Brain Res. (2001) [Pubmed]
  15. The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K(+) channels TREK-1 and TRAAK. Meadows, H.J., Chapman, C.G., Duckworth, D.M., Kelsell, R.E., Murdock, P.R., Nasir, S., Rennie, G., Randall, A.D. Brain Res. (2001) [Pubmed]
  16. Long-term beneficial effects of BW619C89 on neurological deficit, cognitive deficit and brain damage after middle cerebral artery occlusion in the rat. Smith, S.E., Hodges, H., Sowinski, P., Man, C.M., Leach, M.J., Sinden, J.D., Gray, J.A., Meldrum, B.S. Neuroscience (1997) [Pubmed]
  17. The neuroprotective agent sipatrigine blocks multiple cardiac ion channels and causes triangulation of the ventricular action potential. Gao, Z., Milnes, J.T., Choisy, S.C., Leach, M.J., Hancox, J.C., James, A.F. Clin. Exp. Pharmacol. Physiol. (2005) [Pubmed]
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