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AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties

Hiver, Agnes
Szyndralewiez, Cedric
Gaillard, Pascale
Gotteland, Jean-Pierre
Vitte, Pierre-Alain
Published in The Journal of pharmacology and experimental therapeutics. 2004, vol. 310, no. 1, p. 25-32
Abstract Recent evidence suggests that activation of the c-Jun NH2-terminal protein kinase (JNK) signal transduction pathway may play a role in ischemia-induced cell death. Thus, preventing the activation of JNK, or c-Jun phosphorylation could be neuroprotective. In the current study, we report that a small molecule, AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile), which has been shown to inhibit the JNK signaling pathway, promotes cell survival after cerebral ischemia. In vivo, AS601245 (40, 60, and 80 mg/kg) administered i.p. provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. This effect is mediated by JNK inhibition and therefore by c-Jun expression and phosphorylation. A significant neuroprotective effect of AS601245 administered either by i.p. injection (6, 18, and 60 mg/kg) or as i.v. bolus (1 mg/kg) followed by an i.v. infusion (0.6 mg/kg/h) was also observed in rats after focal cerebral ischemia. These data suggest that the use of JNK inhibitors such as AS601245 may be a relevant strategy in the therapy of ischemic insults.
Keywords Acetonitriles/pharmacology/therapeutic useAnimalsBenzothiazolesBrain Ischemia/complications/etiology/prevention & controlDisease Models, AnimalGerbillinaeJNK Mitogen-Activated Protein KinasesLipopolysaccharides/pharmacologyMiceMice, Inbred C3HMitogen-Activated Protein Kinases/antagonists & inhibitors/metabolismNeuroprotective Agents/pharmacology/therapeutic usePhosphorylation/drug effectsRatsRats, WistarThiazoles/pharmacology/therapeutic useTumor Necrosis Factor-alpha/metabolism
PMID: 14988419
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CARBONI, Sonia et al. AS601245 (1,3-benzothiazol-2-yl (2-[[2-(3-pyridinyl) ethyl] amino]-4 pyrimidinyl) acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. In: The Journal of pharmacology and experimental therapeutics, 2004, vol. 310, n° 1, p. 25-32. doi: 10.1124/jpet.103.064246

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Deposited on : 2016-12-06

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