c-Jun N-terminal kinases (JNK) are a family of mitogen-activated protein kinases that can be activated in response to inflammatory cytokines, ischemia, UV irradiation, and heat shock. AS-601245 is a benzothiazole acetonitrile derivative that inhibits three human JNK isoforms JNK1, JNK2, and JNK3 with IC50 values of 150, 220, and 70 nM, respectively. It also exhibited 10- to 20-fold selectivity over c-Raf, CDK2, and c-src and > 50- to 100-fold selectivity over Ser/Thr- and Tyr-protein kinases. The oral administration of C3H/HEN mice with AS-601245 at 0.3, 1, 3, and 10 mg/kg decreased LPS-induced TNF-α release in a dose-dependent manner. The i.p. injection of AS601245 (40, 60, and 80 mg/kg) 1 h before and 24 h after the reperfusion dose-dependently decreased hippocampal damage in mice (16, 74, and 83%, respectively). When mice were injected with AS-601245 15 min and 24 h after the reperfusion at the above-mentioned doses, the hippocampal damage was decreased by 29, 40, and 52%, respectively. The i.p. administration of AS-601245 at 60 mg/kg led to a significant reduction in the number of phospho-c-Jun-stained neurons. AS-601245 at the doses of 18 and 60 mg/kg significantly reduced the size of cortical lesions in mice following middle cerebral artery occlusion by 27 and 52%, respectively[2].
作用机制
AS-601245 is a structurally unique JNK inhibitor. It inhibits isolated human JNK3 in an ATP-competitive manner[2].
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