KCL-440

KCL-440 is a CNS-penetrated PARP inhibitor, with an IC50 of 68 nM. KCL-440 has strong inhibition of PARP-1[1][2].

Signaling Pathways >> Epigenetics >> PARP

Research Areas >> Inflammation/Immunology

Research Areas >> Neurological Disease

Signaling Pathways >> Cell Cycle/DNA Damage >> PARP

IC50: 68 nM (PARP)[1].

The brain concentration of KCL-440 is sufficient to inhibit the PARP activity during the intravenous infusion at the rate of 1 mg/kg/h[1]. KCL-440 (over 0.03 mg/kg/h) exhibits neuroprotective effects of KCL-440 in the in vivo cerebral ischemia model[1]. Animal Model: Rat acute cerebral infarction model induced by photothrombotic MCA occlusion[1]. Dosage: 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg/h. Administration: Intravenously administered at a rate of 0.33 ml/kg/h for 24 h immediately aftercerebral ischemia. Result: The serum concentration of KCL-440 approached steadystate levels within 1 h in rats that were intravenously infused at the rate of 1 mg/kg/h for 6 h. One hour after the initiation of infusion, the serum concentration of KCL-440 is 0.11 μg/mL, which is equivalent to 0.37 μM. The brain:serum concentration ratio after a 6-h infusion at 10 mg/kg/h is 0.8. Led to a dose-dependent reduction in the cerebral infarct size at 24 h after the MCA occlusion.

[1]. Yasuhiko Ikeda, et al. Neuroprotective effects of KCL-440, a new poly(ADP-ribose) polymerase inhibitor, in the rat middle cerebral artery occlusion model. Brain Res. 2005 Oct 26;1060(1-2):73-80.

[2]. Tatsushi Kamiya, et al. The neuroprotective effects of a newly synthesized poly (ADP-ribose) polymerase (PARP) inhibitor (KCL-440) on neuronal cell death following transient focal ischemia in rat. Journal of Cerebral Blood Flow & Metabolism. 2005.