TS-011 is an inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis.1 It inhibits 20-HETE synthesis in human and rat renal microsomes (IC50s = 8.42 and 9.19 nM, respectively), as well as by the cytochrome P450 (CYP) isoforms CYP4F2, CYP4F3A, CYP4F3B, and CYP4A11 in cell-free assays (IC50s = 30.4, 42.6, 43.0, and 188 nM, respectively). It is selective for these CYPs over CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (IC50s = >60 ?M for all), as well as a panel of receptors and other enzymes at 1 ?M. TS-011 (0.01-1 mg/kg, i.v.) reverses decreases in cerebral blood flow and increases in cerebrospinal fluid 20-HETE levels in a rat model of subarachnoid hemorrhage. It also reduces infarct volume and prevents neurological deficits in a rat model of stroke induced by middle cerebral artery occlusion (MCAO).2
1.Miyata, N., Seki, T., Tanaka, Y., et al.Beneficial effects of a new 20-hydroxyeicosatetraenoic acid synthesis inhibitor, TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide], on hemorrhagic and ischemic strokeJ. Pharmacol. Exp. Ther.314(1)77-85(2005) 2.Omura, T., Tanaka, Y., Miyata, N., et al.Effect of a new inhibitor of the synthesis of 20-HETE on cerebral ischemia reperfusion injuryStroke37(5)1307-1313(2006)