An inhibitor of 20-HETE synthesis
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)
Animal experiment: | The studies are performed using 58 male C57BL/6J mice (8 weeks old) weighing 20 to 26 g. TS-011 (0.3 mg/kg) or a vehicle is infused intravenously for 1 h every 6 h in a mouse model of stroke, induced by transient occlusion of the middle cerebral artery occlusion following photothrombosis. The cerebral blood flow velocity and the vascular perfusion area of the peri-infarct microvessels are measured using in vivo two-photon imaging[1]. |
参考文献: [1]. Marumo T, et al. The inhibitor of 20-HETE synthesis, TS-011, improves cerebral microcirculatory autoregulation impaired by middle cerebral artery occlusion in mice. Br J Pharmacol. 2010 Nov;161(6):1391-402. | |
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