RT Journal Article
SR Electronic
T1 Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [<em>N</em>-(3-Chloro-4-morpholin-4-yl) Phenyl-<em>N</em>′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 77
OP 85
DO 10.1124/jpet.105.083964
VO 314
IS 1
A1 Noriyuki Miyata
A1 Takayuki Seki
A1 Yu Tanaka
A1 Tomohiro Omura
A1 Kazuo Taniguchi
A1 Mariko Doi
A1 Kagumi Bandou
A1 Shunichi Kametani
A1 Masakazu Sato
A1 Shigeru Okuyama
A1 Liana Cambj-Sapunar
A1 David R. Harder
A1 Richard J. Roman
YR 2005
UL http://jpet.aspetjournals.org/content/314/1/77.abstract
AB The present study characterized the effects of TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-N′-hydroxyimido formamide], a new selective inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), on the metabolism of arachidonic acid by human and rat renal microsomes and the inhibitory effects of this compound on hepatic cytochrome P450 enzymes involved in drug metabolism. The effects of TS-011 on the fall in cerebral blood flow following subarachnoid hemorrhage (SAH) and in reducing infarct size in ischemic stroke models were also examined since 20-HETE may contribute to the development of cerebral vasospasm. TS-011 inhibited the synthesis of 20-HETE by human renal microsomes and recombinant CYP4A11 and 4F2, 4F3A, and 4F3B enzymes with IC50 values around 10 to 50 nM. It had no effect on the activities of CYP1A, 2C9, 2C19, 2D6, or 3A4 enzymes. TS-011 inhibited the synthesis of 20-HETE by rat renal microsomes with an IC50 of 9.19 nM, and it had no effect on epoxygenase activity at a concentration of 100 μM. TS-011 (0.01–1 mg/kg i.v.) reversed the fall in cerebral blood flow and the increase in 20-HETE levels in the cerebrospinal fluid of rats after SAH. TS-011 also reduced the infarct volume by 35% following transient ischemic stroke and in intracerebral hemorrhage in rats. Injection of 20-HETE (8 or 12 mg/kg) into the carotid artery produced an infarct similar to that seen in the ischemic stroke model. These studies indicate that blockade of the synthesis of 20-HETE with TS-011 opposes cerebral vasospasm following SAH and reduces infarct size in ischemic models of stroke. The American Society for Pharmacology and Experimental Therapeutics