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 stroke.

Abstract

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 microM. 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.

• Authors: Noriyuki Miyata, Takayuki Seki, Yu Tanaka, Tomohiro Omura, Kazuo Taniguchi, Mariko Doi, Kagumi Bandou, Shunichi Kametani, Masakazu Sato, Shigeru Okuyama, Liana Cambj-Sapunar, David R Harder, Richard J Roman
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 314 Issue 1 Pg. 77-85 (Jul 2005) ISSN: 0022-3565 [Print] United States
• PMID: 15831442 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Formamides
• Hydroxyeicosatetraenoic Acids
• Isoenzymes
• Morpholines
• N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• Cytochrome P-450 CYP4A
• Collagenases

Topics

• Animals
• Brain (pathology)
• Carotid Arteries
• Cerebral Hemorrhage (chemically induced, drug therapy, physiopathology)
• Cerebral Infarction (pathology)
• Cerebrovascular Circulation (drug effects)
• Collagenases
• Cytochrome P-450 CYP4A (biosynthesis)
• Formamides (pharmacology)
• Hydroxyeicosatetraenoic Acids (antagonists & inhibitors, biosynthesis)
• Infarction, Middle Cerebral Artery (pathology, prevention & control)
• Infusions, Intra-Arterial
• Isoenzymes (antagonists & inhibitors)
• Male
• Morpholines (pharmacology)
• Rats
• Rats, Inbred SHR
• Rats, Sprague-Dawley
• Stroke (drug therapy, physiopathology)