Pharmacological studies on the TXA2 synthetase inhibitor (E)-3-(p-(1H-imidazol-1-ylmethyl)phenyl)-2-propenoic acid (OKY-046).
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概要
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The effects of (<I>E</I>)-3-[<I>p</I>-(1<I>H</I>-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046) on thromboxane A<SUB>2</SUB> (TXA<SUB>2</SUB>) synthetase in vitro and on experimental animal models of sudden death and cerebral infarction were studied. IC50 values of OKY-046 for the TXA<SUB>2</SUB> synthetase of human, rabbit, dog and guinea pig washed platelets were 0.004, 0.004, 0.26 and 2.4 μM, respectively. OKY-046 at concentrations up to 1 mM, however, did not inhibit prostacyclin (PGI<SUB>2</SUB>) synthetase from bovine aorta microsomes or cyclooxygenase and PGE<SUB>2</SUB> isomerase from sheep seminal vesicle microsomes. Similarly, platelet 12-lipoxygenase was not affected by OKY-046. Evidence for a re-direction of arachidonate metabolism from thromboxane synthesis toward PGI<SUB>2</SUB> synthesis was obtained using rat peritoneal cells. Namely, OKY-046 increased PGI<SUB>2</SUB> production accompanied by an inhibition of TXA<SUB>2</SUB> production at a concentration of more than 1 μM. OKY-046 at a dose of 0.1 mg/kg (i.v.) in dogs inhibited the aortic and mesenteric arterial contraction of rabbit induced by the addition of arachidonate to extracorporated blood of the dogs. OKY-046 at a dose of 0.3 mg/kg (i.v.) prevented the arachidonate-induced sudden death and also decreased the incidence of cerebral infarction induced by injection of arachidonate into the internal carotid artery in rabbits. Aspirin also decreased the incidence of cerebral infarction at a dose of 30 mg/kg (i.v.). These results suggest that OKY-046 may be valuable for the treatment of cerebrovascular and cardiovascular diseases associated with vasoconstriction and thrombosis due to TXA<SUB>2</SUB>.
- 公益社団法人 日本薬理学会の論文
著者
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Ujiie Arao
Central Research Laboratories Kissei Pharmaceutical Co. Ltd.
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Hiraku Seiji
Research Institute Ono Pharmaceutical Co. Ltd.
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WAKITANI Korekiyo
Research Institute, Ono Pharmaceutical Co., Ltd.
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MIYAMOTO Tsumoru
Research Institute, Ono Pharmaceutical Co., Ltd.
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TANIGUCHI Ken
Research Institute, Ono Pharmaceutical Co., Ltd.
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OMAWARI Nagashige
Research Institute, Ono Pharmaceutical Co., Ltd.
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KIRA Heizo
Research Institute, Ono Pharmaceutical Co., Ltd.
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OKEGAWA Tadao
Research Institute, Ono Pharmaceutical Co., Ltd.
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KAWASAKI Akiyoshi
Research Institute, Ono Pharmaceutical Co., Ltd.
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