| A novel and orally active poly(ADP-ribose) polymerase inhibitor, KR-33889 [2-[methoxycarbonyl(4-methoxyphenyl) methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide], attenuates injury in in vitro model of cell death and in vivo model of cardiac ischemia. | |
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MedLine Citation:
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PMID: 18836068 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Blocking of poly(ADP-ribose) polymerase (PARP)-1 has been expected to protect the heart from ischemia-reperfusion injury. We have recently identified a novel and orally active PARP-1 inhibitor, KR-33889 [2-[methoxycarbonyl(4-methoxyphenyl)-methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide], and its major metabolite, KR-34285 [2-[carboxy(4-methoxyphenyl)methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide]. KR-33889 potently inhibited PARP-1 activity with an IC(50) value of 0.52 +/- 0.10 microM. In H9c2 myocardial cells, KR-33889 (0.03-30 microM) showed a resistance to hydrogen peroxide (2 mM)-mediated oxidative insult and significantly attenuated activation of intracellular PARP-1. In anesthetized rats subjected to 30 min of coronary occlusion and 3 h of reperfusion, KR-33889 (0.3-3 mg/kg i.v.) dose-dependently reduced myocardial infarct size. KR-34285, a major metabolite of KR-33889, exerted similar patterns to the parent compound with equi- or weaker potency in the same studies described above. In separate experiments for the therapeutic time window study, KR-33889 (3 mg/kg i.v.) given at preischemia, at reperfusion or in both, in rat models also significantly reduced the myocardial infarction compared with their respective vehicle-treated group. Furthermore, the oral administration of KR-33889 (1-10 mg/kg p.o.) at 1 h before occlusion significantly reduced myocardial injury. The ability of KR-33889 to inhibit PARP in the rat model of ischemic heart was confirmed by immunohistochemical detection of poly(ADP-ribose) activation. These results indicate that the novel PARP inhibitor KR-33889 exerts its cardioprotective effect in in vitro and in vivo studies of myocardial ischemia via potent PARP inhibition and also suggest that KR-33889 could be an attractive therapeutic candidate with oral activity for several cardiovascular disorders, including myocardial infarction. |
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Authors:
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Kwang-Seok Oh; Sunkyung Lee; Kyu Yang Yi; Ho Won Seo; Hyun-Na Koo; Byung Ho Lee |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-10-03 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 328 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2008-12-19 Completed Date: 2009-02-03 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 10-8 Citation Subset: IM |
Affiliation:
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Drug Discovery Division, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yuseong, Daejeon 305-343, Republic of Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Animals Benzimidazoles / chemistry, pharmacology*, therapeutic use Cardiotonic Agents / therapeutic use* Cell Death / drug effects* Cell Line Enzyme Activation / drug effects Hydrogen Peroxide / pharmacology Male Mitochondria, Heart / drug effects, physiology Myocardial Infarction / drug therapy*, prevention & control Myocardial Ischemia / physiopathology, prevention & control*, therapy Myocardial Reperfusion Phenylacetates / pharmacology*, therapeutic use Poly(ADP-ribose) Polymerases / antagonists & inhibitors*, metabolism Rats Rats, Sprague-Dawley |
| Chemical | |
Reg. No./Substance:
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0/2-(methoxycarbonyl(4-methoxyphenyl)methylsulfanyl)-1H-benzimidazole-4-carboxylic acid amide; 0/Benzimidazoles; 0/Cardiotonic Agents; 0/Phenylacetates; 7722-84-1/Hydrogen Peroxide; EC 2.4.2.30/Adprt protein, rat; EC 2.4.2.30/Poly(ADP-ribose) Polymerases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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