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.

Abstract

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.

• Authors: Kwang-Seok Oh, Sunkyung Lee, Kyu Yang Yi, Ho Won Seo, Hyun-Na Koo, Byung Ho Lee
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 328 Issue 1 Pg. 10-8 (Jan 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 18836068 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(methoxycarbonyl(4-methoxyphenyl)methylsulfanyl)-1H-benzimidazole-4-carboxylic acid amide
• Benzimidazoles
• Cardiotonic Agents
• Phenylacetates
• Poly(ADP-ribose) Polymerase Inhibitors
• Hydrogen Peroxide
• Parp1 protein, rat
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases

Topics

• 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) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Rats
• Rats, Sprague-Dawley