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.
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.
Drug Discovery Division, Korea Research Institute of Chemical Technology, 100 Jang-dong, Yuseong, Daejeon 305-343, Republic of Korea.
Kwang-Seok
KS
Oh
Sunkyung
S
Lee
Kyu Yang
KY
Yi
Ho Won
HW
Seo
Hyun-Na
HN
Koo
Byung Ho
BH
Lee
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000517:prevention & control* / Q000628:therapy; D015425:Myocardial Reperfusion; D010648:Phenylacetates / Q000494:pharmacology* / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C534784:2-(methoxycarbonyl(4-methoxyphenyl)methylsulfanyl)-1H-benzimidazole-4-carboxylic acid amide; D001562:Benzimidazoles; D002316:Cardiotonic Agents; D010648:Phenylacetates; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D006861:Hydrogen Peroxide; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases