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Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP) : A Comparison with Standard PARP Inhibitors

Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP) : A Comparison with Standard PARP Inhibitors

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ELTZE, Tobias, Rainer BOER, Thomas WAGNER, Steffen WEINBRENNER, Michelle C. MCDONALD, Christoph THIEMERMANN, Alexander BÜRKLE, Thomas KLEIN, 2008. Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP) : A Comparison with Standard PARP Inhibitors. In: Molecular Pharmacology. 74(6), pp. 1587-1598. ISSN 0026-895X. eISSN 1521-0111

@article{Eltze2008Imida-1258, title={Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP) : A Comparison with Standard PARP Inhibitors}, year={2008}, doi={10.1124/mol.108.048751}, number={6}, volume={74}, issn={0026-895X}, journal={Molecular Pharmacology}, pages={1587--1598}, author={Eltze, Tobias and Boer, Rainer and Wagner, Thomas and Weinbrenner, Steffen and McDonald, Michelle C. and Thiemermann, Christoph and Bürkle, Alexander and Klein, Thomas} }

Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the Poly(ADP-ribose) Polymerase (PARP) : A Comparison with Standard PARP Inhibitors Wagner, Thomas Publ. in: Molecular Pharmacology 74 (2008), 6, pp. 1587-1598 2011-03-23T09:07:28Z Wagner, Thomas McDonald, Michelle C. We have identified three novel structures for inhibitors of the poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA and implicated in DNA repair, apoptosis, organ dysfunction or necrosis. 2-[4-(5-Methyl-1H-imidazol-4-yl)-piperidin-1-yl]-4,5-dihydro-imidazo[4,5,1-i,j]quinolin-6-one (BYK49187), 2-(4-pyridin-2-yl-phenyl)-4,5-dihydro-imidazo[4,5,1-i,j]quinolin-6-one (BYK236864), 6-chloro-8-hydroxy-2,3-dimethyl-imidazo-[1,2-α]-pyridine (BYK20370), and 4-(1-methyl-1H-pyrrol-2-ylmethylene)-4H-isoquinolin-1,3-dione (BYK204165) inhibited cell-free recombinant human PARP-1 with pIC50 values of 8.36, 7.81, 6.40, and 7.35 (pKi 7.97, 7.43, 5.90, and 7.05), and murine PARP-2 with pIC50 values of 7.50, 7.55, 5.71, and 5.38, respectively. BYK49187, BYK236864, and BYK20370 displayed no selectivity for PARP-1/2, whereas BYK204165 displayed 100-fold selectivity for PARP-1. The IC50 values for inhibition of poly(ADP-ribose) synthesis in human lung epithelial A549 and cervical carcinoma C4I cells as well in rat cardiac myoblast H9c2 cells after PARP activation by H2O2 were highly significantly correlated with those at cell-free PARP-1 (r2 = 0.89-0.96, P < 0.001) but less with those at PARP-2 (r2 = 0.78-0.84, P < 0.01). The infarct size caused by coronary artery occlusion and reperfusion in the anesthetized rat was reduced by 22% (P < 0.05) by treatment with BYK49187 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. during 2-h reperfusion), whereas the weaker PARP inhibitors, BYK236864 and BYK20370, were not cardioprotective. In conclusion, the imidazoquinolinone BYK49187 is a potent inhibitor of human PARP-1 activity in cell-free and cellular assays in vitro and reduces myocardial infarct size in vivo. The isoquinolindione BYK204165 was found to be 100-fold more selective for PARP-1. Thus, both compounds might be novel and valuable tools for investigating PARP-1-mediated effects. 2008 2011-03-23T09:07:28Z Bürkle, Alexander Boer, Rainer Eltze, Tobias Thiemermann, Christoph eng Weinbrenner, Steffen Thiemermann, Christoph deposit-license Bürkle, Alexander McDonald, Michelle C. Klein, Thomas Weinbrenner, Steffen Klein, Thomas Boer, Rainer Eltze, Tobias

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