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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.
Mol Pharmacol. 2008 Dec; 74(6):1587-98.MP

Abstract

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-alpha]-pyridine (BYK20370), and 4-(1-methyl-1H-pyrrol-2-ylmethylene)-4H-isoquinolin-1,3-dione (BYK204165) inhibited cell-free recombinant human PARP-1 with pIC(50) values of 8.36, 7.81, 6.40, and 7.35 (pK(i) 7.97, 7.43, 5.90, and 7.05), and murine PARP-2 with pIC(50) 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 IC(50) 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 H(2)O(2) were highly significantly correlated with those at cell-free PARP-1 (r(2) = 0.89-0.96, P < 0.001) but less with those at PARP-2 (r(2) = 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.

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Authors+Show Affiliations

Eltze T
University of Konstanz, Germany.
Boer R
No affiliation info available
Wagner T
No affiliation info available
Weinbrenner S
No affiliation info available
McDonald MC
No affiliation info available
Thiemermann C
No affiliation info available
Bürkle A
No affiliation info available
Klein T
No affiliation info available

MeSH

AnimalsCell LineCell Line, TumorFibroblastsHumansImidazolesIsoquinolinesKineticsMaleMiceMyocardial InfarctionMyocardial Reperfusion InjuryMyocardiumPoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesPyridinesQuinolonesRatsRats, WistarRecombinant ProteinsSolubilityStructure-Activity Relationship

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

18809672

Citation

Eltze, Tobias, et al. "Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the poly(ADP-ribose) Polymerase (PARP): a Comparison With Standard PARP Inhibitors." Molecular Pharmacology, vol. 74, no. 6, 2008, pp. 1587-98.
Eltze T, Boer R, Wagner T, et al. Imidazoquinolinone, imidazopyridine, and isoquinolindione derivatives as novel and potent inhibitors of the poly(ADP-ribose) polymerase (PARP): a comparison with standard PARP inhibitors. Mol Pharmacol. 2008;74(6):1587-98.
Eltze, T., Boer, R., Wagner, T., Weinbrenner, S., McDonald, M. C., Thiemermann, C., Bürkle, A., & Klein, T. (2008). Imidazoquinolinone, imidazopyridine, and isoquinolindione derivatives as novel and potent inhibitors of the poly(ADP-ribose) polymerase (PARP): a comparison with standard PARP inhibitors. Molecular Pharmacology, 74(6), 1587-98. https://doi.org/10.1124/mol.108.048751
Eltze T, et al. Imidazoquinolinone, Imidazopyridine, and Isoquinolindione Derivatives as Novel and Potent Inhibitors of the poly(ADP-ribose) Polymerase (PARP): a Comparison With Standard PARP Inhibitors. Mol Pharmacol. 2008;74(6):1587-98. PubMed PMID: 18809672.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Imidazoquinolinone, imidazopyridine, and isoquinolindione derivatives as novel and potent inhibitors of the poly(ADP-ribose) polymerase (PARP): a comparison with standard PARP inhibitors. AU - Eltze,Tobias, AU - Boer,Rainer, AU - Wagner,Thomas, AU - Weinbrenner,Steffen, AU - McDonald,Michelle C, AU - Thiemermann,Christoph, AU - Bürkle,Alexander, AU - Klein,Thomas, Y1 - 2008/09/22/ PY - 2008/9/24/pubmed PY - 2008/12/17/medline PY - 2008/9/24/entrez SP - 1587 EP - 98 JF - Molecular pharmacology JO - Mol Pharmacol VL - 74 IS - 6 N2 - 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-alpha]-pyridine (BYK20370), and 4-(1-methyl-1H-pyrrol-2-ylmethylene)-4H-isoquinolin-1,3-dione (BYK204165) inhibited cell-free recombinant human PARP-1 with pIC(50) values of 8.36, 7.81, 6.40, and 7.35 (pK(i) 7.97, 7.43, 5.90, and 7.05), and murine PARP-2 with pIC(50) 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 IC(50) 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 H(2)O(2) were highly significantly correlated with those at cell-free PARP-1 (r(2) = 0.89-0.96, P < 0.001) but less with those at PARP-2 (r(2) = 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. SN - 1521-0111 UR - https://www.unboundmedicine.com/medline/citation/18809672/Imidazoquinolinone_imidazopyridine_and_isoquinolindione_derivatives_as_novel_and_potent_inhibitors_of_the_poly_ADP_ribose__polymerase__PARP_:_a_comparison_with_standard_PARP_inhibitors_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=18809672 DB - PRIME DP - Unbound Medicine ER -