Design and Synthesis of Poly ADP-ribose Polymerase-1 Inhibitors. 2. Biological Evaluation of Aza-5[<i>H</i>]-phenanthridin-6-ones as Potent, Aqueous-Soluble Compounds for the Treatment of Ischemic Injuries

Ferraris, Dana; Ko, Yao Sen; Pahutski, Thomas F.; Ficco, Rica Pargas; Serdyuk, L.S.; Alemu, Christina; Bradford, Chadwick; Chiou, Tiffany; Hoover, Randall; Huang, Shirley; Lautar, Susan; Shi, Liang; Lin, Qian; Lu, May; Mooney, Maria Lourdes; Morgan, Lisa; Qian, Yongzhen; Tran, Scott B.; Williams, Lawrence R.; Wu, Qi; Zhang, Jie; Zou, Yinong; Kalish, Vincent J.

doi:10.1021/jm030109s

Cited by 53 publications

(27 citation statements)

References 36 publications

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“…Namely, the amide moiety invariably interacts with the backbone atoms of Gly863, whereas the aromatic portion (benzene ring) interacts, presumably throughinteraction, with Tyr907 (Costantino et al, 2001;Ferraris et al, 2003). Thus, most of the PARP inhibitors contain the moiety of benzamide (Fig.…”

Section: Neuroprotective Profiles Of a New Parp Inhibitor Dr2313 477mentioning

confidence: 99%

“…For the treatment of acute ischemic stroke, a compound should ideally be soluble in aqueous vehicle such as saline and deliverable by bolus injection or infusion. Thus, to develop a new class of PARP inhibitor as a neuroprotectant for stroke, many efforts have been focused on enhancing the potency, improving the pharmacokinetic characteristics, and increasing the water solubility (Abdelkarim et al, 2001;Chiarugi et al, 2003;Ferraris et al, 2003;Komjati et al, 2004;Zhang et al, 2000).…”

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confidence: 99%

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A Newly Synthesized Poly(ADP-Ribose) Polymerase Inhibitor, DR2313 [2-Methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]-pyrimidine-4-one]: Pharmacological Profiles, Neuroprotective Effects, and Therapeutic Time Window in Cerebral Ischemia in Rats

Nakajima

Kakui

Ohkuma

et al. 2004

J Pharmacol Exp Ther

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We investigated the pharmacological profiles of DR2313 [2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidine-4-one], a newly synthesized poly(ADP-ribose) polymerase (PARP) inhibitor, and its neuroprotective effects on ischemic injuries in vitro and in vivo. DR2313 competitively inhibited poly(ADPribosyl)ation in nuclear extracts of rat brain in vitro (K i ϭ 0.23 M). Among several NAD ϩ -utilizing enzymes, DR2313 was specific for PARP but not selective between PARP-1 and PARP-2. DR2313 also showed excellent profiles in water solubility and rat brain penetrability. In in vitro models of cerebral ischemia, exposure to hydrogen peroxide or glutamate induced cell death with overactivation of PARP, and treatment with DR2313 reduced excessive formation of poly(ADP-ribose) and cell death. In both permanent and transient focal ischemia models in rats, pretreatment with DR2313 (10 mg/kg i.v. bolus and 10 mg/kg/h i.v. infusion for 6 h) significantly reduced the cortical infarct volume. To determine the therapeutic time window of neuroprotection by DR2313, the effect of posttreatment was examined in transient focal ischemia model and compared with that of a free radical scavenger, MCI-186 (3-methyl-1-phenyl-2-pyrazolone-5-one). Pretreatment with MCI-186 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. infusion for 6 h) significantly reduced the infarct volume, whereas the posttreatment failed to show any effects. In contrast, posttreatment with DR2313 (same regimen) delaying for 2 h after ischemia still prevented the progression of infarction. These results indicate that DR2313 exerts neuroprotective effects via its potent PARP inhibition, even when the treatment is initiated after ischemia. Thus, a PARP inhibitor like DR2313 may be more useful in treating acute stroke than a free radical scavenger.The excessive release of the excitotoxic amino acid glutamate plays a critical role in the pathogenesis of neuronal cell death following cerebral ischemia. NO produced by nNOS has been implicated in N-methyl-D-asparate (NMDA) receptor-mediated neurotoxicity of glutamate in cerebral ischemia . NMDA receptor activation causes an increase in intracellular calcium concentration leading to activation of nNOS. A part of the neurotoxicity evoked by NO is a result of the reaction of NO with superoxide anion to form a highly toxic radical, peroxynitrite Pieper et al., 1999). Postischemic injury is also exacerbated by the increased formation of hydroxyl radical, the most reactive molecule of all oxygen radicals (Chan, 2001). These reactive oxygen species (ROS) can contribute to the DNA strand breakage, which is followed by overactivation of poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) (Szabo and Dawson, 1998;Pieper et al., 1999).PARP-1 is an abundant nuclear protein which is activated Article, publication date, and citation information can be found at

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Section: Neuroprotective Profiles Of a New Parp Inhibitor Dr2313 477mentioning

confidence: 99%

mentioning

confidence: 99%

A Newly Synthesized Poly(ADP-Ribose) Polymerase Inhibitor, DR2313 [2-Methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]-pyrimidine-4-one]: Pharmacological Profiles, Neuroprotective Effects, and Therapeutic Time Window in Cerebral Ischemia in Rats

Nakajima

Kakui

Ohkuma

et al. 2004

J Pharmacol Exp Ther

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“…GPI-16539 was synthesized and purified as described previously, stored in DMSO in a 10-mM concentration, and diluted to the indicated concentrations in assay buffers. 15 A Wallac VIC-TOR3 fluorescence microplate reader equipped with an injector (PerkinElmer) was used for the fluorescence measurements. The excitation/emission filter pair (485/535 nm) was used in the experiments, with a 0.1-s measuring time per data point.…”

Section: Methodsmentioning

confidence: 99%

Development and Validation of a Cell-Based High-Throughput Screening Assay for TRPM2 Channel Modulators

Song¹,

Buelow²,

Perraud³

et al. 2008

SLAS Discovery

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TRPM2 is a member of the transient receptor potential melastatin (TRPM)-related ion channel family. The activation of TRPM2 induced by oxidative/nitrosative stress leads to an increase in intracellular free Ca 2+. Although further progress in understanding TRPM2's role in cell and organism physiology would be facilitated by isolation of compounds able to specifically modulate its function in primary cells or animal models, no cell-based assays for TRPM2 function well suited for high-throughput screening have yet been described. Here, a novel suspension B lymphocyte cell line stably expressing TRPM2 was used to develop a cellbased assay. The assay uses the Ca 2+ -sensitive fluorescence dye, Fluo-4 NW (no wash), to measure TRPM2-dependent Ca 2+ transients induced by H 2 O 2 and N-methyl-N′-nitrosoguanidine in a 96-well plate format. Assay performance was evaluated by statistical analysis of the Z′ factor value and was consistently greater than 0.5 under optimal conditions, suggesting that the assay is very robust. For assay validation, the effects of known inhibitors of TRPM2 and TRPM2 gating secondary messenger production were determined. Overall, the authors have developed a cell-based assay that may be used to identify TRPM2 ion channel modulators from large compound libraries. (Journal of Biomolecular Screening 2008:54-61)

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“…Early PARP-1 inhibitors were benzamide derivatives, which characterized by low potency and poor selectivity. Subsequently, there are various compounds reported as PARP-1 inhibitors, including imidazobenzodiazepines (21), quinazolinone and quinoxaline derivatives (22), substituted uracil derivatives (23), adenosine substituted isoindolones (24), phthalazinones (25), phenanthridin-6-ones (26), and naphthyridin-6-ones (27). Although some of these PARP-1 inhibitors displayed potent in vitro activity, they lacked specificity and had poor physical properties, complicated synthesis, or in vivo sideeffects.…”

mentioning

confidence: 99%

Molecular Modeling Studies on Benzimidazole Carboxamide Derivatives as PARP‐1 Inhibitors Using 3D‐QSAR and Docking

Zhang¹,

Jang

Zhao

et al. 2011

Chem Biol Drug Des

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Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP-1 inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. To understand the structure-activity correlation of cyclic amine-containing benzimidazole carboxamide-based PARP-1 inhibitors, we have carried out a combined molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling study. Two types of satisfactory substructure-based 3D-QSAR models were built, including the comparative molecular field analysis (CoMFA) model (r 2 , 0.913; q 2 , 0.743) and comparative molecular similarity indices analysis (CoMSIA) model (r 2 , 0.869; q 2 , 0.734), to predict the biologic activity of new compounds. Docking studies were performed to explore the binding mode between all of the inhibitors and the PARP-1 and produce the bioactive conformation of each compound in the whole data set. The docked conformer-based alignment strategy gave the best 3D-QSAR models, CoMFA model (r 2 , 0.899; q 2 , 0.712) and CoMSIA model (r 2 , 0.889; q 2 , 0.744), respectively. The structural insights obtained from both the 3D-QSAR contour maps and molecular docking help to better interpret the structureactivity relationship. The information obtained from molecular modeling studies helped us to predict the activity of new inhibitors and further design some novel and potent PARP-1 enzyme inhibitors.

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Design and Synthesis of Poly ADP-ribose Polymerase-1 Inhibitors. 2. Biological Evaluation of Aza-5[H]-phenanthridin-6-ones as Potent, Aqueous-Soluble Compounds for the Treatment of Ischemic Injuries

Cited by 53 publications

References 36 publications

A Newly Synthesized Poly(ADP-Ribose) Polymerase Inhibitor, DR2313 [2-Methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]-pyrimidine-4-one]: Pharmacological Profiles, Neuroprotective Effects, and Therapeutic Time Window in Cerebral Ischemia in Rats

A Newly Synthesized Poly(ADP-Ribose) Polymerase Inhibitor, DR2313 [2-Methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]-pyrimidine-4-one]: Pharmacological Profiles, Neuroprotective Effects, and Therapeutic Time Window in Cerebral Ischemia in Rats

Development and Validation of a Cell-Based High-Throughput Screening Assay for TRPM2 Channel Modulators

Molecular Modeling Studies on Benzimidazole Carboxamide Derivatives as PARP‐1 Inhibitors Using 3D‐QSAR and Docking

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