Neuroprotection by polyADPribosepolymerase inhibitors

Poly(ADP-ribose) polymerase-1 (PARP-1) is a chromatin-bound nuclear enzyme involved in a variety of physiological functions related to genomic repair, including DNA replication and repair, cellular proliferation and differentiation, and apoptosis [30]. PARP-1 functions as a DNA damage sensor and signaling molecule. Upon binding to DNA breaks, activated PARP cleaves NAD + , the nicotin-amide, and ADP-ribose and polymerizes the latter into nuclear acceptor proteins including histones, transcription factors and PARP itself. A cellular suicide mechanism of necrosis and apoptosis by PARP activation has been implicated in the pathogenesis of brain injury and neurodegenerative disorders, and PARP inhibitors have been shown to be effective in animal models for stroke, traumatic brain injury and Parkinson's disease [31,32]. Therefore, inhibition of PARP by pharmacological agents may be useful for the therapy of neurodegenerative disorders and several other diseases. In stroke, many studies have demonstrated that PARP inhibitors such as 3-aminobenzamide (7) [33], PJ34 (8) [34] and 3,4-dihydro-5-[4-(1-piperi-dinyl)butoxy]1-(2H)-isoquinoline (9) lead to significant reduction in brain damage and improvement of neurological outcome in a focal cerebral ischemia model. Several PARP inhibitors were advanced in the clinic for the treatment of cerebro-vascular ischemia. Currently, the most advanced compound is INO-1001 (10, IC50< 5 nM), which is being developed by Inotek [35,36]. Results from phase I have confirmed its safety and tolerance. A phase II study with INO-1001 was initiated in late 2003 but no results have been published to date.

F
10, INO-1001

Ono pharmaceuticals has reported the development of ONO-2231, the lead from a series of PARP inhibitors (including ONO-1924H, 11) [37] for the potential intravenous treatment of ischemic stroke. A UK phase I trial on ONO-2331 was underway by May 2005. In November 2004, the company published results showing that ONO-1924H, administered i.v., led to a significant in vivo decrease in cerebral damage in rats with cytotoxicity induced by hydrogen peroxide.

GlaxoSmithKline, under license from the University of Florence, is investigating a series of poly (ADP-ribose) polymerase enzyme inhibitors, including TIQ-A (12) [38], for the potential treatment of cerebrovascular ischemia. In vitro, TIQ-A showed an IC50 value of 0.45 mM for PARP-1 inhibition and displayed significant neuroprotective activity when rat cortical cell cultures were exposed to oxygen and glucose deprivation [38]. In the transient rat model of focal ischemia, administration of TIQ-A (12) (3 and 10mg/kg, i.p.) at 0 and 120 min after the occlusion reduced infarct volume by 40% and 70%, respectively. In a permanent occlusion model, administration of TIQ-A reduced the infarct volume by 35%, 24 h after occlusion [38,39]. Additional compounds that are being investigated for the treatment of cerebrovascular ischemia include GP-6150 (13), which constitutes a prototype of a series of tetracyclic compounds that inhibited PARP activity at IC50 values ranging from 0.046 to 5 mM. GPI 6150 is described as a powerful PARP inhibitor with an IC50 value of 0.15 mM (Ki value of 0.060 mM) [40]. GPI-6150, at 15mg/kg i.p., given 30 min before and 3 h after brain injury induced by fluid percussion, attenuated the size of the lesion without affecting TUNEL-positive apoptotic cells [32]. Several

11, ONO-1924H

compounds from MGI pharma (formerly Guilford) have recently been identified as PARP inhibitors. These include compounds, such as 14, having IC50 values for PARP inhibition in the range of 0.131-40 mM, with one example shown to reduce infarct volume at 10mg/kg i.p. in a rat model using transient middle cerebral artery occlusion [41,42].

13, GP-6150

13, GP-6150

FR247304 (15) is a novel PARP-1 inhibitor that has recently been identified through structure-based drug design [43]. In an enzyme kinetic analysis, FR247304 exhibits potent and competitive inhibition of PARP-1 activity, with a Ki value of 35 nM. In cell death model, treatment with FR247304 (10nM-10 mM) significantly reduced NAD depletion by PARP-1 inhibition and attenuated cell death after exposure to 100 mM hydrogen peroxide. After 90min of middle cerebral artery occlusion in rats, poly(ADP-ribosy)lation and NAD depletion were markedly increased in the cortex and striatum from 1 h after reperfusion. The increased poly(ADP-ribose) immunoreactivity and NAD depletion were attenuated by FR247304 (32mg/kg i.p.) treatment and FR247304 significantly decreased ischemic brain damage measured at 24 h after reperfusion [43]. Other compounds in this class that demonstrated significant neuroprotective properties are FR257516 (16), FR197262 (17) and FR142057 (18) [44-48].

15, FR247304

15, FR247304

16, FR257516

16, FR257516

Cl O

17, FR197262

17, FR197262

18, FR142057

18, FR142057

Despite significant progress in the understanding of the medicinal chemistry and pharmacology of PARP, crucial issues remain to be resolved. In particular, selectivity for PARP-1 over PARP-2 is of utmost importance. Many of the reported compounds in this class are nonselective inhibitors that are potentially mutagenic due to inhibition of PARP-2 [49]. Furthermore, solubility, formulations and brain penetration are key issues that remain to be optimized.

Was this article helpful?

0 0
Your Heart and Nutrition

Your Heart and Nutrition

Prevention is better than a cure. Learn how to cherish your heart by taking the necessary means to keep it pumping healthily and steadily through your life.

Get My Free Ebook


Post a comment