Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-04-10
2003-10-21
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C544S386000, C544S387000, C514S255030, C514S617000, C514S621000
Reexamination Certificate
active
06635786
ABSTRACT:
The invention is directed to symmetrically disubstituted aromatic compounds and pharmaceutical compositions containing such compounds that inhibit and/or modulate the activity of poly(ADP-ribose) glycohydrolase, also known as PARG. The invention is also directed to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating diseases and disorders described herein, by administering effective amounts of such compounds.
A major focus of current biomedical research is on the mechanisms of cell death as new specific therapeutic agents that modulate these processes continue to be developed. Cell death is generally separated into two categories: apoptosis and necrosis. Apoptosis, commonly termed programmed cell death, is a genetically controlled process that follows physiologic stimuli in individual cells and typically involves ruffling of the cell membrane, nuclear and cytoplasmic condensation, intranucleosomal cleavage of DNA, and eventual phagocytosis of the cell without significant inflammation. Necrosis is a more rapid and severe process that occurs in groups of cells in response to pathologic injury. This mode of cell death is characterized by swelling of mitochondria and endoplasmic reticulum followed by a loss of membrane integrity and random destruction of DNA and other macromolecules culminating in substantial inflammatory response.
Although the vast majority of cell death literature suggests that all instances of cell death can be classified as apoptosis or necrosis, aspects of both mechanisms exist in a variety of cell death paradigms. To design rational therapeutic approaches to cell death, researchers should probably consider individual disease paradigms as occupying unique positions somewhere on a continuum between the extremes of apoptosis and necrosis.
The DNA repair enzyme poly (ADP-ribose) polymerase (PARP) has emerged as a major player along the continuum of cell death. When activated by DNA damage, PARP becomes the major consumer of NAD (&bgr;-nicotinamide adenine dinucleotide). Extensive PARP activation leads to severe depletion of NAD in cells suffering from massive DNA damage. Depletion of NAD, an important co-enzyme in energy metabolism, results in lower ATP production. As the cell consumes ATP in an effort to re-synthesize NAD, this energy crisis culminates in cell death.
After its activation by DNA strand breaks, PARP is believed to bind to damaged DNA and catalyze the synthesis and addition of long, branched chains of poly (ADP-ribose) (PAR) to a variety of nuclear proteins, including PARP itself, using NAD as substrate. PAR that is synthesized in response to massive DNA damage has a short half-life close to one minute as it is rapidly hydrolyzed at ribose-ribose bonds and converted to free ADP-ribose by poly(ADP-ribose) glycohydrolase (PARG), together with phosphodiesterase and (ADP-ribose) protein lyase. Alvarez-Gonzalez et al.,
Mutat. Res.,
218, 67-74 (1989); Wielckens et al.,
J. Biol. Chem.,
257, 12872 (1983). PARP and PARG constitute a cycle that converts a large amount of NAD to ADP-ribose. PARG is about 13- to 50-fold less abundant than PARP, but its specific catalytic activity is about 50- to 70-fold times higher so that there are no kinetic constraints in its ability to cope with large amount of PAR formed by PARP. Hatakeyama et al.,
J. Biol. Chem.,
261, 14902-14911 (1986). The rapid response of PARG to PAR synthesis indicates that PAR degradation is also an important nuclear response to DNA damage.
In less than an hour, overstimulation of PARP can cause a drop of NAD and ATP to less than 20% of the normal level. Berger,
Radiat. Res.,
101, 4 (1985). Such a scenario is especially detrimental during ischemia when deprivation of oxygen has already drastically compromised cellular energy output. Calcium overload and subsequent free radical production during reperfusion are assumed to be a major cause of tissue damage. Part of the ATP drop, which is typical during ischemia and reperfusion, could be linked to NAD depletion due to poly(ADP-ribose) turnover. Endres et al.,
J. Cereb. Blood Flow Metab.,
17, 1143 (1997). Thus, by maintaining cellular NAD level, PARP inhibitors have therapeutic potential to rescue cells from ischemia and other oxidative stress. Preserving cellular energy level appears to be the main effect that PARP inhibitors exhibit in reducing necrotic cell death.
The conversion of PAR to free ADP-ribose by PARG could further promote PARP activity by providing additional substrate (ADP-ribose) for PARP and additional targets for poly(ADP-ribosyl)ation (sites where PARG has cleaved away ADP-ribose units). The activation of PARG thereby promotes the PARP-induced depletion of cellular energy, increased cell damage and cell death associated with the diseases and disorders linked to PARP activity. The rapid activation of PARG in response to PAR synthesis and PARP activation indicates that PAR degradation via PARG should promote the disorders and diseases associated with PARP activity. Although this is believed to be the mode of action, other mechanisms of action may be responsible for, or contribute to, the usefulness of PARG inhibitors including methods for treating or preventing the disorders or diseases described herein.
Accordingly, PARG inhibitors should be useful in down-regulating PARP by decreasing substrate and targets for PARP activity, and thus PARG inhibitors are useful for treating disorders and diseases associated with PARP activity. PARG inhibitors should be useful for any methods and therapies where the use of PARP inhibitors are utilized. See Ha,
Neurobiology of Disease,
7, 225-239 (2000); Swanson et al.,
NeuroReport,
11, 1385-1388 (2000) (reporting results that “provide the first evidence that PARG inhibitors could be used to prevent oxidative cell death.”).
Diseases implicated by PARP activation and the use of PARP inhibitors are known. For example, it has been reported that PARP activation plays a key role in both NMDA- and NO-induced neurotoxicity. See, e.g., Zhang et al.,
Science,
263, 687-689 (1994); Wallis,
NeuroReport,
5, 245-248 (1993). The potential role of PARP inhibitors in treating neurodegenerative diseases and head trauma has been reported. See, e.g., Whalen et al.,
J. Cereb. Blood Flow Metabol.,
835-842 (1999); Endres et al.,
J. Cereb. Blood Flow Metabol.,
17, 1143-1151 (1997); Wallis et al.,
Brain Res.,
710, 169-177 (1996). It has been demonstrated that single injections of PARP inhibitors (3-aminobenzamide and 1,5-dihydroxyisoquinoline) have reduced the infarct size caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits. Thiemermann et al.,
Proc. Natl. Acad. Sci. USA,
94, 679-683 (1997). PARP inhibitors are also proposed to play a role in the intestinal injury, cardiovascular failure, and multiple organ damage associated with resuscitated hemorrhagic shock. See, e.g., Liaudet et al.,
Proc. Natl. Acad. Sci.,
97, 10203-10208 (2000); Liaudet et al.,
Shock,
14, 134-141 (2000); McDonald et al.,
Br. J. Pharm.,
130, 843-850 (2000).
PARP activation has also been shown to provide an index following neurotoxic insults by glutamate (via NMDA receptor stimulation), reactive oxygen intermediates, amyloid &bgr;-protein, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite N-methyl-4-phenylpyridine (MPP+), which participate in pathological conditions such as epilepsy, stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, schizophrenia, chronic pain, ischemia, and neuronal loss following hypoxia, hypoglycemia, ischemia, trauma, and nervous insult. See, e.g., U.S. Pat. No. 5,587,384 (using PARP inhibitors benzamide and 1,5-dihydroxy-isoquinoline to prevent NMDA-mediated neurotoxicity, and thus to treat stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease); WIPO International Publication Nos. WO 00/68206, 00/64878, 00/32579, and 00/67734 (using benzimidazole and phthalazine derivatives as inhibitors
Ferraris Dana Victor
Kletzly Paul W.
Li Jia-He
Li Weixing
Wang Eric Yanjun
Guilford Pharmaceuticals Inc.
Killos Paul J.
Merchant & Gould
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