Tricyclic inhibitors of poly(ADP-ribose) polymerases

Details Tricyclic inhibitors of poly(ADP-ribose) polymerases Tricyclic inhibitors of poly(ADP-ribose) polymerases

2000-08-31

2003-04-15

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S496000, C540S499000

Reexamination Certificate

active

06548494

ABSTRACT:

FIELD OF THE INVENTION
The invention pertains to compounds that inhibit poly(ADP-ribose) polymerases, thereby retarding the repair of damaged DNA strands, and to methods of preparing such compounds. The invention also relates to the use of such compounds in pharmaceutical compositions and therapeutic treatments useful for potentiation of anti-cancer therapies, inhibition of neurotoxicity consequent to stroke, head trauma, and neurodegenerative diseases, and prevention of insulin-dependent diabetes.
BACKGROUND OF THE INVENTION
Poly(ADP-ribose) polymerases (PARPs), nuclear enzymes found in almost all eukaryotic cells, catalyze the transfer of ADP-ribose units from nicotinamide adenine dinucleotide (NAD
+
) to nuclear acceptor proteins, and are responsible for the formation of protein-bound linear and branched homo-ADP-ribose polymers. Activation of PARP and resultant formation of poly(ADP-ribose) are induced by DNA strand breaks, e.g., after exposure to chemotherapy, ionizing radiation, oxygen free radicals, or nitric oxide (NO). The acceptor proteins of poly(ADP-ribose), including histones, topoisomerases, DNA and RNA polymerases, DNA ligases, and Ca
2+
- and Mg
2+
-dependent endonucleases, are involved in maintaining DNA integrity.
Because this cellular ADP-ribose transfer process is associated with the repair of DNA strand breakage in response to DNA damage caused by radiotherapy or chemotherapy, it can contribute to the resistance that often develops to various types of cancer therapies. Consequently, inhibition of PARP may retard intracellular DNA repair and enhance the antitumor effects of cancer therapy. Indeed, in vitro and in vivo data show that many PARP inhibitors potentiate the effects of ionizing radiation or cytotoxic drugs such as DNA methylating agents. Thus, inhibitors of the PARP enzyme are useful as adjunct cancer chemotherapeutics.
PARP inhibitors are additionally useful in therapy of cardiovascular diseases. Ischemia, a deficiency of oxygen and glucose in a part of the body, can be caused by an obstruction in the blood vessel supplying that area or a massive hemorrhage. Two severe forms, heart attack and stroke, are major killers in the developed world. Cell death results directly and also occurs when the deprived area is reperfused. PARP inhibitors are being developed to treat ischemia/reperfusion injuries. See, e.g., Zhang, “PARP inhibition: a novel approach to treat ischemia/reperfusion and inflammation-related injuries,”
Emerging Drugs: The Prospect for Improved Medicines
(1999), Ashley Publications Ltd. Inhibition of PARP has been shown to protect against myocardial ischemia and reperfusion injury (Zingarelli et al., “Protection against myocardial ischemia and reperfusion injury by 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase,”
Cardiovascular Research
(1997), 36:205-215).
Inhibitors of the PARP enzyme are also useful inhibitors of neurotoxicity consequent to stroke, head trauma, and neurodegenerative diseases. After brain ischemia, the distribution of cells with accumulation of poly(ADP-ribose), that is, the areas where PARP was activated, correspond to the regions of ischemic damage (Love et al., “Neuronal accumulation of poly(ADP-ribose) after brain ischaemia,”
Neuropathology and Applied Neurobiology
(1999), 25:98-103). It has been shown that inhibition of PARP promotes resistance to brain injury after stroke (Endres et al., “Ischemic Brain Injury is Mediated by the Activation of Poly(ADP-Ribose)Polymerase,”
J. Cerebral Blood Flow Metab
. (1997), 17:1143-1151; Zhang, “PARP Inhibition Results in Substantial Neuroprotection in Cerebral Ischemia,”
Cambridge Healthtech Institute's Conference on Acute Neuronal Injury: New Therapeutic Opportunities
, Sep. 18-24, 1998, Las Vegas, Nev.).
The activation of PARP by DNA damage is believed to play a role in the cell death consequent to head trauma and neurodegenerative diseases, as well as stroke. DNA is damaged by excessive amounts of NO produced when the NO synthase enzyme is activated as a result of a series of events initiated by the release of the neurotransmitter glutamate from depolarized nerve terminals (Cosi et al., “Poly(ADP-Ribose) Polymerase Revisited: A New Role for an Old Enzyme: PARP Involvement in Neurodegeneration and PARP Inhibitors as Possible Neuroprotective Agents,”
Ann. N.Y. Acad. Sci
. (1997), 825:366-379). Cell death is believed to occur as a result of energy depletion as NAD
+
is consumed by the enzyme-catalyzed PARP reaction.
Parkinson's disease is an example of a neurodegenerative condition whose progression may be prevented by PARP inhibition. Mandir et al. have demonstrated that mice that lack the gene for PARP are “dramatically spared” from the effects of exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that causes parkinsonism in humans and animals (Mandir et al., “Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism,”
Proc. Natl. Acad. Sci. USA
(1999), 96:5774-5779). MPTP potently activates PARP exclusively in dopamine-containing neurons of the substantia nigra, the part of the brain whose degeneration is associated with development of parkinsonism. Hence, potent PARP inhibitors may slow the onset and development of this crippling condition.
Furthermore, inhibition of PARP should be a useful approach for treatment of conditions or diseases associated with cellular senescence, such as skin aging, through the role of PARP in the signaling of DNA damage. See, e.g., U.S. Pat. No. 5,589,483.
PARP inhibition is also being studied at the clinical level to prevent development of insulin-dependent diabetes mellitus in susceptible individuals (Saldeen et al., “Nicotinamide-induced apoptosis in insulin producing cells in associated with cleavage of poly(ADP-ribose) polymerase,”
Mol. Cellular Endocrinol
. (1998), 139:99-107). In models of Type I diabetes induced by toxins such as streptozocin and alloxan that destroy pancreatic islet cells, it has been shown that knock-out mice lacking PARP are resistant to cell destruction and diabetes development (Pieper et al., “Poly (ADP-ribose) polymerase, nitric oxide, and cell death,”
Trends Pharmacolog. Sci
. (1999), 20:171-181; Burkart et al., “Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin,”
Nature Medicine
(1999), 5:314-319). Administration of nicotinamide, a weak PARP inhibitor and a free-radical scavenger, prevents development of diabetes in a spontaneous autoimmune diabetes model, the non-obese, diabetic mouse (Pieper et al., ibid.). Hence, potent and specific PARP inhibitors may be useful as diabetes-prevention therapeutics.
PARP inhibition is also an approach for treating inflammatory conditions such as arthritis (Szabo et al., “Protective effect of an inhibitor of poly(ADP-ribose) synthetase in collagen-induced arthritis,”
Portland Press Proc
. (1998), 15:280-281; Szabo, “Role of Poly(ADP-ribose) Synthetase in Inflammation,”
Eur. J. Biochem
. (1998), 350(1):1-19; Szabo et al., “Protection Against Peroxynitrite-induced Fibroblast Injury and Arthritis Development by Inhibition of Poly(ADP-ribose) Synthetase,”
Proc. Natl. Acad. Sci. USA
(1998), 95(7):3867-72).
The PARP family of enzymes is extensive. It has recently been shown that tankyrases, which bind to the telomeric protein TRF-1, a negative regulator of telomere length maintenance, have a catalytic domain that is strikingly homologous to PARP and have been shown to have PARP activity in vitro. It has been proposed that telomere function in human cells is regulated by poly(ADP-ribosyl)ation. PARP inhibitors have utility as tools to study this function. Further, as a consequence of regulation of telomerase activity by tankyrase, PARP inhibitors should have utility as agents for regulation of cell life-span, e.g., for use in cancer therapy to shorten the life-span of tumor cells, or as anti-aging therapeutics, since telomere lengt

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