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WO 2008/098160 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date PCT 14 August 2008 (14.08.2008) WO 2008/098160 Al (51) International Patent Classification: (74) Agents: SISTRUNK, Melissa, L. et al; Fulbright & AOlN 45/00 (2006.01) A61K 31/56 (2006.01) Jaworski L.L.P., Fulbright Tower, 1301 Mckinney, Suite 5100, Houston, TX 77010-3095 (US). (21) International Application Number: PCT/US2008/053405 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: 8 February 2008 (08.02.2008) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, (25) Filing Language: English CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, (26) Publication Language: English EG, ES, FT, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, (30) Priority Data: LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, 60/889,065 9 February 2007 (09.02.2007) US MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, 60/950,170 17 July 2007 (17.07.2007) US PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, (71) Applicant (for all designated States except US): UNIVER¬ SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, SITY OF MARYLAND, BALTIMORE [US/US]; 520 ZA, ZM, ZW West Lombard Street, Baltimore, MD 21201 (US). (84) Designated States (unless otherwise indicated, for every (72) Inventors; and kind of regional protection available): ARIPO (BW, GH, (75) Inventors/Applicants (for US only): SIMARD, J., Marc GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, [US/US]; 5223 Springlake Way, Baltimore, MD 21212- ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), 3421 (US). GERZANICH, Vladimir [US/US] ;4 11 Chad- European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, ford Rd, Baltimore, MD 21212 (US). FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,MC, MT, NL, [Continued on next page] (54) Title: ANTAGONISTS OF A NON-SELECTIVE CATION CHANNEL IN NEURAL CELLS (57) Abstract: The present invention is directed to a combination of ther apeutic compounds and treatment methods and kits using the combina tion. In particular, one of the combination affects the NCca- ATP channel of neural tissue, including neurons, glia and blood vessels within the ner vous system. Exemplary SURl and/or TRPM4 antagonists that inhibit the NCca- ATP channel may be employed in the combination. The combina tion therapy also employs one or more of a non-selective cation channel blocker and/or an antagonist of VEFG, NOS, MMP, or thrombin. E x emplary indications for the combination therapy includes the prevention, diminution, and/or treatment of injured or diseased neural tissue, includ ing astrocytes, neurons and capillary endothelial cells, that is due to is chemia, tissue trauma, brain swelling and increased tissue pressure, or other forms of brain or spinal cord disease or injury, for example. In other embodiments, there are methods and compositions directed to antagonists of TRPM4, including at least for therapeutic treatment of traumatic brain injury, cerebral ischemia, central nervous system (CNS) damage, periph eral nervous system (PNS) damage, cerebral hypoxia, or edema, for ex ample. FIG. 1 NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, before the expiration of the time limit for amending the CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). claims and to be republished in the event of receipt of amendments with sequence listing part of description published sep a Published: rately in electronic form and available upon request from ANTAGONISTS OF A NON-SELECTIVE CATION CHANNEL IN NEURAL CELLS [0001] The present application claims priority to U.S. Provisional Patent Application Serial No. 60/889,065, filed February 9, 2007, and U.S. Provisional Patent Application Serial No. 60/950,170, filed on July 17, 2007, both of which applications are incorporated by reference herein in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] This invention was made with government support under Grant No. NS048260 awarded by the National Institutes of Health, a grant awarded by the Heart Lung and Blood Institute (HL051932; HL082517); a Merit Review grant from the United States Department of Veterans Affairs; and a grant from the National Institute of Neurological Disorders and Stroke (NS048260). The United States Government has certain rights in the invention. FIELD OF THE INVENTION [0003] The present invention generally regards at least the fields of cell biology, molecular biology, neurophysiology, and medicine. In particular, the present invention relates to a novel non-selective monovalent cationic ATP-sensitive ion channel (hereinafter referred to as the NCca-ATP channel) that is coupled to sulfonylurea receptor type 1 in neural cells, including astrocytes, neurons and neural endothelial cells, for example. Specifically, the present invention relates to singular and combination therapy employing compounds and treatments that modulate NCca-ATP channel activity, and also relates to kits including compounds useful for treatment of disease or injury conditions, such as stroke or brain trauma, for example. BACKGROUND OF THE INVENTION [0004] Injury to the nervous system has serious consequences. Following traumatic brain injury and stroke, for example, the normal response of the surrounding brain is to mount a cellular response that includes formation of reactive astrocytes that are believed to be important to "contain" and "clean-up" the injury site. Swelling of neural cells is part of the cytotoxic or cell swelling response that characterizes brain damage in cerebral ischemia and traumatic brain injury, and is a major cause of morbidity and mortality. See, Staub et al., 1993; Kimelberg et al., 1995. A number of mediators have been identified that initiate swelling of neural cells, including elevation of extracellular K+, acidosis, release of neurotransmitters and free fatty acids. See, Kempski et al, 1991; Rutledge and Kimelberg, 1996; Mongin et al, 1999. Cytotoxic edema is a well-recognized phenomenon clinically that causes brain swelling, which worsens outcome and increases morbidity and mortality in brain injury and stroke. Spinal cord injury - the clinical problem [0005] Acute spinal cord injury (SCI) results in physical disruption of spinal cord neurons and axons leading to deficits in motor, sensory, and autonomic function. This is a debilitating neurological disorder common in young adults that often requires life-long therapy and rehabilitative care, placing a significant burden on healthcare systems. The fact that SCI impacts mostly young people makes the tragedy all the more horrific, and the cost to society in terms of lost "person-years" all the more enormous. Sadly, many patients exhibit neuropathologically and clinically complete cord injuries following SCI. However, many others have neuropathologically incomplete lesions (Hayes and Kakulas, 1997; Tator and Fehlings, 1991). giving hope that proper treatment to minimize secondary injury may reduce the functional impact. Secondary injury - progressive hemorrhagic necrosis (PHN) [0006] The concept of secondary injury in SCI arises from the observation that the volume of injured tissue increases with time after injury, i.e., the lesion itself expands and evolves over time. Whereas primary injured tissues are irrevocably damaged from the very beginning, right after impact, tissues that are destined to become "secondarily" injured are considered to be potentially salvageable. Secondary injury in SCI has been reviewed in a classic paper by Tator (1991), as well as in more recent reviews (Kwon et al, 2004), wherein the overall concept of secondary injury is validated. Older observations based on histological studies that gave rise to the concept of lesion-evolution have been confirmed with non-invasive MRI (Bilgen et al, 2000; Ohta et al, 1999; Sasaki et al, 1978; Weirich et al, 1990). [0007] Numerous mechanisms of secondary injury are recognized, including edema, ischemia, oxidative stress and inflammation. In SCI, however, one pathological entity in particular is recognized that is relatively unique to the spinal cord and that has especially devastating consequences - progressive hemorrhagic necrosis (PHN) (Fitch et al, 1999; Kraus, 1996; Nelson et al, 1977; Tator, 1991; Tator and Fehlings, 1991; Tator and Koyanagi, 1997). [0008] PHN is a rather mysterious condition, first recognized over 3 decades ago, that has thus far eluded understanding and treatment. Following impact, petechial hemorrhages form in surrounding tissues and later emerge in more distant tissues, eventually coalescing into the characteristic lesion of hemorrhagic necrosis. The specific time course and magnitude of these changes remain to be determined, but papers by Khan et al (1985) and Kawata et al (1993) nicely describe the progressive increase in hemorrhage in the cord. After injury, a small hemorrhagic lesion involving primarily the capillary-rich central gray matter is observed at 15 min, but hemorrhage, necrosis and edema in the central gray matter enlarge progressively over a period of 3-24 h (Balentine, 1978; Iizuka et al, 1987; Kawata et al, 1993). The white matter surrounding the hemorrhagic gray matter shows a variety of abnormalities, including decreased H&E staining, disrupted myelin, and axonal and periaxonal swelling. Tator and Koyanagi (1997) noted that white matter lesions extend far from the injury site, especially in the posterior columns. The evolution of hemorrhage and necrosis has been referred to as "autodestruction", and it is this that forms the key observation that defines PHN. PHN eventually causes loss of vital spinal cord tissue and, in some species including humans, leads to post-traumatic cystic cavitation surrounded by glial scar tissue. Mechanisms of delayed hemorrhage and PHN [0009] Tator and Koyanagi (1997) expressed the view that obstruction of small intramedullary vessels by the initial mechanical stress or secondary injury may be responsible for PHN.
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