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Compounds and methods for cytoprotection

This application is a continuation of U.S. application Ser. No. 11/138,105, filed May 26, 2005 and now allowed, which application claims the benefit of U.S. Provisional Patent Application No. 60/575,162, filed May 27, 2004, which applications are incorporated herein by reference in their entireties.

1. Field of the Invention

The present invention relates generally to novel classes of cytoprotective steroid (cyclopentanophenanthrene-related) compounds, as well as to compositions and methods for using such compounds to treat degenerative disorders including degenerative diseases and related conditions, and in particular, disorders associated with undesirable cell death or cell damage.

2. Description of the Related Art

Numerous degenerative diseases, disorders and conditions afflicting humans and animals are characterized by detrimental damage to tissues and cells, often resulting in undesirably compromised cellular activity and frequently leading to cell death. Recent technological refinements provide insights into a detailed molecular understanding of such cytodegeneration, including, inter alia, appreciation of the roles of: genetic and environmental factors; reactive free radicals (e.g., reactive oxygen species); excitotoxic, autoimmune and inflammatory mechanisms; and characterization of cellular death processes such as apoptosis and necrosis. The scope of degenerative diseases, and their costs to society, are extensive, with massive impacts on the basic quality of life and on human productivity.

Degenerative disorders include a large number of acute, relapsing/remitting and/or chronic debilitating conditions that feature cell death or cellular damage, such as neurological and neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, mild cognitive impairment, etc.), circulatory and cardiac disease (e.g., atherosclerosis, diabetes, ischemia, heart failure, etc.), cancer, autoimmune and inflammatory diseases, inherited genetic diseases and disorders, traumatic injuries, arthritis, metabolic and digestive diseases, ophthalmologic diseases or injuries, dermatological, musculoskeletal, endocrine, renal, hepatic, gastroinstestinal, and respiratory disorders, and many others.

The estrogen steroid hormones (e.g., 17-β-estradiol, estrone) and structurally related derivative compounds have attracted considerable interest as candidate cytoprotectants for use in the treatment of degenerative disorders, and in particular as neuroprotectants, based on a number of chemical and biological properties (see, e.g., U.S. Pat. No. 6,692,763, U.S. Pat. No. 6,511,969, U.S. Pat. No. 6,420,353, U.S. Pat. No. 6,334,998, U.S. Pat. No. 6,333,317, U.S. Pat. No. 6,258,856, U.S. 6,232,326, U.S. Pat. No. 6,172,056, U.S. Pat. No. 6,089,941, U.S. Pat. No. 5,990,177 , U.S. Pat. No. 5,866,561, U.S. Pat. No. 5,521,168, U.S. 5,512,557, U.S. 2004/0067923, WO 03/072109, WO 03/072110, U.S. 2004/0043410, U.S. 2003/0186954, U.S. 2003/0176409, U.S. 2003/0130303, U.S. 2003/0050295, U.S. 2003/0049838, U.S. 2002/0183299, U.S. 2002/0165213, U.S. 2002/0028793, U.S. 2002/0022593, U.S. 2001/0051602, WO 03/015704, U.S. Pat. No. 4,897,389, EP 753,300, U.S. Pat. No. 5,554,603; see also Dykens et al., 2003 Exp. Gerontol. 38(1-2):101-107; Wang et al., 2003 Invest. Ophthalmol Vis. Sci. 44(5):2067-75; Garcia-Segura et al., 2001 Prog. Neurobiol. 63(1):29-60; Deshpande et al., 2000 Ind. J. Physiol Pharmacol. 44(1)43-49; Behl et al., 1995 Biochem. Biophys. Res. Commun. 216:473-82; McCullough et al., 2003 Trends Endocrinol. Metab. 14(5):228-235; Kulkarni et al., 2002 Arch. Women Ment. Health 5:99-104; Zemlyak et al., 2002 Brain Res. 958:272-76; Kompoliti, 2003 Front. Biosci. 8:391-400; Mooradian, 1993 J. Steroid Biochem. Molec. Biol. 45(6):509-511; Kupina et al., 2003 Exp. Neurol 180:55-73).

Despite these efforts, a number of avenues remain unexplored with regard to the relevance of these compounds to particular applications or disease indications, including the relationship of chemical properties to desired biological, physiological and/or pharmacological properties, the relative ease of synthesis (or of isolation in the case of naturally derived estrogen compounds, for which purity and lot-to-lot consistency may also pose challenges), efficacy as cytoprotectants, stability, bioavailability, adaptability to suitable formulations, and other considerations. Recent progress in this area has been described, for example in U.S. Pat. No. 6,844,456, U.S. 2002/0132802, U.S. 2002/0035100, U.S. 5,554,601, U.S. Pat. No. 5,824,672, U.S. Pat. No. 5,843,934, U.S. Pat. No. 5,859,001, U.S. Pat. No. 5,877,169, U.S. 5,939,407, U.S. Pat. No. 5,972,923, U.S. Pat. No. 6,172,088, U.S. Pat. No. 6,197,833, U.S. Pat. No. 6,207,658, U.S. 6,319,914, U.S. Pat. No. 6,326,365, U.S. Pat. No. 6,339,078, U.S. Pat. No. 6,350,739, WO 01/10430, WO 02/13870, U.S. 2003/0105167. Clearly, however, there remains a need for additional compounds that can be optimized for use as cytoprotectants, including demonstration of the suitability of such compounds for use in the treatment of degenerative disorders and diseases in a physiologically relevant context. The present invention addresses this need by providing compositions and methods for therapeutically beneficial cytoprotection, and offers other related advantages.

In brief, this invention is generally directed to compounds that have activity as cytoprotectants, as well as to methods for their use, and to pharmaceutical compositions containing the same. More specifically, the compounds of this invention have the following general structure (I):

including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein R1 and R2 are as defined herein.

The compounds of this invention have utility over a wide range of therapeutic applications, and may be used to treat degenerative disorders, degenerative diseases and related conditions, and in particular, disorders associated with undesirable cell death or cell damage. For example, a number of degenerative disorders and diseases are associated according to non-limiting theory with altered activity of an excitotoxic pathway leading to inappropriate cell death via apoptotic or necrotic processes, such that unexpectedly advantageous cytoprotective properties of compounds described herein may be usefully applied in the management of such conditions. Accordingly, certain embodiments relate to a method for treating a degenerative disorder, comprising administering a therapeutically effective amount of a compound of structure (I) to a subject having or suspected of being at risk for having a degenerative disorder. In certain embodiments the degenerative disorder is selected from (i) a neurodegenerative disorder, (ii) an ophthalmic disease, (iii) a cardiovascular disease, (iv) a disorder of bone, joint, connective tissue or cartilage, (v) a disorder associated with altered activity of an excitotoxic pathway, (vi) tissue transplantation and (vi) a mitochondrial disorder (e.g., Friedreich's ataxia). In another embodiment the degenerative disorder is Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis or multiple sclerosis. In another embodiment the degenerative disorder is an ophthalmic disease that is selected from glaucoma, retinitis pigmentosa, macular degeneration, elevated intraocular pressure and Leber's hereditary optic neuropathy. In another embodiment the degenerative disorder is a cardiovascular disease that is selected from the group consisting of stroke, ischemia and myocardial infarction. In another embodiment the degenerative disorder is a disorder of bone, joint, connective tissue or cartilage that is selected from osteoarthritis, rheumatoid arthritis and psoriatic arthritis.

The methods of this invention include in certain embodiments administering an effective amount of a compound of structure (I) above, preferably in the form of a pharmaceutical composition, to a mammal in need thereof. Thus, in another embodiment, pharmaceutical compositions are disclosed containing one or more compounds of this invention in combination with a pharmaceutically acceptable carrier and/or diluent. In a distinct embodiment the invention provides a pharmaceutical composition comprising (i) a first cytoprotective compound that is a compound of structure (I); (ii) at least one second compound that is selected from an antioxidant, an antiestrogen, a hormone, a mineral, a vitamin, a neuropeptide, a cholesterol-lowering agent, an Alzheimer's disease-treating agent, a stroke-treating agent and a therapeutic antibody; and (iii) a pharmaceutically acceptable carrier. In another embodiment there is provided a method for treating a degenerative disorder, comprising administering, to a subject having or suspected of being at risk for having a degenerative disorder, a therapeutically effective amount of the pharmacutical composition comprising (i), (ii) and (iii) as just described. In another embodiment there is provided a method for treating a degenerative disorder, comprising administering, to a subject having or suspected of being at risk for having a degenerative disorder, a therapeutically effective amount of (i) a first cytoprotective compound that is a compound of structure (I), and (ii) at least one second compound that is selected from an antioxidant, an antiestrogen, a cruciferous indole compound, probucol or an analog of probucol, relaxin hormone, tacrine, a neurotrophin, a statin, melatonin, a sterol or 5-alpha-stanol absorption inhibitor, calcium and vitamin D. In a further embodiment the first cytoprotective compound and the second compound are administered separately, and in a different further embodiment the first cytoprotective compound and the second compound are administered together.

In another embodiment the invention provides a method for isolating a molecular component of an excitotoxic pathway, comprising contacting a biological sample with a compound of structure (I) or a derivative thereof, under conditions and for a time sufficient to permit a binding interaction between the compound and the molecular component, and thereby isolating the pathway component. In certain further embodiments, the compound is immobilized, detectably labeled or retrievably tagged.

These and other aspects of the present invention will become apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference as if set forth in their entirety.