Antiproliferative and neurotrophic molecules

Details Antiproliferative and neurotrophic molecules Antiproliferative and neurotrophic molecules

1999-02-08

2002-04-23

Jones, Dwayne C. (Department: 1614)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S493000, C562S495000, C562S606000, C562S512200

Reissue Patent

active

RE037670

ABSTRACT:

FIELD OF THE INVENTION
This invention provides methods and compositions useful for the prevention and/or treatment of neurodegenerative and proliferative diseases. The compositions of the invention promote neuronal cell maturation and retard their proliferation. In particular, this invention relates to nonprotein neurotrophic molecules capable of passing the blood brain barrier to provide therapeutic effects.
BACKGROUND
Proper function of the nervous system requires the maturation and maintenance of neuronal cells. In addition, the establishment of proper synaptic connections allows for the communication between different neurons. Defects in the survival of neurons, or the ability to maintain synaptic connections is associated with neurodegenerative disorders including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, stroke and degeneration of neurons due to diabetic neuropathy and trauma.
Many of the neurodegenerative disorders are associated with the loss or degeneration of a particular class of neuronal cells. For example, in Parkinson's disease dopaminergic neurons of the substantia nigra degenerate. Whereas ALS is associated with the loss of motor neurons. Wernicke-Korsakoff syndrome, commonly associated with chronic alcoholism, causes amnesia due to damage to the mammillary bodies and medial dorsal nucleus of the thalamus. Butters N., Seminar Neurol. (1984) 4:226-244. Alzheimer's disease appears to be associated with the degeneration of certain cholinergic neurons. The severance of axons as a result of trauma may cause retrograde degeneration and neuronal death.
The association between neurodegeneration and the development of disease has prompted the search for neurotrophic agents capable of retarding, preventing, or reversing such neurodegeneration. To date, much emphasis in this area has focused on the identification and characterization of neurotrophic polypeptides. For example, attention has been given to studying the effects of nerve growth factor (NFG), ciliary neurotrophic factor (CNTF), brain drive neurotrophic factor (BDNF) and others. The general neurotrophic effect of CNTF and, in particular, its trophic action on motor neurons has led to its investigation as a useful agent in the treatment of ALS and other neurodegenerative disorders. See, for example, Collins et al. U.S. Pat. No. 5,141,856 and Masiakowski WO 91/04316 which are incorporated herein by reference. NGF which has been shown to promote neuronal outgrowth from central cholinergic neurons has been suggested as a useful agent in the treatment of Alzheimer's disease. Most of the neurotrophic polypeptides identified to date are active on relatively restricted populations of neuronal cells. Whereas others such as CNTF are active on a greater number of neuronal cell types.
It has generally been observed that agents which induce maturation or differentiation of neuronal cells in culture, also inhibit their proliferation. Normal proliferating embryonic precursors to sympathetic and sensory neurons are induced to mature and stop dividing in the presence of certain growth factors such as NGF. The association between neuronal maturation or differentiation and anti-mitotic action has also been observed for certain neoplastic cells which are responsive to neurotrophic factors. For example, rat pheochromocytoma, PC12, cells in the presence of NGF develop long neurites and stop dividing. Green LA and Tischler AS, Proc. Natl. Acad. Sci. USA (1976) 72:2424-2428. Similar effects have been observed with other neuronal cells.
Cells in the nervous system give rise to a variety of potentially fatal neoplastic diseases. For example, neuroblastoma and pheochromocytoma are believed to arise from cells having an origin in the neural crest. Non-neuronal cells of the nervous system including glial cells, astrocytes and Schwann cells also give rise to different types of tumors. Most present agents used for chemotherapy involving neuronal cells are cytotoxic and have relatively poor specificity and penetrability. Treatment of neoplastic disease through agents causing maturation has been a long sought for goal. Aaronson, S. A. Science (1991) 254:1146-1153.
Although neurotrophic polypeptides may eventually prove useful for treating certain neurodegenerative, and proliferative disorders, they are characterized by poor bio-availability resulting from their relatively large size making them resistant to passing through the blood brain barrier. This poor penetration into the relevant target tissue raises substantial difficulties in their use for treating neurodegenerative disorders and neoplastic disease of the central nervous system.
The anticonvulsant sodium valproate (VPA) is a branched chain carboxylic acid effective in the treatment of primary generalized seizures, especially those of the absence type. Pinder, R. M. et al., Drugs (1977) 13:81-12. Recently, VPA has been reported to be a teratogen and has been suggested as potentially causing neural tube defects in 1% to 2% of exposed fetuses (Robert E. and Rosa F. W., “Maternal valproic acid and neural tube defects,” Lancet (1982) 2:937). In addition, a number of other defects are also induced by valproic acid treatment during pregnancy (Nau et al. J. Pharmacol. Exp. Ther. (1981) 219:768-777. Spina bifida aperta, a most serious birth defect, can now also be induced by valproic acid in an animal model (Ehlers et al., 1992 a,b). Like the neurotrophic polypeptides, valproic acid also shows very limited transfer into the central nervous system of the human (Löscher et al., Epilepsia (1988) 29:311-316). For reviews of clinical and experimental valproic acid teratogenesis. cf. Nau et al., Pharmacol. Toxicol. (1991) 69:310-321; Nau, CIBA Foundation Symposium 181, pp. 615-664; Marcel Dekker, 1993.
Studies in vitro have demonstrated valproate to potently inhibit the rate of neural derived cell proliferation at concentrations within its therapeutic plasma level (Regan, C., Brain Res. (1985) 347:394-398). This antiproliferative action of valproate is restricted to a defined point in the G
1
phase of the cell cycle. Martin M. and Regan C., Brain Res. (1991) 554:223-228. In the presence of valproate, cells assume a differentiated phenotype as judged by morphology, increased cell-substratum adhesivity and decreased affinity for concanavalin A lectin coated surfaces (Martin et al., Toxic in Vitro (1988) 2:43-48; Martin et al., Brain Res. (1988) 459:131-137; Maguire and Regan, Int. J. Devl. Neurosci. (1991) 9:581-586; Regan, C., Brain Res. (1985) 347:394-398. These actions of valproate are likely to be restricted to cells of the developing neural tube as, in in vivo experimental models, valproate has been shown to increase the incidence of neural tube defects and sequester specifically into the neuroephithelium where it generates cellular disarray (Dencker et al., Teratology (1990) 41:699-706; Ehlers et al., Teratology (1992) 45:145-151; Ehlers et al., Teratology (1992) 46:117-130; Kao et al., Teratogen. Mutagen, Carcinogen. (1981) 1:367-382; Turner et al., Teratology (1990) 41:421-442.
Hyperthermia, which induces neural tube defects (Chernoff and Golden, Teratology (1988) 37:37-42; Edwards, Teratogen. Mutagen. Carcinogen. (1986) 6:563-582; Shiota, Am J. Med. Genet. (1982) 12:281-288; Finnell et al., Teratology (1986) 33:247-252), also arrests neural cells in the G
1
phase of the cell cycle both in vivo and in vitro (martin et al. Brain Res. (1991) 554:223-228; Walsh and Morris, Teratology (1989) 40:583-592); and produces similar pro-differentiative effects to those observed with valproate (Martin and Regan, Brain Res. (1988) 459:131-137). Thus, a coincident anti-proliferative and pro-differentiative action may identify agents which are capable of inducing neural tube defects yet provide a basis for the development of compounds useful for treatment or prevention of neurodegenerative diseases.
The studies of the structure activity relationship of teratogenic valproate-related compounds suggest a strict structural

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