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Definitions

• the invention relates to a ⁇ ng-substituted derivative of K-252a for use in methods directed to ameliorating the deleterious effects of a variety of diseases, disorders and conditions.
• the Indolocarbazole ) ⁇ -2S2a K-252a is a compound having an indolocarbazole skeleton [Japanese Published
• PKC protein kinase C
• the indolocarbazolcs are generally lypophilic Because of this feature, the indolocarbazoles are able to cress biological membranes with relative ease, compared to proteins. Also, indolocarbazoles generally have longer in vivo half lives than proteins
• K-252a In addition to K-252a itself, various derivatives of K-252a have been synthesized and tested for biological activity. Among the K-252a derivatives shown to have biological activity is a compound disclosed in Lewis ei. al., U.S. Patent Nos. 5,461,146. and 5,621.100. and PCT Pubhcation WO 94/02488, and designated therein as "Compound 11-51 " Compound II-51 has been shown to enhance the function of cholinergic neurons, striatal neurons, and sensory neurons
• Parkinson's disease is a neurodegenerative disorder that involves progressive and selective loss of doparninergic neurons of the rugro-stnatal pathway (Agid, Lancet; 337 1991)
• Administration of l-methyl-4-phenyl-l,2,3,6- ⁇ etrahydropy ⁇ dine (MPTP) to mice leads to doparninergic neuron degeneration and serves as an animal model for the doparninergic neuronal loss and behavioral deficits observed in Parkinson's disease.
• Peripheral administration of MPTP leads to a highly selective degeneration of the nigrostriatal doparninergic neuronal system in humans, monkeys and mice (Huikkila et al.. Science 224; 1451-1453, 1984; Bums et al , Proc. Natl Acad. Set USA 80:4546-4550, 1983).
• Non-choli ⁇ ergic neurons that use ⁇ -a ⁇ unobutyric acid (GABA) as a neurotxansmittcr i.e., GABA-ergic neurons
• GABA ⁇ -a ⁇ unobutyric acid
• GABA-ergic neurons i.e., GABA-ergic neurons
• GABA-ergic neurons are widespread throughout the brain.
• they are found in the nucleus basalis magnocellularis in the rodent (the equivalent region in the human brain is called nucleus basalis of Meynert), a legion of the basal forcbrain important in attention and memory functions.
• Damage to GABA-c rgic neurons in the basal forebrain may also contribute to behavioral deficits in neurodegenerative diseases such as Alzheimer's disease (Dekker et al , Neurosci. and Biobehav. Rev. , 15:299-317, 1991; Gallagher et al., Seminars in Neuroscwnce, 6:351-358, 1994
• a contributing factor in such neu onal cell death is glutamate excitotoxicity, i.e.
• Neuronal pathology in Alzheimer's disease is first seen in the cntorhinal cortex, and loss of neurons in this region becomes severe as the disease progresses (Braak et al., Acta Neuropathol. 82:239-259, 19S 1; Hyman et al.. Ann. Neurol. 20:472-181, 1986) Neurons in layer 2 of the entorhinaJ cortex project to the dentate gyms of the hippocampus, and this neuronal pathway plays an important role in memory formation (Lcvisohn et al., Brain Res. 564:230-244. 1991; 01ton et al., J3r ⁇ « ⁇ ej 139.295-308, 1978; Steward et al., Bratn Res.
• Peripheral Neuropathy generally refers to a disorder that affects the peripheral nerves, most often manifested as one or a combination of motor, sensory, sensonmotor. or autonomic neural dysfunction.
• the wide variety of morphologies exhibited by peripheral neuropathies can each be uniquely attributed to an equally wide variety of causes For instance, pcnpheral neuropathies can be genetically acquired, can res lit from a systemic disease, or can be induced by a toxic agent. Some toxic agents that cause m urotoxicities arc therapeutic drugs, antincoplastic agents, contaminants in foods or medic inals, and environmental and industrial pollutants.
• chemotherapeutic agents known to cause sensory and/or motor neuropathies include vincristine, an antineop astic drug used to treat haematological malignancies and sarcomas.
• the ncurotoxicity is dose-related, and exhibits as reduced intestinal motihty and pcnpheral neuropathy, expeciaJly in the distal muscles of the hands and feet, postural hypotension, and atony of the urinary bladder. Similar problems have been documented with taxol and cisplatin (Mollman, 1990, New Eng. Jour.
• peripheral neuropathies There are a number of inherited peripheral neuropathies, including: Rcfsum's disease, A- betallpoproteinemia. Tangier disease, Krabbc's disease, Metachromatic leukodystrophy, Fabry ' s disease, Dejenne-Sottas syndrome, and others Of all the inherited neuropathies, the most common by far is Charcot-Marie-Tooth disease ⁇ see also, U S Patent No. 5,420,112 for additional information on peripheral neuropathies). IV. Cytokines
• Tumor necrosis factor ⁇ TNF- ⁇
• IL-l ⁇ intcrleukin-l ⁇
• the inve ⁇ tion features methodologies for ameliorating the deleterious effects of a variety of diseases, disorders and conditions by treating a subject in need thereof with a therapeutically effective amount of Compound A
• the invention features a method for treating the deleterious effects of diseases, disorders and conditiens which lead to or cause the death of, or lead to or cause inhibition of the function of, certain neurons by enhancing die function or survival of a doparninergic, GAB A-ergic, or glutamatcrgic neuron in a mammal, comprising the step of contacting the neuron with Compound A
• the mammal in which the neuron is found is a human.
• the doparninergic, GABA-ergic , or glutamatergic neuron contacted with Compound A has impaired function, or is at risk of dying, because of a neurodegenerative disease.
• the neurodegenerative disease is P.-rkinson's disease or Alzheimer's disease More specifically, the nvenuon also features a method of reducing a peripheral neuropathy comprising administering to a mammal a neuropathy-reducing amount of Compound A While it has been reported that the indolocarbazole compound K-252a reduces the lethality resulting from endotoxin administration, this ability has been ascribed to the ability of K-252a to inhibit protein kinases, especialy protein l ⁇ nase C (Inaba et al., Jpn J Surg 23:234 (1993).
• the invention also features a method of inhibiting production of TNF- ⁇ and IL-l ⁇ in a mammal and a method of treating or alleviating inflarnrna ory conditions or diseases, including but not limited to septic shock, rheumatoid arthritis, ostroarthntis, asthma, bronchitis, chronic obstructive airway disease.
• psoriasis psoriasis, allergic rhinitis, dermititis, and inflammatory bowel disease and other autoimmune diseases
• method compri: es administering to said mammal an effective amount of Compound A and pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable earner.
• Compound A means the compound whose chemical structure is shown below
• Compound A is also referred tci as Compound II-51 ( Lewis et al., U.S . Patent Nos 5,461, 146 and
• ameliorate and “ameliorating” mean to therapeutically improve and/or therapeutically reduce and/or to make more therapeutically tolerable.
• the term “deleterious” when used to modify TNF- ⁇ and IL-l ⁇ means production of TNF- ⁇ and/or IL-l ⁇ leading to deleterious conditions such as, for example, septic shock, allergic conditions, mflamrnatory conditions, etc
• the terms “inhibit” or “inhibiting” means that the presence of Compound A has a comparative ly greater effect on reducing and/or prohibiting and/or preventing the production of a material contacted with Compound A than a comparative material not contacted with Compound A.
• “function” or “survival” means that the presence of Compound A has a comparatively greater effect on the function and/ormaxval of the specified neuron than a comparative neuron not presented with Compound A.
• Compound A would evidence enhancement of the function of a doparninergic neuronal population at nsk of dying (due to, e.g., injury, a disease condition, a degenerative condition or natural progression) when compared to a doparninergic neuronal population not presented with Compound A_ if the treated population has a comparatively greater period of functionality than the non-treated population.
• dcpami ⁇ ergic neuron means a neuron that uses dopa ⁇ une as a neurotransrnittcr.
• GEB A-ergic neuron means a neuron that uses ⁇ -armnobuty ⁇ c acid as a neurotransmitter
• glutamatcrgic neuron means a neuron that uses glutamate as a neurotransmitter.
• nbm means nucleus basalis magnocellularis
• Fig. 1 is a graph of data demonstrating that Compound A is not a monoa ⁇ unc oxidase- A inhibitor.
• the IC S0 of Clorgyline was 21 nm. Upright triangles. Clorgyline; inverted triangles, Compound A; squares, L-depreuyl.
• Fig. 2 is a graph of data demonstrating that Compound A is not a m ⁇ noamine oxidasc- B inhibitor
• the IC 50 of Clorgyline was 21 nm Upright triangles, Clorgyline: inverted triangles.
• Compound A squares, L-dcpreiyl.
• »P ⁇ 0.01 compared to Les, by Ncwman-Keuls tests.
• Fig. 5 shows the effect of Compound A on acrylamide-induced peripheral neuropathy.
• the invention features methodologies for ameliorating the deleterious effects of a variety of diseases, disorders and conditions by treating a subject in need thereof with a therapeutically effective oxyribonucleic acid (e.g., aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-methyl methyl-N-(2-aminoe) of Compound A
• This invention pro •'ides a method for treating the deleterious effects of diseases. disorders and conditions which negatively affect the function and/or survival of neurons at nsk of dying due to such diseases and disorders by enhancing the function or survival of specific types of neurons of the marnmalian ceroral nervous system. More particularly, the invention provides a method for enhancing the fund ion or survival of doparninergic neurons, GAB A-ergic neurons, and glutamatergic neurons in a mammal by administering to the mammal Compound A, a ring- substituted K-252a derivative ⁇ with the following chemical structure.
• Doparninergic neurons, GABA-ergic neurons, and glutamatcrgic neurons are widespread in the mammalian central nervous system Each of these three neuronal ceil types suffers impaired function, or even death, in one or more neurodegenerative diseases of the central nervous system.
• Parkinson's disease involves progressive loss of doparninergic neurons of the nigrostriatal pathway.
• Alzheimer's disease involves the death of various types of neurons. including GABA-ergic neurons in the nucleus basalis of Meynert of the basal forebrain Alzheimer's disease also involves death of glutamatergic neurons in the entorhinal cortex
• One method of treating Parkinson's disease or Alzheimer's disease is to administer a compound that enhances the function or survival of doparninergic neurons.
• Compound A is pharmacologically active in biological assays and in vivo models for enhanced function or survival of doparninergic neurons, GABA-ergic neurons, and glutamatcrgic neurons. Therefore, the present invention has utility for treating Parkinson's disease or Alzheimer's disease.
• the invention is not limited to the treatment of those diseases
• the use of Compound A to enr ance the function or survival of doparninergic neurons, GABA-ergic neurons, or glutamatergic neurons whose impaired function or risk of dying results from causes other than Parkinson's disease or Alzheimer's disease is also within the scope of the present invention.
• This invention also features a method of reducing a peripheral neuropathy.
• the method involves administering a neuropathy-reducing amount of Compound A to a mammal.
• the mammal is a human, or an agriculturcal or domestic mammal that develops a neuropathy, e.g , as a result of treatment of a neoplasm with a chemotherapeutic agent
• Compound A can be administered in a manner deemed effective by one skilled in the art; a preferred mode of administration is subcutaneous injection.
• penph.ral neuropathy refers to a disorder affecting a segment of the peripheral nervous system
• the invention involves using Compound A to reduce a neurotoxicity. including, but not limited to, distal sensorimotor neuropathy, or autonomic neuropathies such as reduced motility of the gastrointestinal tract or atony of the u ⁇ nary bladder.
• Preferred neuropathies hat can be effectively treated with Compound A include neuropathies associated with systemic disease, e.g., post-polio syndrome, genetically acquired neuropathies, e.g., Charcot-Maiie-Tooth disease: and neuropathies caused by a toxic agent, e.g., acrylamide, or a chemotherapeutic agent, e.g., vincnsune.
• a toxic agent e.g., acrylamide
• chemotherapeutic agent e.g., vincnsune.
• Compound A is used to treat a neuropathy induced by a toxic agent, it can be administered before, sunultanecusly with, or after exposure to the toxic agent, or before, dunng or after adrrunistration of a chemoiJierapeutic.
• Compound A and the chemotherapeutic agent are each administered at effective time intervals, during an overlapping period of treatment.
• Compound A can be administered to the mammal following exposure to the neurotoxic agent, or following chemotherapy, to restore at least a portion of the neurofunction destroyed by the neurotoxic agent or chemotherapeutic.
• the chemotherapeutic can be any chemotherapeutic agent that causes neurotoxicity, such as vincristine, taxol, dideoxyinosinc, or cisplatin.
• neoplastic agents such as vincristine, vtnblastine, cisplatin, taxol, or dideoxy-compounds, e.g., dideoxyinosine. alcohol; metals; industrial toxins involved in occupational or environmental exposure; contarninants of fboc or medicinals; or over-doses of vitamins or therapeutic drugs, e.g.. antibiotics such as penicillan oi chloramphenicol, or megadoses of vitamins A.
• Exposure to a toxic agent can occur by direct adrninistrauon, e.g., by i ⁇ gcstion or administration of a food, medicinal, or therapeutic agent, e.g., a chemotherapeutic agent, by accidental contamination, or by environmental exposure, e.g., aerial or aqueous exposure.
• adrninistrauon e.g., by i ⁇ gcstion or administration of a food, medicinal, or therapeutic agent, e.g., a chemotherapeutic agent
• environmental exposure e.g., aerial or aqueous exposure.
• Compound A has also been demonstrated to inhibit production of the cytoki ⁇ e TNF- ⁇ , despite having little or no inhibi Jory activity against PKC Compound A also inhibits the production of the cvtokinc IL-1
• the production of TNF- ⁇ is associated with a variety of diseases and disorders such that the inhibition thereof via use of Compound A can beneficially provide value to a subject in nc ⁇ :d of such inhibition of TNF- ⁇ production.
• Compound A can also be utilized to inhibit production of TNF- ⁇ in a mammal and/or a method of treating or alleviating inflammatory conditions or disease, including but not limited to septic shock, heumatoid arthritis, ostcoarthritis, asthma, bronchitis, chronic obstructive airway disease, psonasis, allergic rhinitis, dermatitis, and inflammatory bowel disease, and other autoimmune diseases which method compnses administering to said mammal a therapeutically effective amoun : of Compound A
• Compound A can be formulated into a pharmaceutical composition by admixture with pharmaceutically acceptable nontoxic excipients and carriers
• a composition can be prepared for administration by any of various routes.
• Routes of administration and pi eferred dosage forms include the following, parenteral, preferably in the form of liquid solutions or suspensions: oral, preferably in the form of tablets or capsules, l ⁇ tranasal, preferably particularly in the form of powders, nasal drops, or aerosols; and dermal. via, for example, trans-dermal patches.
• Composition A can be conveniently administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub Co , Easton, PA. 1980), Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene gl ycol, oils and vegetable origin, hydrogenated naphthalenes and the like In particular, biocompatihle, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylenc-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds.
• Formulations for inhalation adrrumstration contain as excipients, for example, lactose, or may be aqueous sol itions containing, for example, lactose, or may be aqueous solutions containing, for example, polyo ⁇ ycthyle ⁇ e ⁇ 9-lauryl ether, glycocholate and deoxycholate. or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
• Formulations for parenteral administration may also include glycoch ⁇ late for buccal administration, a salicylate for lectal administration, or citric acid for vaginal administration.
• Formulations for trans-dermal patches are preferably lipophilic emulsions.
• Compound A can be employed as the sole active ingredient in a pharmaceutical composition. Alternatively, it can be used in combination with other active ingredients, e.g., growth factors that facilitate neironal survival or axonal regeneration in diseases or disorders.
• the concentration of Compound A used in the practice of this invention in a therapeutic composition can vaiy. The concentration will depend upon factors such as the total dosage of me drug to be administered and the route of administration. Compound A typically would be provided in an aqueoi s physiological buffer solution containing about 0.1 to 10% w/v for parenteral adrninistration.
• Typ cal dose ranges are from about 1 ⁇ g/kg to about I g/kg of body weight per day; a preferred do»: range is from about 0.01 mg/kg to 100 mg/kg of body weight per day.
• a preferred dosage of Compound A to be administered is likely to depend on variables such as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative efficacy of Compound A for the particular disease or disorder treated the particular formulation used, and its route of administration.
• mice were treated with MPTP (20 mg/kg; s.c.) 4-6 hrs after the first Compound A injection. Compound A was then injected every day until the end of the experiment, which was 7 days in duration. Striata were .issessed for tyrosine hydroxylase enzyme activity. Asterisk indicates statistically significanr. difference (p ⁇ 0.05) from MPTP- Vehicle treated animals.
• mice were treated with MPTP (40 mg/kg, s c.) 4-6 hrs after the first Compound A injection Compound A was then injected every day until the end of the experiment which was 7 days in duration. Striata were assessed for ty ⁇ osine hydroxylase enzyme activity. Asterisk indicates statistically significant difference (p ⁇ 0.05) from MPTP -Vehicle treated animals
• MPTP-mediated dspaminergic toxicity is dependent on MAO mediated conversion of MPTP to MPP + (l-mcthyl-4-pl ⁇ enylpyridinium ion) and uptake of MPP + into doptiminergic neurons.
• Compounds found to be active in the MPTP-mouse model should be determined not to be inhibitors of MAO or dopamine uptake.
• Compound A has been found not to inhibit monoaminc oxidase A or B in vitro ( Figure; 1 and 2) or block uptake of catechola ⁇ unes into nerve endings, indicating that this compound daes not prevent the metabolic conversion of MPTP to MPP + or inhibit the active uptake of MP1' 4 into doparninergic neurons.
• Compound A was lested for its ability to prevent depletion (e.g., enhance the survival) of GABA-ergic neurons in the nucleus basalis magnocellularis, using the well-established ibotemc acid lesion model.
• Ibotenic acid an excitotoxin, is known to reduce numbers of GAB A-cxprcssi ⁇ g neurons in the nbm region (Linciefors et al., Neurosci. Lett., 135:262-264, 1992: Shaugnessy et al., Brain Res., 637:15-26, 1994).
• Rats received injections of ibotenic acid (5.0 g) into the nbm unilaterally. The rats wen: then dosed with Compound A (0.03 mg/kg) via subcutaneous injection beginning 18 hours afier the lesion, and continuing q.o.d. until 18 days post-lesion. Tissue sections were then collected throughout the rostral-caudal extent of the nbm, and processed to detect glutamic acid decarboxylase. an enzyme required for biosynthesis of GABA.
• the numbers of neurons expressing glutamic acid decarboxylase were then counted throughout the rostral-caudal extent of the nucleus basalis magnocellularis, in a region where glutamic acid decarboxylase-cxpressing neurons of the nbm are easily distinguished from glutamic acid decarboxylasc-cxpressing neurons in adjacent structures (white matter medial and ventral to the globus pallidus).
• the results were expressed as percent glutamic acid decarboxylase-expressing neurons on the lesioned side relative to the number on the opposite, unlesioned side. The results were also calculated separately for the rostral nbm, mid-nbm. and caudal nbm.
• nbm neurons in adult male Sprague- Dawley rats were first labeled with a long-lasting marker. This was done by injecting Fluoro-Gold (FG), a neuronal tracer that is taken up by nerve terminals and transported back to the cell body (Book et al., J. Neuropath. Exp. Neurology, 53.95-102. 1994), into target regions of nbm neurons in the frontal and parietal cortex. 7-10 days later the animals received lesions of the nbm unilaterally, using 5 ug of ibotenic acid.
• FG Fluoro-Gold
• the animals received Compound A (0.03mg/kg) via subcutaneous injection, every other day until 18 days post-lesion.
• Tissu sections were collected throughout the entire rostral-caudal extent of the nbm on both sides of the brain, and numbers of nbm neurons with the FG label were counted. The counts were c ⁇ r ⁇ ictcd for size differences using standard procedures, and the results expressed as the percent of labeled neurons in the- nbm on the lesioned side of each animal relative to the number of labeled neurots in the nbm on the opposite unlesioned side of the brain.
• Glutamate-contair ⁇ ng neurons in layer 2 of the entorhinal cortex project to the molecular layer of the dentate gyms, where they form synapses on the dend ⁇ tes of the dentate gyrus granule cells
• a lesion cirn be created in layer 2 of entorhinal cortex by stereotaxic injection of the excitotoxin N-methyl-D-; ⁇ spartatc (NMDAJ).
• NMDAJ excitotoxin N-methyl-D-; ⁇ spartatc
• rats received an injection of NMD A (15 nmols/sitc) at each of 2 sites in the entorhinal cortex Two i' weeks later, the rats were sacriiiced and perfusedilwith a 50 mM sodium sulfide solution.
• the brains were removed, sectioned In the horizontal plane at a thickness of 40 ⁇ m, and stained with either Cresvl violet or Timm's ;;tain.
• Compound A is useful in treating neurological disorders that involve loss of or damage lo glutamatergic neurons and neurons of the cerebral cortex, including but not limited to Alzheimer's disease, (stroke and head trauma.
• Acrylamide produces s "dying back" central-peripheral distal neuropathy ui humans and animals.
• the lesion is a mixed sensory/motor neuropathy characterized by weakness, tremor and ataxia in humans.
• lcrylarrude produces changes in behavior (sensory, motor and proprioceptive), histopatholog) , ekctrophysiolotiy and weight loss.
• AA fibers are preferenually affected by acrylamide.
• acrylamide administration produces an axcuiopathy as measured by increased landing foot spread (LFS), a measure of proprioccption.
• LFS landing foot spread
• Acrylamide-induced neuropathy is a model of chemically induced toxicity. It differs from other chemically-induced mode Is (such as chem ⁇ therapeutic models) in that the duration is relatively short (3 weeks) and the animals are in (relatively good health. Acrylamide does not produce gross systemic toxicity.
• Compound A has an 1C 50 of 139 nM, asian inhibitor of the production of TNF-ot, and an ICJ O value of 261nM as an inhibitor of the production of IL-l ⁇ , concentrations at which Compound A is inactive as an inhibitor of protein kinase C.
• UT comprised the test medium Lipopolysaccharide (LPS) (Sigma. St. Louis, MO) from E coh scrotype 0111 :B4, extracted wi Ji tnchloroacctic acid, was used.
• LPS Lipopolysaccharide
• Stock solutions of LPS were prepared and stored at 4°C in phosphate-buffered Isaline (PBS).
• ELISA kits for assaying tumor necrosis factor alpha CTNF- ⁇ ) iind IL-l ⁇ were purchased from Boehringer-Mannheim,
• THP-1 cells a human monocyte-de ⁇ ved cell hie, was obtained from the American Type Culture Collection

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