Patent Application
20160263189
Provided herein are methods for treating a neurodegenerative disease or disorder, or stroke using a combination of one or more RXR agonist and/or one or more Nurr1 agonist and one or more trophic factor, or pharmaceutically acceptable salts thereof. Additionally, provided herein are compositions comprising one or more RXR agonist and/or one or more Nurr1 agonist and one or more trophic factor, or pharmaceutically acceptable salts thereof for treatment of a neurodegenerative disease or disorder, or stroke.
Nuclear receptor related 1 protein (NURR1) also known as NR4A2 (nuclear receptor subfamily 4, group A, member 2), henceforth Nurr1 is a nuclear hormone receptor (NucHR) strongly implicated in the growth, maintenance, and survival of dopaminergic neurons, that represents a very promising therapeutic target for Parkinson's disease (PD). The essential role of Nurr1 in dopaminergic cell development was dramatically demonstrated in mouse gene knockout experiments in which homozygous mice lacking Nurr1 failed to generate midbrain dopaminergic neurons (Zetterstrom et al., 1997). Nurr1 was shown to be directly involved in the regulation of genes coding for aromatic amino acid decarboxylase, tyrosine hydroxylase (TH), and the dopamine transporter (DAT) (Hermanson et al., 2003). In addition, Nurr1 limits inflammatory responses in the central nervous system (CNS) and specifically protects dopaminergic neurons from neurotoxicity (Saijo et al., 2009). These observations suggest that Nurr1 play a pathophysiological role in aspects of neurodegenerative diseases ranging from inflammatory responses to dopaminergic nerve function and survival.
It has been shown that GDNF protects and repair dopaminergic neurons from insults such as MPTP and 6-hydroxydopamine toxicity, and axotomy (Beck et al. 1995; Bowenkamp et al. 1995; Kearns and Gash 1995; Tomac et al. 1995). Moreover, it has been demonstrated that GDNF is essential for the survival of midbrain dopamine (DA) neurons during post-natal development (Pascual et al. 2008). Because of its strong trophic actions on DA neurons, GDNF or analogs of GDNF such as neurturin are being tested clinically
RET (rearranged during transfection) is the tyrosine kinase signaling component of the receptor complex for the family ligands of the glial cell line-derived neurotrophic factor (GDNF) (Airaksinen and Saarma, 2002). Transgenic mice expressing a constitutive active mutant RET gene have increased number of midbrain DA (as assessed by tyrosine hydroxylase (TH) expression) neurons (Mijatovic et al. 2007). Conversely, mice lacking RET suffer progressive and late degeneration of dopaminergic nigro-striatal system (Kramer et al., 2007) and also show impaired capacity to regenerate dopaminergic axon terminals (Kowsky et al. 2007).
RET expression has been shown to be regulated by Nurr1 (Galleguillos et al., 2010). Specifically, Nurr1 induced the transcription of the human RET promoter in cell type and concentration-dependent manner. Conversely, knockdown of Nurr1 caused a significant reductions of both RET mRNA in the Substantia Nigra (SN) and RET protein in the striatum.
For example Nurr1 agonists have potential for treating neurodegenerative diseases such Parkinson's disease as they enhance TH and DAT expression in primary mensencephalic cultures and exert a beneficial effect on dopaminergic neurons in animal models of PD (Ordentlich et al., 2003; Jankovic et al., 2005; Dubois et al., 2006). However, the molecular basis for the actions of existing ligands is not well defined. Nurr1 may mediate its beneficial effects alone, or more likely in concert with other nuclear hormone receptor partners (Sacchetti et al., 2006; Carpentier et al., 2008). To date, there are a few examples of such ligands available for experimental testing (Shi, 2007).
Nurr1 can form dimers and is known to associate with other NucHRs including peroxisome proliferator-activated receptor gamma (PPARγ), glucocorticoid receptor (GR), farnesoid X receptor (FXR), and retinoid X receptor (RXR) (Sacchetti et al., 2006; Carpentier et al., 2008). It is currently unknown which Nurr1 interaction is therapeutically important in the treatment of PD. However, it is agreed that Nurr1 involvement in dopaminergic neuronal activation and cell survival is important (Shi, 2007). Several of the most potent Nurr1 binding compounds enhance TH and DAT expression in primary mensencephalic cultures and exert a beneficial effect on dopaminergic neurons in animal models of PD (Jankovic et al., 2005).
Provided herein are methods for treating a neurodegenerative disease or disorder, or stroke using one or more RXR agonist and/or one or more Nurr1 agonist and one or more trophic factor, or pharmaceutically acceptable salts thereof.
Also provided are compositions comprising one or more RXR agonist and/or one or more Nurr1 agonist and one or more trophic factor, or pharmaceutically acceptable salts thereof.
Also provided herein are compositions comprising one or more RXR agonist and/or one or more Nurr1 agonist and one or more trophic factor, or pharmaceutically acceptable salts thereof for treating a neurodegenerative disease or disorder, or stroke.
Also provided herein are one or more RXR agonists, such as bexarotene and one or more trophic factors such as GDNF which in combination (optionally as separate components) both administered to a subject upregulate RET.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
The term “in combination” is intended to mean that the individual components are used in combination. This for example means that to components such as active pharmaceutical compounds are administered together, simultaneously, or a in such a manor that a combined effect is achieved. This may for example include that the components are administered separately but to give a combined effect.
The term “neurodegenerative disease or disorder” as used herein refers to a disease or disorder selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, frontotemporal lobar degeneration associated with protein TDP-43 (FTLD-TDP, Dementia with Lewy bodies (DLB), vascular dementia, Amyotrophic lateral sclerosis (ALS), Mild Cognitive Impairment (MCI), Parkinson's disease with MCI, and other neurodegenerative related dementias due to changes in the brain caused by ageing, disease or trauma; or spinal cord injury.
The term “neuroprotection” as used herein refers to the prevention of further loss of neuronal cells, or loss of neuronal function as a result of exposure to a neurotoxin or resulting from a neurodegenerative disease or disorder. As used herein, the term “neuroprotection” is synonymous with “protection of neurons”.
As used herein, promotion of neuronal survival is considered equivalent to neuroprotection
The term “regeneration” as used herein refers to enabling an increase in the activity of an injured or disabled cell, or a cell having below normal activity relative to the natural activity of a corresponding healthy cell. Such a cell may be a neuron. In some embodiments provided herein, “regeneration” refers to the regeneration of neurons in a patient having a neurodegenerative disease or disorder.
Thus, in some embodiments “neuroregeneration” refers to the regeneration of neurons in a patient having a neurodegenerative disease or disorder. In some embodiments, “neuroregeneration refers to the process of reversing either the loss of neuronal cells, or the loss of neuronal function occurring as a result of exposure to a neurotoxin or resulting from a neurodegenerative disease.
Neurorestoration shall be defined to be equivalent to neuroregeneration.
The term “neuronal function” as used herein refers to the capability of a neuron to synthesize, store, release, transport and respond to a neurotransmitter. Thus, changes in expression or integrity of certain components of neurons, including but not limited to receptors transporters, vesicles, cell bodies, axons or dendrites may affect neuronal function.
Neurotransmitters shall be defined as diffusible molecules released by neurons that either stimulate or inhibit neuronal activity.
A “pharmaceutically acceptable salt” refers to a salt of a compound that does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Base-formed salts include, without limitation, ammonium salt (NH4)+; alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, piperidine, piperazine, methylpiperazine, N-methyl-D-glucamine, diethylamine, ethylenediamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine. Useful acid-based salts include, without limitation, hydrochlorides, hydrobromides, acetates, adipates, aspartates, ascorbates, benzoates, butyrates, caparate, caproate, caprylate, camsylates, citrates, decanoates, formates, fumarates, gluconates, glutarate, glycolates, hexanoates, laurates, lactates, maleates, nitrates, oleates, oxalates, octanoates, propanoates, palmitates, phosphates, sebacates, succinates, stearates, sulfates, sulfonates, such as methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, tartrates, tosylates.
Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent of water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
A “prodrug” refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have better solubility than the active parent drug in pharmaceutical compositions. An example, without limitation, of a prodrug would be a compound disclosed herein, which is administered as an ester (the “prodrug”) to facilitate absorption through a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized in vivo to release the active parent compound. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g. Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).
“Anti-drug” refers to a compound or composition acting against or opposing illicit drugs or their use. Compounds of the present application may act as anti-drugs.
To “modulate” means the function of a bromodomain or a bromodomain containing protein means either to increase its cellular function over the base level measured in the particular environment in which it is found, or decrease its cellular function to less than the measured base level in the environment in which it is found and/or render it unable to perform its cellular function at all.
An “agonist” is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
A “partial agonist” refers to a compound that has an affinity for a receptor but, unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response normally associated with the receptor even if a large number of receptors are occupied by the compound.
An “inverse agonist” is defined as a compound, which reduces, or suppresses the basal activity of a receptor, such that the compound is not technically an antagonist but, rather, is an agonist with negative intrinsic activity.
An “antagonist” refers to a compound that binds to a receptor to form a complex that does not give rise to any response, as if the receptor was unoccupied. An antagonist attenuates the action of an agonist on a receptor. An antagonist may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.
A “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as birds, fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
A “patient” refers to a subject that is being treated by a medical professional such as an M.D. or a D.V.M. to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.
A “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
A “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
An “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.
A “receptor” is intended to include any molecule present inside or on the surface of a cell that may affect cellular physiology when it is inhibited or stimulated by a ligand. Typically, a receptor comprises an extracellular domain with ligand-binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and a cytoplasmic domain that generates a cellular signal in response to ligand binding (“signal transduction”). A receptor also includes any intracellular molecule that in response to ligation generates a signal. A receptor also includes any molecule having the characteristic structure of a receptor, but with no identifiable ligand. In addition, a receptor includes a truncated, modified, mutated receptor, or any molecule comprising partial or all of the sequences of a receptor.
“Ligand” is intended to include any substance that interacts with a receptor.
The “Nurr1 receptor” is defined as a receptor having an activity corresponding to the activity of the Nurr1 receptor subtype characterized through molecular cloning and pharmacology. Nurr1 (nur-related factor 1, NR4A2) is an orphan nuclear hormone receptor
The “RET (rearranged during transfection) receptor” is the tyrosine kinase signaling component of the receptor complex for the glial cell line-derived neurotrophic factor (GDNF) related family of ligands including GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). As used herein, “co-administration” of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Co-administration means the simultaneous delivery of separate agents; the simultaneous delivery of a mixture of agents; as well as the delivery of one agent followed by delivery of a second agent or additional agents. Agents that are co-administered are typically intended to work in conjunction with each other.
As used herein “in combination” of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. In combination means the compounds may be coadministered but also that the compounds may be delivered sequentially, that is the delivery of one agent followed by delivery of a second agent or additional agents. Agents that are coadministered by sequential administration are typically intended to work in conjunction with each other. This may for example include that the components are administered separately but to give a combined effect.
The term “an effective amount” as used herein means an amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or palliation of the symptoms of the disease being treated.
The term “one or more” means as provided herein that it may be one or two or three or more of the specified item, for example one RXR agonist, or two Nurr 1 agonists. Thus for example two RXR agonists may be combined with one antidepressant medication.
The term “upregulation” refers to the process by which a cell increases the quantity of a cellular component, such as RNA or protein, in response to an external variable or stimulus.
The term “Parkinson's drug” refers to one or more pharmaceutically active methods or compounds to treat Parkinson's disease or symptoms caused by the disease or by other treatments not including the “Parkinson's drug”.
The “retinoid X receptor” (denoted RXR receptor) is the family of nuclear hormone receptors that are activated by 9-cis retinoic acid and not all trans retinoic acid.
RXR means one or more of RXR subtypes α, β and γ. The term “RXR agonist” refers to a compound or composition which, when combined with a Retinoid X Receptor (RXR), increases the transcriptional regulation activity of RXR homodimers and heterodimers.
The RXR agonist can include known RXR agonists that are described in, for example, the following U.S. patents and patent applications, which in their entirety are incorporated by reference herein: U.S. Pat. Nos. 5,399,586, 5,466,861, 5,780,676, and 5,801,253; U.S. patent application Ser. Nos. 07/809,980, 08/003,223, 08/027,747, 08/045,807, 08/052,050, 08/052,051, 08/179,750, 08/366,613, 08/480,127, 08/481,877, 08/872,707, and 08/944,783. See also, WO 93/11755, WO 93/21146, WO 94/15902, WO94/23068, WO 95/04036, and WO 96/20913. Other RXR agonists that can be used herein can include RXR agonists described for example, in the following articles, which in their entirety are incorporated by reference herein: Boehm et al. J. Med. Chern. 38:3146 (1994), Boehm et al. J. Med. Chern. 37:2930 (1994), Antras et al., J. Biol. Chern. 266:1157-61 (1991), Salazar-Olivo et al., Biochem. Biophys. Res. Commun. 204: 10 257-263 (1994), and Safanova, Mol. Cell. Endocrin. 104:201 (1994). Such compounds may be prepared according to methods known in the art as described in the aforementioned references, as well as in M. L. Dawson and W. H. Okamura, Chemistry and Biology of Synthetic Retinoids, Chapters 3, 8, 14 and 16, CRC Press, Inc., Florida (1990); M. L. Dawson and P. D. Hobbs, The Retinoids, Biology, Chemistry and Medicine, M. B. Sporn et al., Eds. (2nd ed.), Raven Press, New York, N.Y., pp. 5-178 (1994); Liu et al., Tetrahedron, 40:1931 (1984); Cancer Res., 43:5268 (1983); Eur. 1. Med. Chem. 15:9 (1980); Allegretto et al., J. Bio. Chem., 270:23906 (1995); Bissonette et al., Mol. Cell. Bio., 15:5576(1995); Beard et al., J. Med. Chem., 38:2820 (1995), Koch et al., J. Med. Chem., 39:3229 (1996); and U.S. Pat. Nos. 4,326,055 and 4,578,498. In some embodiments, the RXR agonists can include Bexarotene, LGD 100268, and LGD 100324. The structures of RXR agonists designated LGD 1069, LGD 100268, and LGD 100324 are shown below, and the synthesis of these compounds is described in U.S. Pat. Nos. 7,655,699 and 5,780,676. The synthesis of compounds LGD1069, LGD100268, and LGD100324 is also described in, e.g., WO 94/15902 and Boehm et al., J. Med. Chem. 38(16):3146 (1994).
More examples of RXR agonist compounds as provided herein are for example: 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid, p[3,5,5,8,8-pentamethyl-1,2,3,4-tetrahydro-2-naphthyl-(2carbonyl)]-benzoic acid, also known as 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid; p(5,5,8,8-tetramethyl-1,2,3,4-tetrahydro-3-isopropyl-2-naphthyl-(2-carbonyl)]-benzoic acid, also known as 4-[(3-isopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid; p[5,5,8,8-tetramethyl-1,2,3,4-tetrahydro-3-isopropyl-2-naphthyl-(2-methano)]-benzoic acid, also known as 4-[1(3-isopropyl-5,5,8,8-tetramethyl-5,6,7,8 tetrahydro-2-naphthyl)ethenyl]benzoic acid; p[5,5,8,8-tetramethyl-1,2,3,4-tetrahydro-3-ethyl-2-naphthyl-(2-methano)]-benzoic acid, also known as 4-[1-(3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid; p[(5,5,8,8-tetramethyl-1,2,3,4-tetrahydro-3-bromo-2-naphthyl-(2-methano)]-benzoic acid, also known as 4-[1-(3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid; p[5,5,8,8-tetramethyl-1,2,3,4-tetrahydro-3]-chloro-2-naphthyl-(2-methano)-benzoic acid, also known as 4-[1(3-chloro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl] ethenyl benzoic acid; p[3,5,5,8,8-pentamethyl-1,2,3,4-tetrahydro-2-naphthyl-(2-methano)]-benzoic acid, also known as 4-[1(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl/benzoic acid; p[3,5,5,8,8-pentamethyl-1,2,3,4-tetrahydro-2-naphthyl-(2-hydroxymethyl)]benzoic acid, also known as 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)hydroxymethyl]benzoic acid; p[5,5,8,8-tetramethyl-1,2,3,4-tetrahydro-3-bromo-2-naphthyl-(2-carbonyl)]-benzoic acid, also known as 4-[(3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]benzoic acid; p[5,5,8,8-tetramethyl-1,2,3,4-tetrahydro-3-chloro-2-naphthyl-(2-carbonyl)]-benzoic acid, also known as 4-[(3-chloro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid; p[5,5,8,8-tetramethyl-1,2,3,4-tetrahydro-3-hydroxy-2-naphthyl-(2-carbonyl)]-benzoic acid, also known as 4-[(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid; p[5,5,8,8-tetramethyl-1,2,3,4-tetrahydro-3-ethyl-2-naphthyl-(2-carbonyl)]-benzoic acid, also known as 4-[(3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl] benzoic acid; p[3,5,5,8,8-pentamethyl-1,2,3,4-tetrahydro-2-naphthyl-(2-thioketo)]-benzoic acid, also known as 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)thioketo] benzoic acid; p[3,5,5,8,8-pentamethyl-1,2,3,4-tetrahydro-2-naphthyl-(2-carbonyl)]-N-(4-hydroxyphenyl)benzamide, also known as 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]-N-(4-hydroxyphenyl)benzamide; p[3,5,5,8,8-pentamethyl-1,2,3,4-tetrahydro-2-naphthyl-(2-methano)]-N-(4-hydroxyphenyl)benzamide, also known as 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]-N-(4-hydroxyphenyl)benzamide; 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]pyridine-5-carboxylic acid; ethyl 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]pyridine-5-carboxylate; 2-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]pyridine-5-carboxylic acid; 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)epoxy]benzoic acid; 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]benzoic acid; 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzenetetrazole; 5-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]pyridine-2-carboxylic acid; 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]pyridine-5-carboxylic acid; methyl 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]pyridine-5-carboxylate; 3-methyl-7-propyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2E,4E,6Z,8E nonatetranoic acid; 3-methyl-7-isopropyl-9-(2,6,6-trimethyl-1-cyclohexen-yl)-2E,4E,6Z,8E nonatetranoic acid; 3-methyl-7-t-butyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2E,4E,6Z,8E nonatetranoic acid; 3-methyl-5-{2-12-(2,6,6-trimethylcyclohexen-1-yl)ethenyl-1-cyclohexyl}-2E,4E-pentadienoic acid; (2E,4E)-3-methyl-5-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]penta-2,4-dienoic acid; (2E,4E)-3-methyl-6-(1-[2,6,6-trimethyl-1-cyclohexenyl)ethenyl]cyclopropyl)-2,4-hexadienoic acid; (2E,4E,6Z)-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-3,8-dimethyl-nona-2,4,6-trienoic acid; (2E,4E,6Z)-7-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-3-methylocta-2,4,6-trienoic acid; 2-[1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl] pyridine-5-carboxylic acid; 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl] benzoic acid oxime; 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl] benzoic acid methyloxime; 4-[1-(2-methyl-4-t-butylphenyl)ethenyl] benzoic acid; 4-[1-(2-methyl-4-t-butylphenyl)cyclopropyl] benzoic acid; 4-[(2-methyl-4-t-butylphenyl)carbonyl] benzoic acid; 4-[(2-methyl-4-t-butylphenyl)carbonyl] benzoic acid oxime; and 4-[1-(2-methyl-4-t-butylphenyl)carbonyl] benzoic acid methyloxime; or a pharmaceutically acceptable salt thereof
A Nurr1 agonist as provided herein, is for example, selected from one or more of the following:
or (6-Chloroimidazo[1,2-a]pyridin-2-yl)(pyridin-2-yl) methanone; Benzoxazol-2-yl(6-chloroimidazo[1,2-a]pyridin-2-yl)methanone; (6-Chloroimidazo[1,2-a]pyridin-2-yl)(3-fiJryl)methanone; (6-Chloroimidazo[1,2-a]pyridin-2-yl)(thien-2-yl)methanone; (6-Chloroimidazo[1,2-a]pyridin-2-yl)(thien-3-yl)methanone; 1,3-Benzodioxol-5-yl(6-chloroimidazo[1,2-a]pyridin-2-yl)methanone; Benzothiazol-2-yl(6-chloroimidazo[1,2-a]pyridin-2-yl) methanone; (6-Methylimidazo[1,2-a]pyridin-2-yl)(thien-2-yl)methanone; (5-Methylimidazo[1,2-a]pyridin-2-yl)(thien-2-yl)methanone, (6-Pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)(thien-2-yl) methanone, or pharmaceutically acceptable salts thereof.
Additional examples of Nurr1 agonist are found and indicated in the following table:
There is a need for compounds, such as Nurr1 agonists, or compounds that induce activation of Nurr1 indirectly through Nurr1 binding partners that are neuroprotective via activity at the Nurr1 receptor in the central nervous system, both as pharmacological tools and as therapeutic agents. Because such compounds may increase expression of RET, using such compounds in combination with GDNF, or analogs of GDNF which utilize RET to exert trophic effects on DA neurons would be particularly beneficial.
Combining bexarotene, or another RXR or Nurr1 agonist with one of the trophic factors listed herein may offer superior efficacy as neuroprotective agents than any of these agents alone, while maintaining an acceptable or improved side effect and safety profile. For example, bexarotene may have the potential to ‘prime’ neurons, rendering them more responsive to the trophic, neurogenic, and neuroprotective actions of other agents, such as those described above, by driving transcriptional upregulation of receptors such as RET.
For example, combining RXR agonists, or Nurr1 agonists, with trophic factors may produce greater neuroprotective activity together than the sum of the neuroprotective activity afforded by each agent separately. In some embodiments, sub-effective concentrations (concentrations that do not provide significant neuroprotection administered alone) of bexarotene are combined with sub-effective concentrations of GDNF to provide greater neuroprotective activity against the neurotoxin MPP+ than either agent alone and greater than the sum of neuroprotective activity of each agent given alone (i.e. a synergistic effect is obtained), for example, as shown in
Also provided herein is a method for upregulation of RET, for example when a trophic factor such as GDNF and bexarotene are combined.
Also provided herein is a method for treating a neurodegenerative disease or disorder, or stroke using one or more RXR agonist and/or one or more Nurr1 agonist and one or more trophic factor, or pharmaceutically acceptable salts thereof.
Also provided herein is a composition comprising one or more RXR agonist and/or one or more Nurr1 agonist and one or more trophic factor, or pharmaceutically acceptable salts thereof.
Also provided herein is a composition comprising one or more RXR agonist and/or one or more Nurr1 agonist and one or more trophic factor, or pharmaceutically acceptable salts thereof for treating a neurodegenerative disease or disorder, or stroke.
In some embodiments the neurodegenerative disease relates to disease or disorders selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, frontotemporal lobar degeneration associated with protein TDP-43 (FTLD-TDP, Dementia with Lewy bodies (DLB), vascular de-mentia, Amyotrophic lateral sclerosis (ALS), Mild Cognitive Impairment (MCI), Parkinson's disease with MCI, and other neurodegenerative related dementias due to changes in the brain caused by ageing, disease or trauma; or spinal cord injury. In some embodiments the RXR agonist is selected from Bexarotene and 3,7-dimethyl-6(S),7(S)methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid. In some embodiments the trophic factor is selected from the group consisting of glial-cell-line-derived neurotrophic factor (GDNF) or analogs of GDNF, Neurturin (NTN), brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF), fibroblast growth factor 9 (FGF-9), ciliary neurotrophic factor (CNTF), bone morphogenetic proteins (BMPs), mesencephalic astrocyte-derived neurotrophic factor (MANF), and Cerebral dopamine neurotrophic factor also called Conserved dopamine neurotrophic factor (CDNF), hepatocyte growth factor (HGF), nerve growth factor (NGF), Neurotrophin 3 (NT-3), Neurotrophin 4/5 (NT-4/5), Neurotrophin 6 (NT-6), Neurotrophin 7 (NT-7), artemin (ARTN), and persephin (PSPN), CERE-120 (AAV2 vector encoding human neurturin), granulocyte macrophage colony-stimulating factor (GM-CSF), Insulin-like growth factor (IGF)-1, transforming growth factor beta 1 (TGF-beta1), In some embodiment the trophic factor is GDNF, BDNF, NGF or NTN. In some embodiments the trophic factor is administered by means of a pump connected to a brain-implantable catheter.
In some embodiments GDNF is administered by means of a pump connected to a brain-implantable catheter.
In some embodiments the trophic factor is administered by injection of a vector expressing the gene encoding the trophic factor, such as an adeno-associated viral (AAV) vector, such as wherein the AAV vector is serotype 2 (AAV2).
A vector is a gene therapy delivery vehicle, or carrier, that encapsulates therapeutic genes for delivery to cells. These include both genetically disabled viruses such as adenovirus and nonviral vectors.
Adeno-associated virus (AAV) mean a viral vector system for gene therapy delivery including a small virus from the parvovirus family which is a small virus with a genome of single stranded DNA which infects human cells and can insert genetic material into the human genome, and a gene encoding a therapeutic agent and AAV2 shall mean an AAV vector with serotype 2.
Additionally “vg” shall mean viral genomes, a means of calculating the dosage of an AAV vector delivered gene encoding a therapeutic agent.
CERE-120 shall mean an AAV2 vector carrying a gene encoding NRTN, CERE-110 shall mean an AAV2 vector carrying a gene encoding NGF, CERE-130 or CERE-135 shall mean an AAV2 vector carrying a gene encoding IGF-1, CERE-140 shall mean an AAV2 vector carrying a gene encoding NT4.
In some embodiments the vector is selected from one or more from the group consisting of CERE-120, CERE-110, CERE-130, CERE-135, CERE-140.
In some embodiments the vector is CERE-120 and/or CERE-110.
In some embodiments CERE-120 and/or CERE-110 is administered by intracerebral injection, for example CERE-120 can be injected into the substantia nigra (SN), and/or into the putamen, and CERE-110 is injected into the basal forebrain region of the brain containing the nucleus basalis of Meynert (NBM). Examples of doses are: CERE-120 administered in a total ranging from 1×1010 vg to 1×1013 vg, such as 1×1011 vg to 6×1012 vg, such as 1×1011 vg to 3×1012 vg. Examples thereof are about 1.3×1011 vg, about 4×1011 vg, such as about 5.4×1011 vg, such as about 1×1012 vg. Another example is about 2×1012 vg to the putamen, and 4×1011 vg to the substantia nigra.
In some embodiments CERE-110 administered in a total dose ranging from 5×109 vg to 5×1012 vg, such as 5×109 vg to 1×1012 vg, for example 2×1010 vg, such as about 1.0×1011 vg or such as about 2.0×1011 vg.
In some embodiments, CERE-110 is administered by 2-7, such as 3-5, such as 4 stereotactic injections targeted to the NBM. In some embodiments two sites of the NBM are targeted.
In some embodiments CERE-120 is administered by 2-7, such as 3-5, such as 4stereotactic injections per hemisphere into the putamen.
In some embodiments CERE-120 is administered by 2-7, such as 3-5, such as 3stereotactic injections per hemisphere into the putamen
In some embodiments CERE-120 is administered by 1-4, such as 1-2, such as 1 injection(s) per hemisphere into the substantia nigra (SN).
In some embodiments CERE-120 is administered by a combination of 2-7, such as 3-5, such as 3 injections per hemisphere into the putamen and 1-4, such as 1-2, such as 1 injection(s) per hemisphere into the substantia nigra (SN).
In some embodiments CERE-120 is administered by a combination of 3 injections per hemisphere into the putamen and 1 injection per hemisphere into the substantia nigra (SN).
In some embodiments the tracts for stereotactic injections of CERE-120 are separated by about 5 mm.
In some embodiments two or more deposits per injection are made along the same tract for stereotactic injections of CERE-120
In some embodiments one of these deposits is ventral and one is rostral, separated by about 4 mm.
In some embodiments the infusion rate for stereotactic injections of CERE-110 or CERE-120 is about 1 to about 4 μl/min, such as 2 to about 3 μl/min.
In some embodiments the RXR agonist is bexarotene. Bexarotene can for example be administered in a dose of at least 0.05 mg/day, such as 0.05-600 mg/day, such as 0.05-300 mg/day, such as 0.05-150 mg/day, such as 0.05-75 mg/day or 75-150 mg/day. In some embodiments the trophic factor is selected from the group consisting of NRTN, GDNF, IGF-1, NGF, or NT4 and the RXR agonist is bexarotene.
In some embodiments the trophic factor is GDNF and the RXR agonist is bexarotene. In some embodiments, provided herein is a method for treating a neurodegenerative disease or disorder, or stroke using a RXR agonist and/or a Nurr1 agonist and a trophic factor
In some embodiments the trophic factor and the RXR agonist and/or Nurr1 agonist are administered to a subject. In some embodiments the RXR agonist is bexarotene and the trophic factor is GDNF, which in some embodiments upregulate RET.
In the following examples reference is made to the appended drawings which illustrate the following.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2014/065502 | 10/21/2014 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 61894755 | Oct 2013 | US | |
| 61902032 | Nov 2013 | US |
