CN117320713A

CN117320713A - Certain fascin-binding compounds for dendritic spine production

Info

Publication number: CN117320713A
Application number: CN202280035620.1A
Authority: CN
Inventors: S·T·撒拉弗; V·F·西蒙; P·W·范德克里什
Original assignee: Spirogynex
Current assignee: Spirogynex
Priority date: 2021-03-23
Filing date: 2022-03-23
Publication date: 2023-12-29

Abstract

In some embodiments, there is provided a method of promoting dendritic spine formation in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of imipramine, celecoxib Ma Mode, or britisin, or a pharmaceutically acceptable salt of each thereof.

Description

Certain fascin-binding compounds for dendritic spine production

Cross Reference to Related Applications

The present application claims the benefits of U.S. patent application Ser. Nos. 63/165,079 and 63/291,077, filed on day 17 of year 12 of 2021, and 23 of day 2021, 35 U.S. C. ≡119 (e), each of which is incorporated herein by reference in its entirety.

Technical Field

Provided herein are methods for promoting dendritic spine production and for treating neuronal diseases or disorders.

Background

Neurological disorders are diseases of the brain, spinal cord and peripheral nervous system. In terms of epidemiology and individual morbidity, the greatest social costs are caused by neurodegenerative disorders that result in the damage or loss of neurons and synaptic connections between them. The most prominent of these pathologies are Alzheimer's disease and Parkinson's disease. Other neurodegenerative disorders and age-related disorders include, for example, parkinson's disease dementia, vascular dementia, amyotrophic lateral sclerosis, frontotemporal dementia, genetic syndrome (e.g., down's syndrome), injury-related disorders (e.g., traumatic brain injury, chronic traumatic encephalopathy, stroke) and disorders that are generally considered to be purely psychotic in nature, such as schizophrenia and depression.

Researchers have classified hundreds of neurological diseases such as brain tumors, epilepsy, alzheimer's disease, parkinson's disease, and stroke, as well as conditions associated with the elderly (such as dementia). Some such disorders are caused by progressive loss of synapses (junctions between two different neurons) and loss of final neurons (neurodegeneration). Unfortunately, the development of therapeutic agents effective in the treatment of neurodegenerative diseases is almost impossible. Neurons in the brain communicate with each other by releasing neurotransmitters (chemicals that bind to receptors on dendrites) into synapses, altering the potential of the receiving neurons. The portion of the neuron that releases neurotransmitter is the axon (presynaptic side of the synapse), and the portion of the synapse that is affected by neurotransmitter is called the dendritic spine (postsynaptic side of the synapse). The number, location and even shape of the synaptic joints form the basis for memory, learning, thinking and our personality. Various parts of the brain may be affected by degeneration of neurons and suffer from a significant loss of synapses and neurons. The development of new methods to restore spine density and replace lost synapses in the brain is of great importance for the treatment of hosts of neurodegenerative and developmental cognitive disorders.

The dendritic complexity, synaptogenesis and proper development and function of neurons are endogenously regulated by growth factors such as brain-derived neurotrophic factor (BDNF). Although some small molecules have recently been reported to exhibit a nerve-like activity, it has not been demonstrated that these molecules promote dendritic spine formation. The identification of new cellular targets for small molecules can lead to the treatment of many neurodegenerative and mental developmental disorders and will have the potential to provide improved memory and learning. Thus, small molecules that promote acanthogenesis have potential uses in improving cognitive deficits in neurodegenerative diseases such as alzheimer's disease, and can also be used as general cognitive enhancers. However, there is a need for pharmaceutically acceptable compounds having such activity.

Disclosure of Invention

In some embodiments, methods of promoting dendritic spine production in a patient or treating a neuronal disease or disorder in a patient are provided, the methods comprising contacting fascin (fascin) with compounds that interact with or inhibit the activity of fascin. In some embodiments, there is provided a method of promoting dendritic spine production in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of imipramine (imipramine) having the structure:

Or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of promoting dendritic spine production in a patient is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a plug Ma Mode (semapimod) having the structure:

or a pharmaceutically acceptable salt thereof, or a british (british) having the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of promoting dendritic spine production in a neuron is provided, the method comprising contacting plug Ma Mode or a pharmaceutically acceptable salt thereof, or british or a pharmaceutically acceptable salt thereof, with the neuron.

In some embodiments, methods of treating alzheimer's disease are provided, comprising administering to a patient in need thereof a therapeutically effective amount of imipramine or a pharmaceutically acceptable salt thereof.

In some embodiments, methods of treating or preventing a neuronal disease or disorder are provided, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

In some embodiments, the neuronal disease or disorder is selected from the group consisting of alzheimer's disease, parkinson's disease, amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia (FTD), and traumatic brain injury. In some embodiments, the neuronal disease or disorder is selected from the group consisting of alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, depression, and traumatic brain injury. In some embodiments, the compound is imipramine and the neuronal disease or disorder is selected from the group consisting of alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and traumatic brain injury.

In some embodiments, provided herein are methods of promoting dendritic spine production in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of imipramine or a pharmaceutically acceptable salt thereof.

In some embodiments, compounds that interact with or inhibit fascin as described herein are provided, wherein the compound does not bind to fascin at binding site 1.

Drawings

Fig. 1 is an analysis of synaptic density in neurons after treatment with a compound according to an embodiment of the disclosure.

Detailed Description

Generally, the compositions and methods described herein provide for the administration of certain compounds that interact with fascin. The compound may be imipramine or a pharmaceutically acceptable salt thereof. In some embodiments, these compositions and methods are useful for treating neuronal diseases or disorders. The compounds may be formulated in pharmaceutical compositions. Also provided is a method comprising administering imipramine or a pharmaceutically acceptable salt thereof to a patient in need thereof to a subject suffering from a disease or condition benefiting from dendritic spine production. The compounds may also contain one or more additional pharmaceutically active substances.

The compound may be plug Ma Mode or a pharmaceutically acceptable salt thereof. The compound may also be a british or a pharmaceutically acceptable salt thereof. In some embodiments, these compositions and methods are useful for treating neuronal diseases or disorders. The compounds may be formulated in pharmaceutical compositions. Also provided is a method comprising administering to a subject suffering from a disease or disorder benefiting from dendritic spine production, plug Ma Mode or a pharmaceutically acceptable salt thereof. Also provided is a method comprising administering a british or a pharmaceutically acceptable salt thereof to a subject suffering from a disease or condition benefiting from dendritic spine production. The compounds may also contain one or more additional pharmaceutically active substances.

I. Definition of the definition

The following description sets forth exemplary embodiments of the present technology. However, it should be recognized that this description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, except to the extent the context in which they are used indicates otherwise.

The term "fascin" refers to a 54-58kDa protein which is actin-crosslinking protein. The term "fascin" may refer to the amino acid sequence of human fascin 1. The term "fascin" includes the nucleotide sequence or wild-type form of the protein, and any mutants thereof. In some embodiments, the "fascin" is wild-type fascin. In some embodiments, the "fascin" is one or more mutant forms. In some embodiments, the fascin is human fascin 1. In some embodiments, fascin is encoded in a nucleotide sequence corresponding to reference number GI 347360903. In some embodiments, the fascin is encoded in the nucleotide sequence of RefSeq m_ 003088. In some embodiments, the fascin corresponds to the amino acid sequence of RefSeq np_ 003079.1.

The term "dendritic spine production" and the like in a general and customary sense refers to the development (e.g., growth and/or maturation) of dendritic spines in neurons. In some embodiments, the compounds provided herein promote dendritic spine production without affecting overall spine morphology ratio (e.g., fine, stubby, mushroom-like). The promotion is relative to the absence of administration of the compound.

The term "mood disorder" refers to a major mental disorder in which the patient's general emotional state or emotion is distorted or otherwise inconsistent with the environment and interferes with the patient's performance of daily life functions. The subject may be sad, empty or irritable, or may have periods of negative mood alternating with excessive open (manic) sensations.

As used herein, the term "dendrite" refers to a branch extension of a neuronal cell. Dendrites are generally responsible for receiving electrochemical signals transmitted from axons of neighboring neurons. The term "dendritic spine" or "dendritic spine" refers to a protoplast protrusion on a neuronal cell (e.g., on a dendrite). In some embodiments, the dendritic spine may be described as having a membranous neck that may terminate in a head (e.g., head). Dendritic spines are classified according to their shape: fine, stubby or mushroom. The density of dendritic spines refers to the total number of dendritic spines per unit length of neuronal cells. For example, the dendritic spine density may be given as the number of dendritic spines per micron.

The term "dendritic spine formation" and the like are used in a general and customary sense to refer to a process that results in an increase in the number of dendritic spines or an increase in the development of dendritic spines. The term "dendritic spine morphology" and the like are used in a general and customary sense to refer to physical characterization (e.g., shape and structure) of the dendritic spine. An improvement in dendritic spine morphology is a change in morphology (e.g., an increase in length or an increase in width) that causes an increase in functionality (e.g., an increase in the number of contacts between neurons, or an increase in synaptic width). As known in the art and disclosed herein, exemplary methods for such characterization include measuring the size (i.e., length and width) of the dendritic spine. Thus, the term "improving dendritic spine morphology" generally refers to an increase in the length, width, or both length and width of the dendritic spine.

By "binding" is meant that at least two different substances (e.g., chemical compounds or cells, including biomolecules) become sufficiently close to react or interact to cause the formation of a complex. For example, the binding of two different substances (e.g., proteins and compounds described herein) may result in the formation of a complex, wherein the substances interact via non-covalent or covalent bonds. In some embodiments, when two different substances (e.g., proteins and compounds described herein) interact via non-covalent bonds (e.g., static, van der Waals (van der Waals), or hydrophobic), the resulting complex is formed.

As defined herein, the terms "activation," "activation," and the like with respect to protein-activator (e.g., agonist) interactions mean positively affecting (e.g., increasing) the activity or function of a protein relative to the activity or function of the protein in the absence of an activator (e.g., a compound described herein).

"control" or "control experiment" is used in accordance with its usual ordinary meaning and refers to an experiment in which subjects or reagents of the experiment are treated as in parallel experiments, except for the procedure, reagent or variable in which the experiment is omitted. In some cases, a control was used as a comparative standard for evaluating the experimental effect.

"contact" is used in accordance with its usual meaning and refers to a process that allows at least two different substances (e.g., chemical compounds including biomolecules or cells) to come into close enough proximity to interact. The term "contacting" may include allowing two molecular species to react or physically touch, where the two species may be, for example, a compound, a biomolecule, a protein, or an enzyme as described herein. In some embodiments, contacting comprises allowing a compound described herein to interact with a protein (e.g., fascin) or an enzyme. In some embodiments, contacting may include binding proteins.

As defined herein, the terms "inhibit", "inhibit" and the like are given their conventional meanings to those skilled in the art. With respect to protein-inhibitor (e.g., antagonist) interactions, the terms "inhibit", "inhibit" and "inhibit" mean negatively affecting (e.g., reducing) the functional activity of a protein relative to the functional activity of the protein in the absence of the inhibitor.

A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C (O) NH ₂ Through a carbon atom. Dashes at the front or end of the chemical group are for convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. The wavy line drawn through the lines in the structure indicates the point of attachment of the group. The order in which chemical groups are written or named does not indicate or imply directionality unless chemically or structurally required.

Prefix "C _u-v "indicates that the following groups have u to v carbon atoms. For example, "C _1-6 Alkyl "indicates that the alkyl group has 1 to 6 carbon atoms.

References herein to "about" a value or parameter include (and describe) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes reference to an indicated amount of ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Furthermore, the term "about X" includes descriptions of "X". Furthermore, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

Some compounds exist as tautomers. Tautomers are balanced with each other. For example, the amide-containing compound may exist in equilibrium with the imidic acid tautomer. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between the tautomers, one of ordinary skill in the art will understand that a compound includes all tautomers.

Any formula or structure given herein is also intended to represent an unlabeled form of the compound and an isotopically labeled form. Isotopically-labeled compounds have structures depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure, or counter ions thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to ² H (deuterium, D), ³ H (tritium), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ Cl and Cl ¹²⁵ I. Various isotopically-labeled compounds are possible in accordance with the present disclosure, for example, to incorporate therein, for example ³ H、 ¹³ C and C ¹⁴ Those of the radioisotope of C. Such isotopically-labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), contain drug or substrate tissue distribution assays, or are useful in the radiation treatment of patients.

The present disclosure also includes "deuterated analogs" of compounds wherein 1 to n hydrogens attached to a carbon atom are replaced with deuterium, wherein n is the number of hydrogens in the molecule, and their counter ions. Such compounds exhibit increased metabolic resistance upon administration to mammals, especially humans, and are therefore useful for increasing the half-life of the compounds. See, e.g., foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci.5 (12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced with deuterium.

Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or improved therapeutic index. ¹⁸ F-labeled compounds can be used in PET or SPECT studies. Isotopically-labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or examples, and by preparing as described below, by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent. It is to be understood that deuterium is considered to be a substituent in the compound in this context.

The concentration of this heavier isotope, in particular deuterium, may be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is explicitly designated as "H" or "hydrogen," that position is understood to have hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

The compounds described herein may exist as salts (such as pharmaceutically acceptable salts). The compounds are capable of forming salts, such as acid and/or base salts. Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. By "pharmaceutically acceptable" or "physiologically acceptable" is meant compounds, salts, compositions, dosage forms, and other materials that are useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use. Salts of the compounds described herein may be prepared according to procedures described herein and known in the art.

The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if the compounds described herein are obtained in the form of acid addition salts, the free base may be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be made by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, for example, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH ₂ (alkyl)), dialkylamine (i.e., HN (alkyl) ₂ ) Trialkylamine (i.e. N (alkyl) ₃ ) Substituted alkylamines (i.e. NH ₂ (substituted alkyl)), di (substituted alkyl) amine (i.e., HN (substituted alkyl) ₂ ) Tri (substituted alkyl) amines (i.e., N (substituted alkyl) ₃ ) Alkenyl amines (i.e. NH ₂ (alkenyl)), dienylamine (i.e., HN (alkenyl) ₂ ) Trialkenylamine (i.e., N (alkenyl) ₃ ) Substituted alkenylamines (i.e. NH) ₂ (substituted alkenyl)), di (substituted alkenyl) amine (i.e., HN (substituted alkenyl) ₂ ) Tris (substituted alkenyl) amine (i.e., N (substituted alkenyl) ₃ Mono-, di-, or tricycloalkylamines (i.e. NH ₂ (cycloalkyl), HN (cycloalkyl) ₂ N (cycloalkyl) ₃ ) Mono-, di-, or triarylamines (i.e. NH) ₂ (aryl), HN (aryl) ₂ N (aryl) ₃ ) Or mixed amines, etc. Specific examples of suitable amines include, for example, isopropylamine, trimethylamine, diethylamine, tri (isopropyl) amine, tri (N-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. The method of preparing the salt also includes mixing the compound with the active metal by a redox reaction, or by ion exchange, for example due to the different solubilities of the salt.

A "solvate" is a solid form of a compound in which a solvent molecule is incorporated. Solvates are formed by the interaction of the solvent and the compound. Hydrates are solvates in which the solvent is water. Solvates of salts of the compounds described herein are also provided.

As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional medium or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

"treatment" is a method for achieving a beneficial or desired result, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) Treating a disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder, and/or reducing the extent of the disease or disorder); b) Slowing or arresting the progression of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the progression or worsening of the disease or disorder, and/or preventing or delaying the spread (e.g., metastasis) of the disease or disorder); and/or c) alleviating a disease, i.e., causing resolution of clinical symptoms (e.g., improving the disease state, providing partial or complete relief of the disease or disorder, enhancing the effect of another drug, delaying the progression of the disease, improving quality of life, and/or extending survival).

"preventing" means any treatment of a disease or disorder that results in the absence of the development of clinical symptoms of the disease or disorder. In some embodiments, the compound may be administered to a subject (including a human) at risk of, or having a family history of, the disease or disorder.

"subject" refers to an animal, such as a mammal (including a human being), that has been or will be the subject of treatment, observation or experiment. The methods described herein may be used for human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. When the subject is a human, the subject may be referred to as a "patient.

The term "therapeutically effective amount" or "effective amount" of a compound or pharmaceutically acceptable salt thereof as described herein refers to an amount sufficient to effect treatment when administered to a subject to provide a therapeutic benefit such as improvement in symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to reduce symptoms of a neuronal disorder. The therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administration, and can be readily determined by one of ordinary skill in the art.

The methods described herein may be applied to a population of cells in vivo or ex vivo. By "in vivo" is meant within a living individual, such as within an animal or human. In this context, the methods described herein may be therapeutically useful for an individual. By "ex vivo" is meant outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including liquid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo for a given indication, cell type, individual, and other parameters to determine the optimal schedule and/or dosage of administration of the compounds of the present disclosure. The information gathered from this use may be used for experimental purposes or in the clinic for setting up a regimen for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized as examining safe or tolerating doses in human or non-human subjects. Such properties may be checked using methods generally known to those skilled in the art.

Compounds of formula (I)

Provided herein are agents that promote dendritic spine production. Such agents are useful in the treatment of neuronal diseases and disorders.

In some embodiments, the compound that promotes dendritic spine formation is imipramine having the structure:

or a pharmaceutically acceptable salt thereof. The salt of imipramine may be imipramine hydrochloride.

In some embodiments, the compound that promotes dendritic spine formation is plug Ma Mode having the structure:

or a pharmaceutically acceptable salt thereof. The salt of plug Ma Mode can be plug Ma Mode hydrochloride.

In some embodiments, the compound that promotes dendritic spine formation is a bristatin having the structure:

or a pharmaceutically acceptable salt thereof. The salt of british can be british.

The compounds described herein may be prepared according to methods known to those skilled in the art. Compounds, if available, are commercially available, for example, from Sigma Aldrich or other chemical suppliers.

The synthesis may be carried out by known procedures or modified methods thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, wisconsin, USA), bachem (Torrance, california, USA), emka-Chemce, or Sigma (St. Louis, missouri, USA). Other starting materials may be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley, and Sons, 1991), rodd's Chemistry of Carbon Compounds, volumes 1-5 and journals (Elsevier Science Publishers, 1989) organic Reactions, volumes 1-40 (John Wiley, and Sons, 1991), march 'sAdvanced Organic Chemistry (John Wiley, and Sons,2001 5 th edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or modifications thereof.

Therapeutic methods and uses

Fascin

Described herein are methods of regenerating a spinous process lost due to a neurodegenerative disorder by targeting cytoskeletal proteins with an agent, such as a compound described herein. Unexpectedly, it was observed that the interaction with or inhibition of the cytoskeletal protein fascin 1 (FSCN 1) resulted in rapid up-regulation of dendritic spines in vivo and in vitro. Dendritic spines contain filiform actin (F-actin), a cytoskeletal polymer that imparts a specialization to cell structures and their subcellular components. The extension of the F-actin filaments and the alteration of their organization are important for the formation, maturation and plasticity of dendritic spines. Prior to the present disclosure, it was believed that the ability of fascin 1 to bundle F-actin filaments into parallel arrays would be necessary to form a broad range of cell processes such as invasive pseudopodia, filopodia, and possibly dendritic spines. Fascin 1 is believed to promote cell migration and the associated processes of cancer metastasis resulting from such processes. It has been observed that small molecule inhibitors of fascin 1, which block its ability to cluster F-actin, reduce F-actin-rich cell processes. Thus, previous work indicated that fascin inhibitors also block the formation of dendritic spines, which are the cell processes rich in F-actin. However, contrary to expectations, the fact is exactly the opposite: inhibitors of the structural differences of fascin 1 and gene knockdown of fascin 1 can cause a rapid increase in dendritic spine density. Without wishing to be bound by theory, it is believed that dendritic spines require the formation of highly branched F-actin assemblies, and that the formation of such assemblies can be prevented or significantly reduced by bundling F-actin into parallel arrays by fascin 1.

Fascin binding sites are described in International publication No. WO 2020/046991. In some embodiments, there is provided a method of interacting or binding with fascin at position 2 or position 3, the method comprising contacting the fascin with an effective amount of imipramine or a pharmaceutically acceptable salt thereof. In some embodiments, the method causes an interaction with fascin. In some embodiments, the method inhibits fascin. Imipramine or a pharmaceutically acceptable salt thereof is believed to promote dendritic spine formation by interacting with or inhibiting fascin.

In some embodiments, there is provided a method of interacting or binding with fascin at position 2, the method comprising contacting the fascin with an effective amount of imipramine or a pharmaceutically acceptable salt thereof. In some embodiments, a method of interacting or binding to fascin at position 3 is provided, comprising contacting fascin with an effective amount of plug Ma Mode or a pharmaceutically acceptable salt thereof. In some embodiments, there is provided a method of interacting or binding with fascin at position 3, the method comprising contacting the fascin with an effective amount of british or a pharmaceutically acceptable salt thereof. In some embodiments, the method causes an interaction with fascin. In some embodiments, the method inhibits fascin. Imipramine or a pharmaceutically acceptable salt thereof, plug Ma Mode or a pharmaceutically acceptable salt thereof, britin or a pharmaceutically acceptable salt thereof is believed to promote dendritic spine formation by interacting with or inhibiting fascin.

Fascin is an important actin-crosslinking agent that has no amino acid sequence homology with other actin-binding proteins. Three forms of fascin are found in vertebrates: fascin 1, widely found in the nervous system and elsewhere; fascin 2 found in retinal photoreceptor cells; and fascin 3 found only in testes. In some embodiments, the fascin is human fascin 1. Fascin has a molecular mass of 55kDa, acts as a monomeric entity, and crosslinks actin filaments into straight, tight and rigid bundles to give mechanical stiffness to the actin bundles. Fascin is believed to hold parallel actin filaments together to form filopodia with a diameter of about 60nm-200 nm. The structure of fascin and actin binding site are illustrated in FIG. 1 of International patent publication No. WO 2020/046991.

During neuronal development, long bundles of f-actin are thought to push out of the neuronal membrane to form structures such as axons, dendrites, filopodia, and lamellipodia. Fascin is thought to be involved in cytoskeletal reorganization of primary dendritic projections. Thus, actin bundling by actin is generally considered to be required for the formation and extension of axons and dendrites. Surprisingly, the present results indicate that interaction with or inhibition of the activity of fascin in the formation of actin bundles promotes the formation of dendritic spines (processes of the cytoplasmic membrane of dendrites).

Fascin is believed to have at least three actin binding sites, binding site 1, binding site 2 and binding site 3. Thus, fascin appears to have three sites to which actin can bind. Binding site 2 was not seen in the early apo (ligand-free) crystal structure of fascin, probably due to movement of the protein structure after ligand binding. It is believed that the compounds disclosed in International patent publication No. WO 2017/120198 bind to fascin at binding site 1. However, it is emphasized that the mode of action is not well understood.

In some embodiments, fascin binding site 1 is defined at least in part by V10, Q11, L40, K41, a137, H139, Q141, Q258, S259, R383, R389, E391, G393, F394, S409, Y458, K460, E492, and/or Y493. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof does not bind to any of the fascin residues selected from V10, Q11, L40, K41, a137, H139, Q141, Q258, S259, R383, R389, E391, G393, F394, S409, Y458, K460, E492, and/or Y493. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof does not bind to fascin binding site 1 and/or binding site 3. In some embodiments, plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimycin or a pharmaceutically acceptable salt thereof, does not bind to any of the fascin residues selected from V10, Q11, L40, K41, a137, H139, Q141, Q258, S259, R383, R389, E391, G393, F394, S409, Y458, K460, E492, and/or Y493. In some embodiments, plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimonin or a pharmaceutically acceptable salt thereof, does not bind to fascin binding site 1.

Fascin binding site 2 is believed to be defined at least in part by F14, L16, L48, Q50, L62, W101, L103, E215, and/or S218. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof binds to at least one fascin residue selected from the group consisting of F14, L16, L48, Q50, L62, W101, L103, E215, and S218. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof binds to two, three, four, five, six, seven, or eight fascin residues selected from F14, L16, L48, Q50, L62, W101, L103, E215, and S218. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof binds to at least one group I fascin residue selected from F14 and L16. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof binds to at least one group II fascin residue selected from L48, Q50 and L62. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof binds to at least one group III fascin residue selected from W101 and L103. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof binds to at least one group IV fascin residue selected from E215 and S218. In some embodiments, fascin binding site 2 is defined at least in part by F14, L16, L48, a58, V60, L62, I93, a95, W101, L103, V134, T213, L214, E215, F216, and/or R217.

In some embodiments, plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimycin or a pharmaceutically acceptable salt thereof, does not bind to any of the fascin residues selected from F14, L16, L48, Q50, L62, W101, L103, E215, and/or S218. In some embodiments, plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimycin or a pharmaceutically acceptable salt thereof, does not bind to any of the fascin residues selected from F14, L16, L48, a58, V60, L62, I93, a95, W101, L103, V134, T213, L214, E215, F216, and/or R217. In some embodiments, plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimonin or a pharmaceutically acceptable salt thereof, does not bind to fascin binding site 2.

In some embodiments, fascin binding site 3 is defined at least in part by Q291, R308, H310, T311, G312, K313, Y314, L317, T318, T320, T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and/or K379. In some embodiments, the imipramine or a pharmaceutically acceptable salt thereof binds to at least one fascin residue selected from the group consisting of: q291, R308, H310, T311, G312, K313, Y314, L317, T318, T320, T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and K379. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof binds to two, three, four, five, six, seven, or eight fascin residues selected from the group consisting of: q291, R308, H310, T311, G312, K313, Y314, L317, T318, T320, T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and K379.

In some embodiments, plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimycin or a pharmaceutically acceptable salt thereof, is conjugated to at least one fascin residue selected from the group consisting of: q291, R308, H310, T311, G312, K313, Y314, L317, T318, T320, T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and K379. In some embodiments, plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimycin or a pharmaceutically acceptable salt thereof, is conjugated to two, three, four, five, six, seven, or eight fascin residues selected from the group consisting of: q291, R308, H310, T311, G312, K313, Y314, L317, T318, T320, T326, S328, K329, N330, N331, S333, E339, R341, R344, R348, K353, S350, N351, F354, T356, S357, K358, K359, N360, Q362, L363, S366, V367, E368, T369, D372, S373, L375, L377, I381, and K379.

In some embodiments, the binding site of imipramine or a pharmaceutically acceptable salt thereof may be determined by site-directed mutagenesis. For example, the amino acid residues in a mutant fascin may be altered relative to wild-type fascin. For example, if a decrease in binding affinity of an agent is determined between wild-type fascin and mutant fascin in which an amino acid residue at binding site 1, binding site 2 or binding site 3 is replaced with a non-natural residue (e.g., an alanine residue), then the decrease can be attributed to a loss of binding affinity at the replacement site. Site-directed mutagenesis may be performed according to known methods, for example, kunkel method, cassette mutagenesis, PCR site-directed mutagenesis or CRISPR.

Likewise, in some embodiments, the binding site of plug Ma Mode or a pharmaceutically acceptable salt thereof or british or a pharmaceutically acceptable salt thereof, such as described herein (including embodiments), can be similarly determined by site-directed mutagenesis.

In some embodiments, the imipramine or a pharmaceutically acceptable salt thereof binds to fascin, K _d At least about 10nM, at least about 100nM, at least about 1 μM, at least about 5 μM, at least about 10 μM, at least about 20 μM, at least about 50 μM, at least about 100 μM, or at least about 500 μM, as determined by isothermal titration calorimetry.

In some embodiments, plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimycin or a pharmaceutically acceptable salt thereof binds to fascin, K _d At least about 10nM, at least about 100nM, at least about 1 μM, at least about 5 μM, at least about 10 μM, at least about 20 μM, at least about 50 μM, at least about 100 μM, or at least about 500 μM, as determined by isothermal titration calorimetry.

In some embodiments, compounds other than those described above (e.g., brimycin and plug Ma Mode) that bind at fascin binding site 3 ("binding site 3 compound") or a pharmaceutically acceptable salt thereof may be used in place of or in addition to those described herein (including embodiments). Such compounds include, for example, urea C-13 (or (13C) urea), uracil (or 1,2,3, 4-tetrahydropyrimidine-2, 4-dione), N- (7-formamidinylnaphthalen-1-yl) -3-hydroxy-2-methylbenzamide, N- [2- ({ [ amino (imino) methyl ] amino } oxy) ethyl ] -2- { 6-chloro-3- [ (2, 2-difluoro-2-phenylethyl) amino ] -2-fluorophenyl } acetamide, methyl 6-formamidinyl-4- (3-hydroxy-2-methyl-benzoylamino) -naphthalene-2-carboxylate (or methyl 6-formamidinyl-4- (3-hydroxy-2-methylbenzylamino) -naphthalene-2-carboxylate), panthenol-aminoethanol-acetate pivalic acid, [4- (2-amino-4-methyl-thiazol-5-yl) -pyrimidin-2-yl ] - (3-nitro-phenyl) -amine.

In some embodiments, other compounds that bind at fascin binding site 1 ("compounds of binding site 1") or pharmaceutically acceptable salts thereof may be used in place of or in conjunction with those described herein (including embodiments). Such compounds include, for example, (2R) -14-fluoro-2-methyl-6,9,10,19-tetraazapentacyclo [14.2.1.0 {2,6}.0 {8,18}.0 {12,17} ] nonadeca-1 (18), 8,12 (17), 13, 15-penten-11-one, hexadien-epinephrine, N- (2-amino-4-fluorophenyl) -4- { [ (2E) -3- (pyridin-3-yl) prop-2-enamido ] methyl } benzamide, N- (4-sulfamoylphenyl) -1H-indazole-3-carboxamide, 2-hydroxy-5- (3, 5, 7-trihydroxy-4-oxochromen-2-yl) phenoxyphosphonic acid, allantoin, 4- [ (4E) -1- (carboxymethyl) -4- [ (4-hydroxyphenyl) methylene ] -5-oxoimidazol-2-yl ] -4-iminobutyric acid, N- (1H-indazol-5-yl) -2- (6-methylpyridin-2-yl) quinazolin-4-amine, and green-amine.

Neuronal diseases and disorders and treatment thereof

A unified feature of neurodegenerative disorders with cognitive components is the loss of synapses that utilize the amino acid glutamate as neurotransmitter ("glutamatergic" synapses), which are believed to be the most abundant type of synapses in humans and other mammals. Importantly, about 90% of glutamatergic synapses involve post-synaptic dendritic spines. Most of the synapses lost in neurodegenerative disorders are the synapses in which the axons are in contact with the dendritic spines, so-called "axon synapses". Under normal conditions, changes in the density, shape and protein composition of dendritic spines affect the strength of synaptic communication and are the basis for several forms of synaptic changes (i.e. "plasticity") that involve learning and memory, cognitive flexibility, adaptation to injury and disease, and other processes. These changes in the axonal synapses are believed to be important for memory coding functions of structures such as the hippocampus. Thus, it is believed that early and progressive loss of dendritic spines in the hippocampus and other areas is a driving factor for memory loss and cognitive decline in alzheimer's disease and other dementias. The development of new methods for regenerating spine density is of great importance for the treatment of hosts for neurodegenerative and developmental cognitive disorders.

Dendritic spines are specialized protrusions responsible for receiving synaptic inputs, providing important functions in communication between neurons. The morphology of dendritic spines and their overall density are related to synaptic function and are closely related to memory and learning. Cell changes in brain cells may contribute to the pathogenesis of neuronal diseases. For example, abnormal levels (e.g., decreased) of dendritic spine density in the brain may contribute to the pathogenesis of neuronal disorders. Thus, it is believed that changes or misregulation of dendritic spines affect synaptic function and play a major role in various neurological and psychiatric disorders such as autism, fragile X syndrome, parkinson's Disease (PD) and Alzheimer's Disease (AD). For example, there is increasing evidence in AD that defects begin to alter hippocampal synaptic function before neurons are lost, which may or may not be caused by amyloid- β (aβ) proteins. Thus, a therapeutic strategy directed to initial synaptic loss, rather than late disease intervention, or even a reduction in aβ, may provide a better prognosis for the treatment of AD. For example, fragile X syndrome is characterized by an excessive number of immature spines.

Provided herein are methods useful for promoting dendritic spine generation. In some embodiments, the method comprises administering to the subject an effective amount of imipramine or a pharmaceutically acceptable salt thereof, as described herein (including embodiments). Dendritic spine generation can be observed as an increase in the average spine number per unit length per neuron or neuron, which can be referred to as an increase in dendritic spine density. Dendritic spine production can be observed as an improvement in dendritic spine morphology. For example, improvement in dendritic spine morphology can be observed as an increase in the average size of the spine. Dendritic spine generation can be observed as an improvement in dendritic spine size, spine plasticity, spine motility, spine density, and/or synaptic function. Tree structure The process generation can be observed as an increase in the local spatial average of the membrane potential. Dendritic spine formation can be observed as Ca ²⁺ An increase in postsynaptic concentration (e.g., volume average concentration). Dendritic spine generation can be observed as an average ratio of mature spine to immature spine, such as an increase in the ratio of "mushroom" or "stubby" spine relative to the fine spine. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof increases the density of dendritic spines relative to a control. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof increases the density of dendritic spines relative to the density of dendritic spines observed at the beginning of the treatment. In some embodiments, an increase in the density of dendritic spines results in a decrease in the symptoms of a neuronal disease or disorder in a subject or patient. In some embodiments, the increase in dendritic spine density is explained by anatomical observations. In some embodiments, an increase in dendritic spine density is observed in primary hippocampal neurons.

In some embodiments, the method comprises administering to the subject an effective amount of imipramine or a pharmaceutically acceptable salt thereof, as described herein (including embodiments).

In some embodiments, the average dendritic spine density is increased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or any range between any two numbers (inclusive) relative to the time of onset of treatment with imipramine or a pharmaceutically acceptable salt thereof. In some embodiments, the extent of dendritic spine production is proportional to the lack of spine density present prior to treatment, and treatment restores spine density to a level deemed normal or physiologically relevant. In some embodiments, the duration of treatment with imipramine or a pharmaceutically acceptable salt thereof is 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days. In some embodiments, the administration is not continuous, but is performed in discrete administrations, for example, on a given day.

In some embodiments, the method increases the density of the spine by promoting the formation of new spines. In some embodiments, the method increases the average spine density by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or any range between any two numbers (inclusive) relative to a control (e.g., spine density in the absence of compound). In some embodiments, the method increases the average spinous density by about 50% relative to a control (e.g., the spinous density in the absence of the compound).

In some embodiments, the method increases the average number of spines per neuron relative to the time at which treatment with imipramine or a pharmaceutically acceptable salt thereof is initiated. In some embodiments, the average number of spikes per unit length of a neuron increases by at least about 10, 20, 30, 40, 50, 60, or more, or any range between any two numbers (inclusive). In some embodiments, the time is 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days.

In some embodiments, a method for promoting dendritic spine production comprises administering to a subject an effective amount of plug Ma Mode or a pharmaceutically acceptable salt thereof, as described herein (including embodiments). In some embodiments, the method comprises administering to the subject an effective amount of a british hormone or a pharmaceutically acceptable salt thereof, as described herein (including embodiments). In some embodiments, the plug Ma Mode, or a pharmaceutically acceptable salt thereof, or the british hormone, or a pharmaceutically acceptable salt thereof, increases the density of the dendritic spine relative to a control. In some embodiments, the plug Ma Mode, or a pharmaceutically acceptable salt thereof, or the brimycin, or a pharmaceutically acceptable salt thereof, increases the density of dendritic spines relative to the density of dendritic spines observed at the beginning of the treatment. In some embodiments, the average dendritic spine density is increased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or any range between any two numbers (inclusive) relative to the time of onset of treatment with imipramine or a pharmaceutically acceptable salt thereof.

In some embodiments, the extent of dendritic spine production is proportional to the lack of spine density present prior to treatment, and treatment restores spine density to a level deemed normal or physiologically relevant. In some embodiments, the density of dendritic spines is increased by about 50% to about 100% relative to the time of starting treatment with plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimycin or a pharmaceutically acceptable salt thereof. In some embodiments, the duration of treatment with plug Ma Mode, or a pharmaceutically acceptable salt thereof, or british or a pharmaceutically acceptable salt thereof, is 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days. In some embodiments, the administration is not continuous, but is performed in discrete administrations, for example, on a given day.

In some embodiments, the method increases the average number of spines per neuron relative to the time to begin treatment with plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimycin or a pharmaceutically acceptable salt thereof. In some embodiments, the average number of spikes per unit length of a neuron increases by at least about 10, 20, 30, 40, or more, or any range between any two numbers (inclusive). In some embodiments, the time is 1 hour, 2 hours, 4 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 14 days, 28 days, 90 days, 180 days, or 365 days.

In some embodiments, these compounds are useful in the treatment of neuronal diseases and disorders. Neuronal disorders are diseases or conditions in which the function of the subject's nervous system is impaired. The neuronal disease or disorder may be a neurological disease or disorder. The neuronal disease or disorder may be associated with a neurodegenerative disease or disorder.

In one aspect, there is provided a method of treating a neuronal disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of imipramine or a pharmaceutically acceptable salt thereof. In some embodiments, the neuronal disease is alzheimer's disease. In some embodiments, the neuronal disease is Amyotrophic Lateral Sclerosis (ALS). In some embodiments, the neuronal disease is frontotemporal dementia (FTD). In some embodiments, the neuronal disorder is parkinson's disease. In some embodiments, the neuronal disorder is parkinson's disease dementia. In some embodiments, the neuronal disease is autism. In some embodiments, the neuronal disease is fragile X syndrome, angeman's syndrome (Angelman syndrome) or other neurological disorders characterized by abnormally low levels of mature or total spine density. In some embodiments, the disease or disorder is associated with (e.g., characterized by) the accumulation of amyloid plaques. In some embodiments, the neuronal disease is traumatic brain injury. In some embodiments, a patient suffering from a neuronal disorder has suffered a traumatic brain injury before, during, or after the onset of the neuronal disorder. In some embodiments, the neuronal disease comprises neuronal damage. Neuronal damage may include atrophy or other reduction in the effective functioning of neurons. For example, alzheimer's disease is known to exhibit neuronal damage, particularly in cortical neurons, such as hippocampal neurons and neurons in the vicinity of the hippocampus. Loss of synapses may be associated with loss of dendritic spines and neurodegeneration.

In some aspects, a method of treating a neuronal disorder in a patient in need thereof, such as those described herein (including embodiments), the method comprising administering to the patient a therapeutically effective amount of plug Ma Mode or a pharmaceutically acceptable salt thereof, or a british hormone or a pharmaceutically acceptable salt thereof.

In some embodiments, the neuronal disorder is associated with abnormal dendritic spine morphology, spine size, spine plasticity, spine motility, spine density, and/or abnormal synaptic function. In some embodiments, the neuronal disease is associated with abnormal (e.g., reduced) levels of dendritic spine density.

In some embodiments, the neuronal disease is alzheimer's disease. In some embodiments, the neuronal disorder is parkinson's disease. In some embodiments, the neuronal disorder is parkinson's disease with dementia. In some embodiments, the neuronal disease is autism. In some embodiments, the neuronal disorder is stroke. In some embodiments, the neuronal disease is post-traumatic stress disorder (PTSD). In some embodiments, the neuronal disorder is a Traumatic Brain Disorder (TBD). In some embodiments, the neuronal disease is Chronic Traumatic Encephalopathy (CTE). In some embodiments, the neuronal disorder is schizophrenia. In some embodiments, the neuronal disorder is dementia (e.g., general dementia). In some embodiments, the neuronal disorder is attention deficit/hyperactivity disorder (ADHD). In some embodiments, the neuronal disease is Amyotrophic Lateral Sclerosis (ALS). In some embodiments, the neuronal disease is frontotemporal degeneration (FTLD) (e.g., FTLD- τ, FTLD-TDP, or FTLD-FUS) or ALS/FTD. In some embodiments, the neuronal disease is memory loss. In some embodiments, the neuronal disease comprises memory loss. In some embodiments, the neuronal disease is age-related memory loss. In some embodiments, the neuronal disease comprises age-related memory loss. In some embodiments, the neuronal disorder is hypertensive encephalopathy. In some embodiments, the neuronal disease is chronic stress. In some embodiments, the neuronal disease comprises chronic stress. In some embodiments, the neuronal disorder is FTLD-TDP type a. In some embodiments, the neuronal disorder is FTLD-TDP type B. In some embodiments, the neuronal disorder is FTLD-TDP type C. In some embodiments, the neuronal disorder is FTLD-TDP type D.

In some embodiments, the neuronal disease or disorder is Amyotrophic Lateral Sclerosis (ALS), wherein loss of spinous processes in motor cortex and spinal motor neurons contributes to motor dysfunction. In some embodiments, the neuronal disorder is a mixture of motor and cognitive/dementia disorders, involving symptoms of ALS and FTD that are believed to represent different endpoints of a range of genetically and mechanically related neurodegenerative diseases. The neuronal disease or disorder may be tauopathy.

The neuronal disease or disorder may be schizophrenia. Symptoms of schizophrenia are generally classified into the following three categories: psychotic symptoms include altered perception (e.g., changes in vision, hearing, smell, touch, and taste), abnormal thinking, and strange behavior. People with psychotic symptoms may lose a common sense of realism and experience themselves and the world in a distorted manner. Specifically, an individual typically experiences: hallucinations, delusions, and thought disorders (such as irregular thinking and/or speech disorders). Negative symptoms include reduced motility, difficulty planning, reduced pleasure, apathy and reduced language expression. Cognitive symptoms include difficulty in handling information, difficulty concentrating, and difficulty maintaining attention.

Examples of neuronal diseases that can be treated with the compounds or methods described herein include Alexander's disease, alper's disease, alzheimer's disease, depression, perinatal asphyxia, parkinson's disease dementia (PD dementia), amyotrophic lateral sclerosis, ataxia telangiectasia, baten disease (Batten disease) (also known as schw-shore-bafour disease (Spielmeyer-Vogt-Sjogren-Batten disease)), spongiform encephalopathy (e.g., spongiform encephalopathy (mad cow disease), kuru, kezfeldt-Jakob disease (Creutzfeldt-Jakob disease), fatal familial insomnia (fatal familial insomnia), kanavan disease (Canavan disease), kekappaN syndrome (Cockayne syndrome), corticobasal degeneration, fragile X syndrome, frontotemporal dementia, gerstmann-schafer-Sha Yinke (Gerstmann-Straussler-Scheinker syndrome), huntington's disease (Huntington's disease), human immunodeficiency virus-associated dementia, kennedy's disease (Kennedy's disease), krabbe's disease, lewy body dementia (Lewy body dementia), mado-Joseph disease (Machado-Joseph disease) (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neurospirate, parkinsonism, etc. in a bovine spongiform encephalopathy (mad-bovine spongiform encephalopathy), kuh-jaundice (kul disease), kul-jaundice, kul disease, lewy-jaundice, lewy disease, lewy-back disease, lewy-bezed disease, lewy-sence, lewy disease, lewy-back disease, lewy disease, and, petizaeus-Merzbacher Disease), pick's disease, primary lateral sclerosis, prion disease, refsum's disease, sandhoff disease (Sandhoff s disease), hilder's disease, spinal cord subacute joint degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, s-li-aotris (Steele-Richardson-Olszewski disease), spinal cord tuberculosis, drug-induced parkinsonism (drug-induced Parkinsonism), progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, idiopathic parkinsonism, autosomal dominant parkinsonism (familial type 1) (PARK 1), parkinsonism 3, autosomal lewisdom (PARK 3), parkinsonism 4 (autosomal) (parkinsonism) 4 (autosomal) (type 6), parkinsonism (parkinsonism) 5), parkinsonism (parkinsonism) or (parkinsonism 5) (parkinsonism) in the recessive regimen (parkinsonism) (10), parkinsonism (parkinsonism-7), parkinsonism (parkinsonism-8) (10), parkinsonism-10 (parkinsonism-8), parkinsonism-10 (parkinsonism-7), parkinsonism-10 (parkinsonism-8), neuronal disorders are Alzheimer's disease, parkinson's dementia, autism, stroke, post-traumatic stress disorder (PTSD), traumatic Brain Disorder (TBD), chronic traumatic brain lesions (CTE), schizophrenia, dementia (e.g., dementia vulgaris), attention deficit/hyperactivity disorder (ADHD), amyotrophic Lateral Sclerosis (ALS), frontotemporal lobar degeneration (FTLD) (e.g., FTLD-tau, FTLD-TDP or FTLD-FUS), memory loss (e.g., age-related memory loss), hypertensive brain lesions or chronic stress.

In some embodiments, the neuronal disease is Alzheimer's Disease (AD). Alzheimer's disease is characterized by symptoms of memory loss at an early stage of the disease. Apo epsilon 4 carriers are at higher risk of developing AD. APO epsilon 4 is believed to be less efficient at scavenging a epsilon than other isoforms and thus may be associated with higher amyloid burden, tau phosphorylation, synaptic toxicity and reduced synaptic density. Traumatic Brain Injury (TBI) was another risk factor for developing AD, and studies indicated that those experiencing TBI had a significantly increased risk for AD. Cognitive decline is associated with progressive loss of synapses. Symptoms include confusion, long-term memory loss, speech confusion, reduced vocabulary, aggression, irritability, and/or mood swings as the disease progresses. More advanced in the disease, there is a loss of bodily function. Patients with Alzheimer's Disease (AD) exhibit many characteristic neuropathies, such as increased oxidative stress, mitochondrial dysfunction, synaptic dysfunction, disruption of calcium homeostasis, deposition of senile plaques and neurofibrillary tangles, and brain atrophy. AD-related disorders include AD-type Senile Dementia (SDAT), frontotemporal dementia (FTD), vascular dementia, mild Cognitive Impairment (MCI) and age-related memory impairment (AAMI). In some embodiments, methods of treating or preventing alzheimer's disease are provided, the methods comprising administering to a patient in need thereof a therapeutically effective amount of imipramine or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is an Apo epsilon 2 or Apo epsilon 3 carrier. In some embodiments, the patient has undergone TBI. In some embodiments, the patient is an Apo epsilon 4 carrier. In some embodiments, the patient is an Apo epsilon 4 carrier that has undergone TBI.

In some embodiments, a method of treating or preventing alzheimer's disease comprises administering to a patient in need thereof (such as those described in the embodiments above) a therapeutically effective amount of plug Ma Mode or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating or preventing alzheimer's disease comprises administering to a patient in need thereof a therapeutically effective amount of imipramine or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder is an autism spectrum disorder. Disorders of the autism spectrum are often associated with changes in spine density and can be treated with compounds that interact with or inhibit fascin. In some embodiments, the neuronal disease is autism. As known in the art, autism is a disorder of neural development. Without wishing to be bound by any theory, it is believed that autism and autism spectrum disorders affect information processing in the brain by altering the way nerves and synapses connect and organize.

In further embodiments, compositions and methods for alleviating, reducing, or reversing the symptoms of a neuronal disease or disorder are provided. The symptom may be any symptom described herein.

The term "memory" and the like in a general and customary sense refers to the process by which a subject encodes, stores, and retrieves information. In the context of memory, the terms "encode", "register" and "register" refer in a general and customary sense to the receipt, processing and combination of information affecting the meaning as a chemical or physical stimulus. In this context, the term "store" or the like refers in a general and customary sense to creating a record of encoded information. In this context, the terms "retrieve", "recall", and the like refer to recalling stored information in a general and customary sense. The retrieval may be in response to a prompt, as is known in the art. In some embodiments, memory loss refers to a decrease in the ability to encode, store, or retrieve information. In some embodiments, the memory may be a reconfirmation memory or a recall memory. In this context, "reconfirmation" refers to the recollection of previously encountered stimuli. The stimulus may be, for example, a word, a scene, a sound, a smell, etc., as known in the art. A more broad class of memories is "recall memories" which require retrieval of previously learned information, such as a list of actions, words or numbers, etc., previously encountered by the subject. The method can be used to treat memory disorders that occur within the major categories of both declarative and non-declarative memory, including episodic memory and "motor memory. Methods for assessing the level of memory encoding, storage, and retrieval exhibited by a subject are well known in the art, including the methods disclosed herein. For example, in some embodiments, the method improves memory in a subject in need thereof, wherein the subject has a neuronal disorder. In some embodiments, the method improves memory in the subject. In some embodiments, the method treats neuronal damage or cognitive damage in a subject. In some embodiments, the method treats neuronal damage in a subject. In some embodiments, the method treats cognitive impairment in a subject.

With further regard to any aspect disclosed herein, in some embodiments, the subject has brain injury. Types of brain damage include brain damage (i.e., destruction or degeneration of brain cells), traumatic brain damage (i.e., damage due to external forces to the brain), stroke (i.e., vascular events that temporarily or permanently damage the brain (e.g., via hypoxia)), and acquired brain damage (i.e., brain damage that does not occur at birth). In some embodiments, the method improves memory in the subject. In some embodiments, the method improves learning in the subject. In some embodiments, the method treats neuronal damage or cognitive damage in a subject. In some embodiments, the method treats neuronal damage in a subject. In some embodiments, the method treats cognitive impairment in a subject.

In some embodiments, methods for promoting dendritic spine production in a patient in need thereof are provided, the methods comprising administering to the patient a compound that interacts with or inhibits fascin. In some embodiments, methods of treating or preventing a neuronal disease or disorder are provided, comprising administering to a patient in need thereof a therapeutically effective amount of imipramine or a pharmaceutically acceptable salt thereof. In some embodiments, compounds for use in the treatment of neuronal diseases or disorders are provided, wherein the compound is imipramine or a pharmaceutically acceptable salt thereof. In some embodiments, compounds are provided for use in the manufacture of a medicament for the treatment of a neuronal disease or disorder, wherein the compound is imipramine or a pharmaceutically acceptable salt thereof. In some embodiments, the neuronal disease or disorder is selected from the group consisting of alzheimer's disease, parkinson's dementia, autism, fragile X syndrome, and traumatic brain injury. In some embodiments, the neuronal disease or disorder is alzheimer's disease. In some embodiments, imipramine or a pharmaceutically acceptable salt thereof interacts with or inhibits cross-linking of f-actin. In some embodiments, the imipramine or pharmaceutically acceptable salt thereof is anti-metastatic.

In some embodiments, methods of treating or preventing a neuronal disease or disorder are provided, comprising administering to a patient in need thereof a therapeutically effective amount of plug Ma Mode or a pharmaceutically acceptable salt thereof, or a britisin or a pharmaceutically acceptable salt thereof. In some embodiments, a compound for use in treating a neuronal disease or disorder is provided, wherein the compound is celecoxib Ma Mode or a pharmaceutically acceptable salt thereof, or britin or a pharmaceutically acceptable salt thereof. In some embodiments, a compound for use in the manufacture of a medicament for the treatment of a neuronal disease or disorder is provided, wherein the compound is celecoxib Ma Mode or a pharmaceutically acceptable salt thereof, or britisin or a pharmaceutically acceptable salt thereof. In some embodiments, the neuronal disorder is selected from the group consisting of alzheimer's disease, parkinson's dementia, autism, fragile X syndrome, and traumatic brain injury. In some embodiments, the neuronal disease or disorder is alzheimer's disease. In some embodiments, plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimycin or a pharmaceutically acceptable salt thereof interacts with or inhibits cross-linking of f-actin. In some embodiments, the plug Ma Mode, or a pharmaceutically acceptable salt thereof, or the british hormone, or a pharmaceutically acceptable salt thereof, is anti-metastatic.

Combination therapy

In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents for and/or developed for the treatment of neuronal diseases or disorders.

When used in the treatment or prevention of the above-described diseases and disorders, imipramine or a pharmaceutically acceptable salt thereof may be administered with one or more additional therapeutic agents, such as additional therapeutic agents approved for the treatment or prevention of a particular disease or disorder, and more particularly agents that are believed to form current standards of care. Where combination therapies are envisaged, the active agents may be administered simultaneously, separately or sequentially in one or more pharmaceutical compositions.

Likewise, plug Ma Mode or a pharmaceutically acceptable salt thereof, or brimycin or a pharmaceutically acceptable salt thereof, may be administered with one or more additional therapeutic agents such as those described herein (including embodiments).

Thus, the latest strategies for treating AD include controlling the production or aggregation state of aβ peptide of a specific isotype. Additional strategies include preventing, reducing or eliminating toxic forms of phosphorylated tau. Other strategies involve small molecule targeting of enzymes that play a role in the production of aβ peptides by processing amyloid precursor proteins in an attempt to reduce the abundance of aβ peptides in the brain. In addition, there is increasing information about the sporadic inherited effects of specific mutations in non-amyloid neuropathies such as tauopathies or apolipoprotein E genes, which motivates additional strategies against neurodegeneration.

Kit for detecting a substance in a sample

Also provided herein are kits comprising a compound described herein, or a pharmaceutically acceptable salt thereof, optionally a second active ingredient, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound or a pharmaceutically acceptable salt thereof, and a label and/or instructions for use of the pharmaceutical composition in treating an indication, including a disease or disorder described herein.

Also provided herein are articles of manufacture comprising a compound described herein or a pharmaceutically acceptable salt thereof in a suitable container. The container may be a vial, a wide-mouth bottle, an ampoule, a prefilled syringe, a nebulizer, an aerosol dispensing device, a dropper, or an intravenous infusion bag (intravenius bag).

Pharmaceutical compositions and modes of administration

The compounds provided herein are generally administered in the form of pharmaceutical compositions. Accordingly, provided herein are also pharmaceutical compositions comprising one or more of the compounds described herein (generally including the compounds described herein) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable vehicles selected from the group consisting of carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical arts. See, e.g., remington's Pharmaceutical Sciences, mace Publishing Co., philadelphia, pa., 17 th edition (1985); and Modern Pharmaceutics, marcel Dekker, inc. 3 rd edition (edited by g.s. Banker and c.t. Rhodes).

The pharmaceutical composition may be administered in a single dose or in multiple doses. The pharmaceutical compositions may be administered by a variety of methods including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenous, intraperitoneal ("i.p."), parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

One mode of administration is parenteral administration, for example by injection. The pharmaceutical compositions described herein may be incorporated for administration by injection in forms including, for example, aqueous or oily suspensions or emulsions having sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions, and similar pharmaceutical vehicles.

Oral administration may be another route of administration for the compositions described herein. Administration may be via, for example, capsules or enteric coated tablets. In preparing pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, the active ingredient is typically diluted with an excipient and/or encapsulated in a carrier which may be in the form of a capsule, sachet, paper or other container. When an excipient is used as a diluent, it may be in the form of a solid, semi-solid, or liquid material, which serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulation may additionally comprise lubricants such as talc, magnesium stearate and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; a sweetener; and a flavoring agent.

The pharmaceutical composition and any containers in which it is dispensed may be sterilized. The pharmaceutical composition may also contain adjuvants such as preserving, stabilizing, emulsifying or suspending agents, wetting agents, salts for altering the osmotic pressure, viscosity-modifying agents (viscosity alerting agent) or buffers.

Compositions comprising at least one compound described herein (such as a compound described herein) or a pharmaceutically acceptable salt thereof may be formulated so as to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems, and dissolution systems containing polymer coated reservoirs (reservoir) or drug-polymer matrix formulations. Examples of controlled release systems are described in U.S. Pat. nos. 3,845,770;4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents is well known in the art. See, for example, U.S. patent nos. 5023252, 4992445 and 5001139. Such patches may be configured for continuous, pulsatile, or on-demand delivery of agents.

To prepare a solid composition such as a tablet, the primary active ingredient may be mixed with pharmaceutical excipients to form a solid pre-formulated composition containing a homogeneous mixture of the compounds described herein or pharmaceutically acceptable salts thereof. When these preformulated compositions are referred to as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, a tablet or pill may include an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids, as well as mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

The pharmaceutical composition may be formulated for nasal administration. Such pharmaceutical compositions may comprise one or more active ingredients of different physical states, such as the compounds described herein or pharmaceutically acceptable salts thereof. For example, the active ingredient may be dissolved or suspended in a liquid carrier. The active ingredient may be in dry form. The dry form may be a powder. The active ingredient in the powder may be amorphous or crystalline. For example, a compound described herein, or a pharmaceutically acceptable salt thereof, may be amorphous or crystalline. The crystalline active material may be a hydrate or solvate.

The solid compound or salt or crystals thereof may be present in the formulation in a selected average particle size. The particles may have an average particle size (in the longest dimension) of 10nm, 100nm, 300nm, 500nm, 1 μm, 10 μm, 50 μm, 100 μm, 300 μm or 500 μm or a range between any two values.

Administration may be by inhalation or insufflation. Compositions for inhalation or insufflation may comprise solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered by the oral or nasal respiratory route. The effect may be local or systemic. In certain embodiments, the effect is local to cranial tissue. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized by use of inert gases. The spray solution may be inhaled directly from the spray device or the spray device may be attached to a facemask curtain (facemask tent) or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered orally or nasally from a device that delivers the formulation in a suitable manner. The pharmaceutical composition for inhalation or insufflation may be an aerosol formulation.

The pharmaceutical composition may comprise a liquid suspension or solution comprising about 0.05% w/w, about 0.1% w/w, about 0.3% w/w, about 0.5% w/w, about 0.7% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, or about 5% w/w of the active ingredient. The liquid may comprise water and/or an alcohol. The liquid may contain a pH adjuster such that the pH is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10, or a range of values therebetween.

The pharmaceutical composition may comprise a pharmaceutically acceptable preservative. Preservatives suitable for use herein include, but are not limited to, preservatives that protect the solution from pathogenic particle contamination, including phenethyl alcohol, benzalkonium chloride (benzalkonium chloride), benzoic acid or benzoates, such as sodium benzoate. In certain embodiments, the pharmaceutical composition comprises about 0.01% w/w to about 1.0% w/w benzalkonium chloride or about 0.01% v/w to about 1% v/w phenethyl alcohol. The preservative may also be present in an amount of from about 0.01% to about 1%, preferably from about 0.002% to about 0.02%, by total weight or volume of the composition.

The pharmaceutical composition may further comprise from about 0.01% to about 90%, or from about 0.01% to about 50%, or from about 0.01% to about 25%, or from about 0.01% to about 10%, or from about 0.01% to about 1% w/w of one or more emulsifying, wetting or suspending agents. Such agents for use herein include, but are not limited to, polyoxyethylene sorbitan fatty acid esters or polysorbates, including, but not limited to, polyethylene sorbitan monooleate (polysorbate 80), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; lecithin; alginic acid; sodium alginate; potassium alginate; ammonium alginate; calcium alginate; propylene-1, 2-glycol alginate; agar; carrageenan (carrageenan); locust bean gum; guar gum (guar); tragacanth gum; acacia gum; xanthan gum; karaya gum; pectin; amidated pectin; ammonium phospholipids; microcrystalline cellulose; methyl cellulose; hydroxypropyl cellulose; hydroxypropyl methylcellulose; ethyl methyl cellulose; carboxymethyl cellulose; sodium, potassium and calcium salts of fatty acids; mono-and diglycerides of fatty acids; acetate esters of mono-and diglycerides of fatty acids; lactic acid esters of mono-and diglycerides of fatty acids; citric acid esters of mono-and diglycerides of fatty acids; tartaric acid esters of mono-and diglycerides of fatty acids; monoacetyltartaric acid esters and diacetyltartaric acid esters of mono-and diglycerides of fatty acids; mixed acetate and tartrate esters of mono-and diglycerides of fatty acids; sucrose esters of fatty acids; sucrose esters of glycerol; polyglycerol esters of fatty acids; polyglycerides of castor oil polycondensed fatty acids; propane-1, 2-diol esters of fatty acids; sodium stearoyl-2 lactate; stearoyl-2-calcium lactate; stearyl tartrate; sorbitan monostearate; sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate; sorbitan monopalmitate; quillaja extract (extract of quillaia); polyglycerol esters of dimerized fatty acids of soybean oil; oxidizing the polymerized soybean oil; and pectin extracts.

In yet another embodiment, the pharmaceutical composition for nasal administration may be provided in powder form. For example, a powdered nasal composition may be used directly as a powder for a unit dosage form. If desired, the powder may be filled in a capsule such as a hard gelatin capsule. The contents of the capsule or single dose device may be administered using, for example, an insufflator.

Thus, a method for treating a neuronal disorder may comprise the step of nasally administering to a subject in need thereof a pharmaceutical composition comprising a compound described herein or a salt thereof.

Administration of drugs

For any particular subject, the particular dosage level of the active ingredient (e.g., a compound or salt thereof described herein) of the present application will depend on a variety of factors including the activity of the particular compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination, and the severity of the particular disease in the subject undergoing therapy. For example, the dosage may be expressed as milligrams of the compound described herein (mg/kg) per kilogram of subject body weight. Dosages of about 0.1mg/kg to 0.01mg/kg may be suitable. In some embodiments, about 0.07mg/kg and 0.03mg/kg may be suitable. In other embodiments, a dosage of 0.06mg/kg to 0.04mg/kg may be appropriate. Normalization according to the body weight of a subject is particularly useful when adjusting the dose between subjects of widely varying sizes, such as occurs when the drug is used in both children and adults, or when converting an effective dose in a non-human subject (such as a dog) into a dose suitable for a human subject.

Daily doses can also be described as the total amount of a compound described herein administered per dose or per day. The daily dosage of a compound described herein or a salt thereof may be from about 1mg to 4,000mg, from about 2,000 mg/day to 4,000 mg/day, from about 1 mg/day to 2,000 mg/day, from about 1 mg/day to 1,000 mg/day, from about 10 mg/day to 500 mg/day, from about 20 mg/day to 500 mg/day, from about 50 mg/day to 300 mg/day, from about 75 mg/day to 200 mg/day, or from about 15 mg/day to 150 mg/day.

When administered nasally, the total daily dose for a human subject may be from 1mg to 1,000mg, from about 1,000 mg/day to about 2,000 mg/day, from about 10 mg/day to about 500 mg/day, from about 50 mg/day to about 300 mg/day, from about 75 mg/day to about 200 mg/day, or from about 100 mg/day to about 150 mg/day. In various embodiments, the daily dose is about 10mg, about 30mg, about 50mg, about 75mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, or about 1000mg, or a range of values therebetween.

The active ingredient of the present application or a pharmaceutical composition thereof may be administered once, twice, three times or four times a day using any suitable means described above. Furthermore, administration or treatment may last for days; for example, for a cycle of treatment, typically the treatment will last for at least 7 days, 14 days, or 28 days. The treatment cycles are well known and often alternate with rest periods of about 1 to 28 days, typically about 7 days or about 14 days between cycles. In other embodiments, the treatment cycle may also be continuous. Administration or treatment may continue indefinitely.

In certain embodiments, the method comprises administering to the subject an initial daily dose of about 1mg to 800mg of a compound described herein, and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5mg, 10mg, 25mg, 50mg or 100mg may be used to increase the dose. The dosage may be increased daily, every other day, twice weekly, or once weekly.

Examples

The following examples are included to demonstrate specific embodiments of the present disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques which function well in the practice of the present disclosure and thus may be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

Fig. 1 shows an analysis of synaptic density in neurons after treatment with three compounds described herein (i.e., imipramine, plug Ma Mode, and brimycin). Specifically, on day 14 of culture, primary mouse hippocampal neurons were treated with one of four compounds (each at concentrations of 10 μm, 500nM, and 50 nM) or with a control (vehicle (0.1% DMSO)) for 24 hours. After treatment, neurons were fixed in 4% paraformaldehyde and stained with phalloidin (phalloidin) after processing and immunolabeling with antibodies directed against post-synaptic marker PSD95 and pre-synaptic marker VGlut. Images were acquired using a laser scanning confocal microscope and analyzed for the number of co-localized pre-and post-synaptic elements per dendrite length. Three (3) biological agents of primary neurons were studied, with a minimum of 12 dendritic segments analyzed per treatment/agent. The synaptic density data was plotted and statistically analyzed using Prism software.

As shown in fig. 1, each of the four compounds analyzed exhibited efficacy in promoting dendritic spine formation. Furthermore, the binding activity is concentration dependent. For example, imipramine, plug Ma Mode and brimycin each exhibited higher activity at a concentration of 10 μm than at a lower concentration.

Of the three compounds tested, imipramine is known to interact with or bind to and interact with or inhibit the actin-binding activity of fascin at actin binding site 2. It is therefore contemplated that other compounds that interact or bind to actin binding site 2 will similarly have the effect of promoting dendritic spine formation. In addition, plug Ma Mode and brimycin were determined to have a favorable docking score for actin binding site 3 of fascin by computer (in silico) docking analysis. It is therefore contemplated that other compounds that bind to actin binding site 3, such as those binding site 3 described herein, will also have efficacy in promoting dendritic spine formation. In addition, since binding to both actin binding sites 2 and 3 results in efficacy, it is further contemplated that compounds that bind to fasciclin at other binding sites (such as actin binding site 1), such as those disclosed herein, will also have efficacy in promoting dendritic spine production.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The disclosure illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," and the like are to be construed expansively and without limitation. In addition, the terms and expressions which have been employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible.

Thus, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modification, variation and variation of the disclosure herein disclosed embodied therein may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided herein are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.

All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

Claims

1. A method of promoting dendritic spine production in a neuron, the method comprising contacting the neuron with imipramine or a pharmaceutically acceptable salt thereof.

2. A method of treating or preventing a neuronal disease or disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of imipramine or a pharmaceutically acceptable salt thereof, provided that the neuronal disease or disorder is not a mood disorder.

3. The method of claim 2, wherein the neuronal disease or disorder is selected from the group consisting of alzheimer's disease, parkinson's disease, amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia (FTD), and traumatic brain injury.

4. The method of claim 2, wherein the neuronal disease or disorder is alzheimer's disease.

5. A method of promoting dendritic spine generation in a neuron, the method comprising contacting the neuron with a plug Ma Mode or a pharmaceutically acceptable salt thereof.

6. A method of promoting dendritic spine production in a neuron, the method comprising contacting the neuron with a british fungus or a pharmaceutically acceptable salt thereof.

7. A method of treating or preventing a neuronal disease or disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of plug Ma Mode or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the neuronal disease or disorder is selected from the group consisting of alzheimer's disease, parkinson's disease, amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia (FTD), and traumatic brain injury.

9. The method of claim 7, wherein the neuronal disease or disorder is alzheimer's disease.

10. A method of treating or preventing a neuronal disease or disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a british hormone or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the neuronal disease or disorder is selected from the group consisting of alzheimer's disease, parkinson's disease, amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia (FTD), and traumatic brain injury.

12. The method of claim 10, wherein the neuronal disease or disorder is alzheimer's disease.