WO2021067089A1 - Compositions that preferentially potentiate subtypes of gabaa receptors and methods of use thereof - Google Patents

Compositions that preferentially potentiate subtypes of gabaa receptors and methods of use thereof Download PDF

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Publication number
WO2021067089A1
WO2021067089A1 PCT/US2020/052167 US2020052167W WO2021067089A1 WO 2021067089 A1 WO2021067089 A1 WO 2021067089A1 US 2020052167 W US2020052167 W US 2020052167W WO 2021067089 A1 WO2021067089 A1 WO 2021067089A1
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Prior art keywords
disorder
gaba
compound
composition
less
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PCT/US2020/052167
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English (en)
French (fr)
Inventor
Andrew D. LEVIN
Neil Buckley
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Athenen Therapeutics, Inc.
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Priority to BR112022006085A priority Critical patent/BR112022006085A2/pt
Priority to EP20872608.3A priority patent/EP4135710A4/en
Priority to JP2022519997A priority patent/JP2022552788A/ja
Priority to KR1020227014562A priority patent/KR20220103707A/ko
Priority to CA3159087A priority patent/CA3159087A1/en
Priority to IL291835A priority patent/IL291835A/en
Priority to CN202080082811.4A priority patent/CN115087450A/zh
Priority to MX2022003823A priority patent/MX2022003823A/es
Publication of WO2021067089A1 publication Critical patent/WO2021067089A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the invention relates generally to compositions containing neurosteroids and methods of using the same to treat GABA A disorders in a subject.
  • Background According the World Health Organization (WHO), neurological disorders affect up to one billion people worldwide.
  • Neurological disorders include a wide range of conditions, such as Alzheimer's disease, brain injuries, epilepsy, headache, infections, multiple sclerosis, and Parkinson's disease, and stroke.
  • GABA A receptors are pentameric transmembrane receptors that include various combinations of 19 different subunit polypeptides. At least 15 GABA A receptor subtypes are known, and particular subtypes are associated with different conditions. For example, altered activity of receptor subtypes that include ⁇ 2 or ⁇ 3 subunits is associated with anxiety disorders, whereas ⁇ 5-containing subtypes appear to play a role in memory and cognition. Neuroactive steroids that alter the activity of GABA A receptors have been investigated as drug candidates for a variety of neurological disorders. However, the therapeutic potential of such molecules remains largely untapped.
  • compositions that contain isomerically pure forms of selected neurosteroids.
  • the invention recognizes that interactions between neurosteroids and GABA A receptors are highly sensitive to the stereochemical structure of the neurosteroids and that certain neurosteroids display strong GABA A receptor subtype specificity when provided in compositions that are substantially free of isomeric contaminants. Because the compositions of the invention selectively target particular GABA A receptor subtypes, they have greatly improved pharmacological efficacy over prior compositions, including those that contain biologically active compounds contaminated with isomers that are less active.
  • the invention provides compositions that contain an isomerically pure form of a compound of Formula (I):
  • the present invention includes the finding that isomerically pure compositions of Formula (I) are considerably more active on ⁇ 4 ⁇ 3 ⁇ GABA A receptors than on ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • such compositions modulate the activity of ⁇ 4 ⁇ 3 ⁇ receptors with an EC 50 at least 5-fold lower than for ⁇ 1 ⁇ 2 ⁇ 2 receptors.
  • the stereochemical configurations at all of the chiral centers of the molecule and the atomic bonding patterns within the molecule are important in conferring GABA A receptor subtype selectivity.
  • compositions that contain the compound of Formula (I) together with isomers thereof, such as regioisomers of Formula (I) or stereoisomers that differ structurally from Formula (I) at only a single chiral center lack such selectivity.
  • compositions that contain an isomerically pure form of the compound of Formula (I) preferentially target ⁇ 4 ⁇ 3 ⁇ GABA A receptors, they are useful for therapeutic applications in which altering the activity of this receptor is beneficial.
  • the invention provides pharmaceutical compositions containing an isomerically pure form of a compound of Formula (I): wherein the compound of Formula (I) is present in a therapeutically effective amount to preferentially potentiate an ⁇ 4 ⁇ 3 ⁇ GABA A receptor as compared to an ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptor.
  • the invention provides methods for treating a GABA A disorder by providing to a subject a pharmaceutical composition comprising an isomerically pure form of a compound of Formula (I): wherein the compound of Formula (I) is present in a therapeutically effective amount to preferentially potentiate an ⁇ 4 ⁇ 3 ⁇ GABA A receptor as compared to an ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptor.
  • the composition may be chemically pure, i.e., free from other molecules or chemical species.
  • the other molecule or chemical species may have a distinct chemical formula, structural formula, empirical formula, molecular formula, or condensed formula.
  • the composition may have a defined level of chemical purity.
  • the compound of Formula (I) may be present at at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the total amount of a mixture that includes the compound of Formula (I) and one or more distinct molecules or chemical species.
  • the composition may be isomerically pure with respect to all isomers.
  • the composition may be isomerically pure with respect to one or more particular types of isomers.
  • the composition may be substantially free of structural isomers or a particular type of structural isomers, such as a regioisomers.
  • the composition may be substantially free of stereoisomers or a particular type of stereoisomers, such as enantiomers or diastereomers.
  • the composition may contain the compound of Formula (I) at any level of isomeric purity to achieve preferential modulation of an ⁇ 4 ⁇ 3 ⁇ GABA A receptor as compared to an ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptor.
  • the compound of Formula (I) may be present at at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the total amount of isomeric molecules that include the compound of Formula (I) and an isomer thereof.
  • the composition may contain the compound of Formula (I) and be substantially free of stereoisomers.
  • the stereoisomer may differ from Formula (I) at one, two, three, four, five, six, seven, or eight chiral centers.
  • the stereoisomer may be a diastereomer or an enantiomer.
  • the stereoisomer may be a compound of Formulas (II) or (III):
  • the composition may contain one or more stereoisomers of the compound of Formula (I), such as a compound of Formula (II) or (III), at less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% of the total of the compound of Formula (I) and the one or more stereoisomers thereof.
  • the composition may contain the compound of Formula (I) and one or more stereoisomer thereof at a ratio of at least 19:1, 20:1, 25:1, 30:1, 40:1, 50:1, 100:1, 200:1, 500:1, or 1000:1.
  • the compound may potentiate a GABA A receptor, a GABA A receptor subtypes, or a subset of GABA A receptor subtypes by any mechanism.
  • the compound may potentiate a GABA A receptor, subtype, or subset by allosteric modulation, activation, or inhibition.
  • the allosteric modulation may be positive or negative.
  • the composition may preferentially potentiate an ⁇ 4 ⁇ 3 ⁇ GABA A receptor as compared to an ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptor to any degree.
  • the composition may preferentially potentiate an ⁇ 4 ⁇ 3 ⁇ GABA A receptor as compared to an ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptor by any measure or parameter.
  • the composition may have an EC50 for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is lower than the EC50 for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • the EC50 for ⁇ 4 ⁇ 3 ⁇ GABA A receptors may be lower than the EC 50 for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors by about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 10-fold, about 20-fold, about 50-fold, about 100- fold, about 200-fold, about 500-fold, or about 1000-fold.
  • the EC50 for ⁇ 4 ⁇ 3 ⁇ GABA A receptors may be less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% of the EC50 for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • the composition may have a binding affinity (which may be expressed, e.g., as a dissociation constant KD) for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is lower than the binding affinity for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • the binding affinity for ⁇ 4 ⁇ 3 ⁇ GABA A receptors may be lower than the binding affinity for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors by about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 10-fold, about 20-fold, about 50- fold, about 100-fold, about 200-fold, about 500-fold, or about 1000-fold.
  • the binding affinity for ⁇ 4 ⁇ 3 ⁇ GABA A receptors may be less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% of the binding affinity for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • the composition may have an EC50 for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is below a defined value.
  • the composition may have an EC 50 for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is less than about 1 ⁇ M, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, less than about 2.5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, or less than about 0.1 nM.
  • the composition may have a binding affinity for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is below a defined value.
  • the composition may have an binding affinity for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is less than about 1 ⁇ M, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, less than about 2.5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, or less than about 0.1 nM.
  • the composition may be effective for treatment of a GABA A disorder.
  • the GABA A disorder may be any disease, disorder, or condition associated with altered GABA A receptor function or any disorder may be disease, disorder, or condition that can be ameliorated by altered GABA A receptor function.
  • the GABA A disorder may be acute pain, an addictive disorder, Alzheimer’s disease, Angelman's syndrome, anti-social personality disorder, an anxiety disorder, attention deficit hyperactivity disorder (ADHD), an attention disorder, an auditory disorder, autism, an autism spectrum disorder, bipolar disorder, chronic pain, a cognitive disorder, a compulsive disorder, a convulsive disorder, dementia, depression, dysthymia, an epileptic disorder, essential tremor, epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington’s disease, injury related pain syndrome, insomnia, ischemia, Lewis body type dementia, a memory disorder, migraines, a mood disorder, movement disorder, a neurodegenerative disease, neuropathic pain, an obsessive compulsive disorder, pain, a panic disorder, Parkinson’s disease, a
  • the composition may be formulated for administration by a particular mechanism.
  • the composition may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical nasal, or pulmonary administration.
  • the composition may be formulated for administration by injection or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
  • the composition may be formulated a single daily dosage.
  • the composition may be formulated for multiple daily dosages, e.g., two, three, four, five, six or more daily dosages.
  • the composition may be provided to the subject according to any dosing schedule.
  • the composition may be provided once per day.
  • the composition may be provided multiple times per day.
  • the composition may be provided two time, three times, four times, five times, six times, or more per day.
  • the invention provides compositions that contain isomerically pure forms of neurosteroids and methods of using such compositions to treat neurological and other disorders.
  • the invention is based on the recognition that isomerically pure neurosteroids allow modulation of specific subtypes of ⁇ -aminobutyric acid (GABA) receptors. Because the compositions permit selective modulation of subtypes of GABA receptors, they are useful for treating conditions in which alteration of those receptor subtypes provides therapeutic benefit. Definitions Definitions of specific functional groups and chemical terms are described in more detail below.
  • a “pure isomeric” compound or “isomerically pure” compound is substantially free of other isomers of the compound.
  • the term “pure isomeric” compound or “isomerically pure” denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the compound with the specified structure.
  • the weights are based upon total weight of all isomers of the compound.
  • a "pure stereoisomeric” compound or “stereoisomerically pure” compound is substantially free of other stereoisomers of the compound.
  • the composition is substantially free of isomers that differ at any chiral center. If the compound has multiple chiral centers, a substantial majority of the composition contains compounds having identical stereochemistry at all of the chiral centers.
  • pure stereoisomeric compound or “stereoisomerically pure” denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the compound with the specified stereochemistry.
  • the weights are based upon total weight of all stereoisomers of the compound.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an "S" form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the "R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium); C may be in any isotopic form, including 12 C, 13 C, and 14 C; N may be any isotopic form, including 14 N and 15 N; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • the articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article.
  • an analogue means one analogue or more than one analogue.
  • modulation and “potentiation” refer to the inhibition or stimulation of GABA receptor function.
  • a “modulator” or “potentiator” may be, for example, an agonist, partial agonist, antagonist, or partial antagonist of the GABA receptor.
  • the “modulator” or “potentiator” may act at the active site or at an allosteric site on a GABA receptor. It may promote or inhibit ligand binding. It may facilitate or attenuate ligand-mediated, e.g., GABA- mediated, signaling.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, el al., J. Pharm.
  • Solidvate refers to forms of the compound that are associated with a solvent or water (also referred to as "hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • solvents include water, ethanol, acetic acid, and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solidvate encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • isotopic variant refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an "isotopic variant” of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the following atoms, where present, may vary, so that for example, any hydrogen may be 2 H/D, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as 11 C, 18 F, 15 O, and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.
  • Steps It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers”, and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, and an atom, such as a carbon atom, is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • “Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons.
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non- human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ("prophylactic treatment”).
  • therapeutic treatment an action that occurs while a subject begins to suffer from the specified disease, disorder or condition
  • prophylactic treatment the "effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, is sufficient to induce anesthesia or sedation.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • terapéuticaally effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • compositions can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • compositions Compounds The invention provides compositions with isomerically pure forms of neurosteroids.
  • the invention provides pharmaceutical compositions containing an isomerically pure form of a compound of Formula (I):
  • the composition may be chemically pure, i.e., free from other molecules or chemical species.
  • the other molecule or chemical species may have a distinct chemical formula, structural formula, empirical formula, molecular formula, or condensed formula.
  • the composition may have a defined level of chemical purity.
  • the compound of Formula (I) may be present at at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the total amount of a mixture that includes the compound of Formula (I) and one or more distinct molecules or chemical species.
  • the composition may contain the compound of Formula (I) at any level of isomeric purity, i.e., the composition may contain the compound of Formula (I) at a level in relation to an isomeric form of the compound.
  • the compound of Formula (I) may be present at at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the total amount of isomeric molecules that include the compound of Formula (I) and an isomer thereof.
  • the composition may be isomerically pure with respect to all isomers.
  • the composition may be isomerically pure with respect to one or more particular types of isomers.
  • the composition may be substantially free of structural isomers or a particular type of structural isomers, such as a regioisomers.
  • the composition may be substantially free of stereoisomers or a particular type of stereoisomers, such as enantiomers or diastereomers.
  • the composition may contain the compound of Formula (I) at any level of isomeric purity to achieve preferential modulation of an ⁇ 4 ⁇ 3 ⁇ GABA A receptor as compared to an ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptor.
  • the compound of Formula (I) may be present at at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, at least 99.5% by weight, at least 99.6% by weight, at least 99.7% by weight, at least 99.8% by weight, or at least 99.9% by weight of the total amount of isomeric molecules that include the compound of Formula (I) and an isomer thereof.
  • the composition may contain the compound of Formula (I) and be substantially free of stereoisomers.
  • the stereoisomer may differ from Formula (I) at one, two, three, four, five, six, seven, or eight chiral centers.
  • the stereoisomer may be a diastereomer or an enantiomer.
  • the stereoisomer may be a compound of Formulas (II) or (III):
  • the composition may contain one or more stereoisomers of the compound of Formula (I), such as a compound of Formula (II) or (III), at less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% of the total of the compound of Formula (I) and the one or more stereoisomers thereof.
  • the composition may contain the compound of Formula (I) and one or more stereoisomer thereof at a ratio of at least 19:1, 20:1, 25:1, 30:1, 40:1, 50:1, 100:1, 200:1, 500:1, or 1000:1.
  • Formulations The invention provides pharmaceutical compositions containing one or more of the compounds described above.
  • a pharmaceutical composition containing the compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the compounds in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin or olive oil.
  • An alternative oral formulation where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound of the invention is encapsulated in an enteric coating.
  • Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stea
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, and agents for flavoring and/or coloring.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the formulation is not a sustained release formulation.
  • the formulation is not injectable.
  • the formulation does not contain particles having a D50 (volume weighted median diameter) of less than 10 microns.
  • the formulation does not contain a polymer surface stabilizer.
  • the formulation is not an aqueous suspension.
  • the composition may be formulated for administration by a particular mechanism.
  • the composition may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical nasal, or pulmonary administration.
  • the composition may be formulated for administration by injection or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).
  • the composition may be formulated a single daily dosage.
  • the composition may be formulated for multiple daily dosages, e.g., two, three, four, five, six or more daily dosages.
  • the composition may be provided to the subject according to any dosing schedule.
  • the composition may be provide once per day.
  • the composition may be provided multiple times per day.
  • the composition may be provided two time, three times, four times, five times, six times, or more per day.
  • compositions of the invention are useful for treating disorders that are associated with, or can be ameliorated by, alteration of activity of a GABA A receptor.
  • GABA A receptors are ligand-gated ion channels that selectively allow C 1- ions to pass through the plasma membrane upon binding of GABA.
  • GABA A receptors are expressed in neurons throughout the central nervous system (CNS) and mediate most of the physiological activities of GABA in the CNS. Within neurons, the type and density of GABA A receptors can vary between cell bodies and dendrites. GABA A receptors are also expressed in other tissues, including Leydig cells, placenta, immune cells, liver, bone growth plates, and other endocrine tissues. Outside the CNS, GABA A receptors can regulate cell proliferation and immune responses.
  • GABA A receptors are pentamers that include five polypeptide subunits.
  • the polypeptide subunits are encoded by 19 genes that are grouped as follows based on sequence similarity: ⁇ (1-6), ⁇ (1-3), ⁇ (1-3), ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ (1-3).
  • Most subtypes are heteropentamers that include two copies of one type of a subunit, two copies of one type of b subunit, and one copy of one type of ⁇ , ⁇ , ⁇ , or ⁇ subunit; other subtypes are homopentamers or heteropentamers of ⁇ subunits.
  • GABA A receptor subtypes include ⁇ 1 ⁇ 1 ⁇ 2, ⁇ 1 ⁇ 2 ⁇ 2, ⁇ 1 ⁇ 3 ⁇ 2, ⁇ 2 ⁇ 1 ⁇ 2, ⁇ 2 ⁇ 2 ⁇ 2, ⁇ 2 ⁇ 3 ⁇ 2, ⁇ 3 ⁇ 1 ⁇ 2, ⁇ 3 ⁇ 2 ⁇ 2, ⁇ 3 ⁇ 3 ⁇ 2, ⁇ 4 ⁇ 1 ⁇ 2, ⁇ 4 ⁇ 3 ⁇ , ⁇ 4 ⁇ 3 ⁇ 2, ⁇ 5 ⁇ 1 ⁇ 2, ⁇ 5 ⁇ 2 ⁇ 2, ⁇ 5 ⁇ 3 ⁇ 2, ⁇ 6 ⁇ 1 ⁇ 2, ⁇ 6 ⁇ 2 ⁇ 2, and ⁇ 6 ⁇ 3 ⁇ 2.
  • GABA A receptor subtypes vary among tissue types and anatomical regions of the CNS, and subtypes may be associated with specific functions.
  • GABA A receptor subtypes may vary between normal and malignant cells of the same tissue type.
  • the active site of a GABA A receptor is the binding site for GABA and for drugs such as muscimol, gaboxadol, and bicuculline.
  • GABA A receptors also have several allosteric binding sites that are the targets of other drugs, including benzodiazepines, nonbenzodiazepines, neuroactive steroids, barbiturates, ethanol, inhaled anaesthetics, and picrotoxin.
  • the activity of GABA A receptors is controlled by binding of molecules to both the active and allosteric binding sites.
  • compositions of the invention preferentially potentiate the activity selected GABA A receptor subtypes.
  • compositions of the invention may preferentially potentiate the activity of one or more GABA A receptor subtypes, such as those described above, relative to one or more GABA A receptor subtypes.
  • the compositions preferentially potentiate the activity of ⁇ 4 ⁇ 3 ⁇ receptors compared to ⁇ 1 ⁇ 2 ⁇ 2 receptors.
  • the compositions of the invention may potentiate one or more GABA A receptors by any mechanism.
  • the isomerically pure form a compound may potentiate a GABA A receptor by allosteric modulation, activation, or inhibition.
  • the allosteric modulation may be positive or negative.
  • the preferential activity of a composition on one or more GABA A receptor as compared to one or more other GABA A receptor may be measured by any suitable means. Activity may be measure using in vitro assays or in vivo assays.
  • methods of measuring the effect of modulators on GABA A receptor activity include anticonvulsant assays, binding assays, fluorescence membrane potential assays, immune response assays, intracranial self-stimulation assays patch clamps assays, proliferation assays receptor occupancy assays seizure induction assays, e.g., using pentylenetetrazol (PTZ) or maximal electroshock (MES), and survival assays.
  • PTZ pentylenetetrazol
  • MES maximal electroshock
  • the preferential activity of a composition on one or more GABA A receptors as compared to one or more other GABA A receptors may be expressed by any suitable means.
  • the preferential activity may be indicated by a comparison of EC 50 values or binding affinity values.
  • compositions of the invention have an EC50 for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is lower than the EC50 for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • the EC50 for ⁇ 4 ⁇ 3 ⁇ GABA A receptors may be lower than the EC 50 for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors by about 2-fold, about 3- fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 10-fold, about 20- fold, about 50-fold, about 100-fold, about 200-fold, about 500-fold, or about 1000-fold.
  • compositions of the invention have an EC 50 for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% of the EC 50 for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • compositions of the invention have an binding affinity (which may be expressed, e.g., as a dissociation constant K D ) for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is lower than the binding affinity for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • the binding affinity for ⁇ 4 ⁇ 3 ⁇ GABA A receptors may be lower than the binding affinity for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors by about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 10-fold, about 20-fold, about 50-fold, about 100-fold, about 200-fold, about 500-fold, or about 1000-fold.
  • compositions of the invention have an binding affinity for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% of the binding affinity for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • compositions of the invention have an EC 50 for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is below a defined value.
  • the composition may have an EC50 for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is less than about 1 ⁇ M, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, less than about 2.5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, or less than about 0.1 nM.
  • compositions of the invention have an binding affinity for ⁇ 4 ⁇ 3 ⁇ GABA A receptors below a defined value.
  • the composition may have an binding affinity for ⁇ 4 ⁇ 3 ⁇ GABA A receptors that is less than about 1 ⁇ M, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, less than about 2.5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, or less than about 0.1 nM.
  • the compositions and methods of the invention may be effective for treatment of a GABA A disorder.
  • the GABA A disorder may be any disease, disorder, or condition associated with altered GABA A receptor function or any disorder may be disease, disorder, or condition that can be ameliorated by altered GABA A receptor function.
  • the GABA A disorder may be acute pain, an addictive disorder, Alzheimer’s disease, Angelman's syndrome, anti-social personality disorder, an anxiety disorder, attention deficit hyperactivity disorder (ADHD), an attention disorder, an auditory disorder, autism, an autism spectrum disorder, bipolar disorder, chronic pain, a cognitive disorder, a compulsive disorder, a convulsive disorder, dementia, depression, dysthymia, an epileptic disorder, essential tremor, epileptogenesis, fragile X syndrome, generalized anxiety disorder (GAD), Huntington’s disease, injury related pain syndrome, insomnia, ischemia, Lewis body type dementia, a memory disorder, migraines, a mood disorder, movement disorder, a neurodegenerative disease, neuropathic pain, an obsessive compulsive disorder, pain, a panic disorder, Parkinson’s disease, a
  • the methods of treating a subject include providing a composition of the invention, as described above, to the subject.
  • Providing may include administering the composition to the subject.
  • the composition may be administered by any suitable means, such as orally, intravenously, enterally, parenterally, dermally, buccally, topically (including transdermally), by injection, nasally, pulmonarily, and with or on an implantable medical device (e.g., stent or drug- eluting stent or balloon equivalents).
  • the composition is provided orally.
  • the composition may be provided under any suitable dosing regimen.
  • the composition may be provided as a single dose or in multiple doses.
  • Multiple doses may be provided in provided separated by intervals, such as 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more. Multiple doses may be provided within a period of time. For example, multiple doses may be provided over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more.
  • the compositions may be provided repeatedly for a specified duration. For example and without limitation, the compositions may be provided for 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months or more. Examples Example 1 The ability of CV-10155 and SPNC-019 to modulate the activity of GABA A receptors of different GABA A was analyzed. CV-10155 and SPNC-019 have the following structures:
  • CV-10155 showed some level of positive allosteric modulating activity in all of the GABA A receptor subtypes tested.
  • SPNC-019 had no modulating activity in 15 of the 18 GABA A receptor subtypes tested.
  • the only structural difference between CV-10155 and SPNC-019 is the stereochemical configuration of the hydroxyl and methyl groups attached to the carbon atom at position 3 of the steroid core.
  • the results show that a change in the stereochemistry of a single chiral center of a steroid-based compound dramatically alters ability of the molecule to modulate GABA A receptor activity.
  • the results further indicate that the isomeric purity of neurosteroid compositions greatly impacts the utility of such compositions as therapeutic agents.
  • Example 2 The ability of various neurosteroids to compete with t-butylbicyclophosphorothionate (TBPS), a ligand for the picrotoxin binding site of GABA A receptors, was analyzed in International Publication No. WO 2016/061527. WO 2016/061527, pages 215-227. Compounds were assayed for binding to GABA receptors in membranes isolated from the cortices of rat brains. WO 2016/061527, page 216. Among the neurosteroids analyzed was Compound 10, which has the following structure: . WO 2016/061527, page 106. Compound 10 is identical to the structure of Formula (II) and is a stereoisomer of the structure of Formula (I).
  • TBPS t-butylbicyclophosphorothionate
  • Compound 10/Formula (II) and Formula (I) are stereoisomers that differ only in the configuration of the hydrogen atom bonded to the carbon atom at position 5: Compound 10/Formula (II) has a 5 ⁇ configuration, whereas Formula (I) has a 5 ⁇ configuration.
  • Another neurosteroid analyzed in WO 2016/061527 was Compound 121, which has the following structure: . WO 2016/061527, page 150.
  • Compound 121 is a regioisomer of the structure of Formula (I).
  • Compound 121 and Formula (I) differ only in the positioning of the cyano substituent on the pyrazole ring: Compound 121 is substituted at the 3 position of the pyrazole ring, whereas Formula (I) is substituted at the 4 position of the pyrazole ring.
  • Compound 10 and Compound 121 are isomers that have two structural differences: the stereochemical configuration at carbon 5, and the position of the cyano substituent on the pyrazole ring. Results of the analysis are provided in Table 1 of WO 2016/061527. WO 2016/061527, pages 217-227.
  • Compound 10 has an IC50 of ⁇ 10 nM in the TBPS displacement assay, whereas Compound 121 has an IC 50 of 10-50 nM.
  • WO 2016/061527 pages 217 and 221. These results show that subtle structural differences in a neurosteroid can drastically affect binding of the molecule to GABA A receptors.
  • Example 3 The pharmacological efficacy of various neurosteroids for ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors and ⁇ 4 ⁇ 3 ⁇ GABA A receptors and was analyzed in International Publication No. WO 2016/061527. WO 2016/061527, pages 227-231.
  • Results are presented as the relative potentiation of GABA-mediated conductance in the presence of 10 ⁇ M neurosteroid compared to GABA-mediated conductance in the absence of neurosteroid.
  • Compound 121 at 10 ⁇ M displayed an efficacy of >500% for both ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors and ⁇ 4 ⁇ 3 ⁇ GABA A receptors.
  • the results show that a regioisomer of Formula (I) displays no preferential modulation of ⁇ 4 ⁇ 3 ⁇ GABA A receptors over ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • a compound that differs from Formula (I) only by the positioning of the cyano substituent on the pyrazole ring has comparable efficacy on the two GABA A receptor subtypes.
  • the data give no indication that compositions containing a compound of Formula (I) can preferentially modulate ⁇ 4 ⁇ 3 ⁇ GABA A receptors over ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors or that such compositions can be administered at concentrations that modulate ⁇ 4 ⁇ 3 ⁇ GABA A receptors but not ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.
  • compositions containing the compound of Formula (I) would be useful for treatment of conditions in which potentiation of ⁇ 4 ⁇ 3 ⁇ GABA A receptors but not ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors is beneficial.
  • the data provided in Example 1 show that the compound of Formula (I) is substantially more active on ⁇ 4 ⁇ 3 ⁇ GABA A receptors than on ⁇ 1 ⁇ 2 ⁇ 2 GABA A receptors.

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EP20872608.3A EP4135710A4 (en) 2019-09-30 2020-09-23 COMPOSITIONS FOR PREFERENTIAL POTENTIATION OF SUBTYPES OF GABAA RECEPTORS AND METHODS OF USE THEREOF
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021252314A1 (en) * 2020-06-08 2021-12-16 Eliem Therapeutics, Inc. Methods of treating female health conditions related to sex hormones
WO2024020953A1 (zh) * 2022-07-28 2024-02-01 湖南科益新生物医药有限公司 治疗中枢神经系统疾病的甾体化合物及其制备方法、用途和药物组合物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6277838B1 (en) * 1994-02-14 2001-08-21 Cocensys, Inc. Methods for allosteric modulation of the GABA receptor by members of the androstane and pregnane series
WO2018071803A1 (en) * 2016-10-14 2018-04-19 Marinus Pharmaceuticals, Inc Method of administering a neurosteroid to effect electroencephalographic (eeg) burst suppression
US20180311262A1 (en) * 2013-04-17 2018-11-01 Sage Therapeutics, Inc. 19-nor c3, 3-disubstituted c21-n-pyrazolyl steroids and methods of use thereof
WO2020210116A1 (en) * 2019-04-08 2020-10-15 Athenen Therapeutics, Inc. Steroids with altered pharmacokinetic properties and methods of use thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016061527A1 (en) * 2014-10-16 2016-04-21 Sage Therapeutics, Inc. Compositions and methods for treating cns disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6277838B1 (en) * 1994-02-14 2001-08-21 Cocensys, Inc. Methods for allosteric modulation of the GABA receptor by members of the androstane and pregnane series
US20180311262A1 (en) * 2013-04-17 2018-11-01 Sage Therapeutics, Inc. 19-nor c3, 3-disubstituted c21-n-pyrazolyl steroids and methods of use thereof
WO2018071803A1 (en) * 2016-10-14 2018-04-19 Marinus Pharmaceuticals, Inc Method of administering a neurosteroid to effect electroencephalographic (eeg) burst suppression
WO2020210116A1 (en) * 2019-04-08 2020-10-15 Athenen Therapeutics, Inc. Steroids with altered pharmacokinetic properties and methods of use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4135710A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021252314A1 (en) * 2020-06-08 2021-12-16 Eliem Therapeutics, Inc. Methods of treating female health conditions related to sex hormones
WO2024020953A1 (zh) * 2022-07-28 2024-02-01 湖南科益新生物医药有限公司 治疗中枢神经系统疾病的甾体化合物及其制备方法、用途和药物组合物

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