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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/20—Spiro-condensed systems
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  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems
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  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies

Definitions

• NMDA N-methyl-d-aspartate
• the NMDA receptor controls the flow of both divalent and monovalent ions into the postsynaptic neural cell through a receptor associated channel (Foster et al , Nature 1987, 329:395-396; Mayer et al, Trends in Pharmacol. Sci. 1990, 11 :254-260).
• the NMDA receptor has been implicated during development in specifying neuronal architecture and synaptic connectivity, and may be involved in experience-dependent synaptic
• NMDA receptors are also thought to be involved in long term potentiation and central nervous system disorders.
• the NMDA receptor plays a major role in the synaptic plasticity that underlies many higher cognitive functions, such as memory acquisition, retention and learning, as well as in certain cognitive pathways and in the perception of pain (Collingridge et al , The NMDA Receptor, Oxford University Press, 1994). In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain that underlies consciousness itself.
• the NMDA receptor has drawn particular interest since it appears to be involved in a broad spectrum of CNS disorders. For instance, during brain ischemia caused by stroke or traumatic injury, excessive amounts of the excitatory amino acid glutamate are released from damaged or oxygen deprived neurons. This excess glutamate binds to the NMDA receptors which opens their ligand-gated ion channels; in turn the calcium influx produces a high level of intracellular calcium which activates a biochemical cascade resulting in protein degradation and cell death. This phenomenon, known as excitotoxicity, is also thought to be responsible for the neurological damage associated with other disorders ranging from hypoglycemia and cardiac arrest to epilepsy.
• NMDA receptors have also been implicated in certain types of spatial learning.
• the NMDA receptor is believed to consist of several protein chains embedded in the postsynaptic membrane.
• the first two types of subunits discovered so far form a large extracellular region, which probably contains most of the allosteric binding sites, several transmembrane regions looped and folded so as to form a pore or channel, which is permeable to Ca ++ , and a carboxyl terminal region.
• the opening and closing of the channel is regulated by the binding of various ligands to domains (allosteric sites) of the protein residing on the extracellular surface.
• the binding of the ligands is thought to affect a conformational change in the overall structure of the protein which is ultimately reflected in the channel opening, partially opening, partially closing, or closing.
• NMDA receptor compounds may exert dual (agonist/antagonist) effect on the NMDA receptor through the allosteric sites. These compounds are typically termed "functional partial agonists". In the presence of the principal site ligand, a partial agonist will displace some of the ligand and thus decrease Ca ++ flow through the receptor. In the absence of or lowered level of the principal site ligand, the partial agonist acts to increase Ca ++ flow through the receptor channel.
• the present disclosure provides compounds that can be NMDA modulators, for example, partial agonists of NMDA. More specifically, the present disclosure provides a compound having the formula:
• R b is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and C1-C6 alkyl
• R 1 is selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl
• R 2 is selected from the group consisting of hydrogen, halogen, and Ci-C6 alkyl.
• compositions including a disclosed compound; and a pharmaceutically acceptable excipient.
• a composition can be suitable for oral or intravenous administration to a patient.
• the compounds described herein bind to NMDA receptor subtypes. In some embodiments, the compounds described herein bind to one subtype and not another.
• a method includes treating depression.
• depression can include one or more of major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, seasonal affective disorder, bipolar disorder, mood disorder, or depression caused by a chronic medical condition.
• a method can treat schizophrenia.
• Such schizophrenia can be paranoid type schizophrenia, disorganized type schizophrenia, catatonic type schizophrenia, undifferentiated type schizophrenia, residual type schizophrenia, post-schizophrenic depression, or simple schizophrenia.
• FIG. 1 depicts the mean 50-kHz USV data for compound A in a positive emotional learning (PEL) model.
• FIG. 2 depicts the potentiation of [ H]MK-801 binding for wild-type NMDAR2 subtypes for compound A.
• FIG. 3 depicts the mean plasma concentration-time profile of compound A following a single intraveneous (2 mg/kg) and oral (10 mg/kg) dose administration in male Sprague Dawley rats.
• FIG. 4 depicts the mean plasma, brain, and CSF concentration-time profile of compound A following a single oral (10 mg/kg) dose administration in male Sprague Dawley rats.
• FIG. 5 depicts the mean 50-kHz USV data for compound B in a PEL model
• FIG. 6 depicts the potentiation of [3H]MK-801 binding for wild-type NMDAR2 subtypes for compound B.
• FIG. 7 depicts the mean plasma concentration-time profile of compound B following a single intraveneous (2 mg/kg) and oral (10 mg/kg) does administration in male Sprague Dawley rats.
• FIG. 8 depicts the mean plasma, brain, and CSF concentration-time profiles of compound B following a single oral (10 mg/kg) dose administration in male Sprague Dawley rats.
• FIG. 9 depicts the results from the in vitro MN, Ames, and hERG assays for compound
• FIG. 10 depicts the results from the in vitro MN, Ames, and hERG assays for compound B.
• FIG. 11 depicts the reversed blast-induced cognitive deficits as measured by PEL for Compound A.
• FIG. 12 depicts the reversed blast-induced cognitive deficits as measured by PEL for Compound B.
• FIG. 13 depicts the results for the novelty-induced hypophagia (NIH) test in rats for Compound A.
• FIG. 14 depicts the results for the novelty-induced hypophagia (NIH) test in rats for Compound B.
• FIG. 15 depicts the analgesic effects of Compound A.
• FIG. 16 depicts the analgesic effects of Compound B.
• FIG. 17 depicts the results from the Porsolt forced swim test for Compound A.
• FIG. 18 depicts the results from the Porsolt forced swim test for Compound B. DETAILED DESCRIPTION
• This disclosure is generally directed to compounds that are capable of modulating NMDA, for example, NMDA antagonists or partial agonists, and compositions and/or methods of using the disclosed compounds. It should be appreciated that the disclosed compounds may modulate other protein targets and/or NMDA receptor subtypes.
• alkyl refers to a saturated straight-chain or branched hydrocarbon, such as a straight-chain or branched group of 1 -6, 1 -4, or 1 -3 carbon atoms, referred to herein as C1-C6 alkyl, C1-C4 alkyl, and C1-C3 alkyl, respectively.
• C1-C6 alkyl C1-C4 alkyl
• C1-C3 alkyl C1-C3 alkyl
• Examples of a C1-C6 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, seobutyl, fert-butyl, isopentyl, and neopentyl.
• Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2- methyl-1 -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 3-methyl-2-butyl, 2,2-dimethy 1-1 -propyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl, 4-methyl-l -pentyl, 2-methyl-2- pentyl, 3-methyl-2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethy 1-1 -butyl, 3,3-dimethyl-l -butyl, 2- ethy 1-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.
• cyano refers to the radical -CN.
• halo or halogen
• F fluoro
• CI chloro
• Br bromo
• I iodo
• hydroxy and "hydroxyl,” as used herein, refer to the radical -OH.
• a compound can refer to a pharmaceutically acceptable salt, or a hydrate, an ester or an N-oxide of a stereoisomer of the compound and/or an isotopically-labelled compound.
• the term "moiety,” as used herein, refers to a portion of a compound or molecule.
• the compounds of the disclosure can contain one or more chiral centers and/or double bonds and therefore, can exist as stereoisomers, such as geometric isomers, and enantiomers or diastereomers.
• stereoisomers when used herein, consists of all geometric isomers, enantiomers and/or diastereomers of the compound.
• the compound depicted without such chirality at that and other chiral centers of the compound are within the scope of the present disclosure, i.e., the compound depicted in two-dimensions with "flat” or "straight” bonds rather than in three dimensions, for example, with solid or dashed wedge bonds.
• Stereospecific compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom.
• the present disclosure encompasses all the various stereoisomers of these compounds and mixtures thereof.
• Mixtures of enantiomers or diastereomers can be designated “( ⁇ )” in nomenclature, but a skilled artisan will recognize that a structure can denote a chiral center implicitly. It is understood that graphical depictions of chemical structures, for example, generic chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise.
• each chiral center may be independently R, S, or any mixture of R and S.
• a chiral center may have an R: S ratio of between about 100:0 and about 50: 50 ("racemate"), between about 100:0 and about 75:25, between about 100:0 and about 85 : 15, between about 100:0 and about 90: 10, between about 100:0 and about 95 :5, between about 100:0 and about 98:2, between about 100:0 and about 99: 1 , between about 0: 100 and 50:50, between about 0: 100 and about 25 :75, between about 0: 100 and about 15 : 85, between about 0: 100 and about 10:90, between about 0: 100 and about 5 :95, between about 0: 100 and about 2:98, between about 0: 100 and about 1 :99, between about 75:25 and 25:75, or about 50:50.
• Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns, or (4) kinetic resolution using stereoselective chemical or enzymatic reagents.
• Racemic mixtures also can be resolved into their component enantiomers by well-known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent.
• Stereoselective syntheses a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art.
• Stereoselective syntheses encompass both enantio- and diastereoselective transformations. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
• Geometric isomers resulting from the arrangement of substituents around a carbon- carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds of the present disclosure.
• the symbol denotes a bond that may be a single, double or triple bond as described herein.
• Substituents around a carbon- carbon double bond are designated as being in the "Z” or configuration, where the terms "Z” and are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E” and "Z” isomers.
• the disclosure also embraces isotopically-labeled compounds which are identical to those compounds recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H ("D"), H, 1 C, 14 C, 15 N, 18 0, 17 0, 1 P, 2 P, 5 S, 18 F, and 6 C1, respectively.
• a compound described herein can have one or more H atoms replaced with deuterium.
• Certain isotopically -labeled compounds can be useful in compound and/or substrate tissue distribution assays.
• Tritiated (i.e., H) and carbon- 14 (i.e., 14 C) isotopes can be particularly preferred for their ease of preparation and
• Isotopically-labeled compounds can generally be prepared by following procedures analogous to those disclosed herein, for example, in the Examples section, by substituting an isotopically- labeled reagent for a non-isotopically-labeled reagent.
• phrases "pharmaceutically acceptable” or “pharmacologically acceptable,” as used herein, refer to compounds, molecular entities, compositions, materials and/or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
• preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
• phrases “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient,” as used herein, refer to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical
• compositions can include phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
• emulsions e.g., such as an oil/water or water/oil emulsions
• the compositions also can include stabilizers and preservatives.
• composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
• Pharmaceutical compositions can also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
• the compounds described in the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, for example, domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
• the mammal treated in the methods described in the disclosure is preferably a mammal in which treatment, for example, of pain or depression is desired.
• treating includes any effect, for example, lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like, including one or more symptoms thereof. Treating can be curing, improving, or at least partially ameliorating the disorder.
• disorder refers to and is used interchangeably with, the terms “disease,” “condition,” or “illness,” unless otherwise indicated.
• modulation refers to and includes antagonism (e.g., inhibition), agonism, partial antagonism, and/or partial agonism.
• phrases "pharmaceutically effective amount” and “therapeutically effective amount,” as used herein, refer to the amount of a compound (e.g., a disclosed compound) that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
• the compounds described in the disclosure can be administered in therapeutically effective amounts to treat a disease.
• a therapeutically effective amount of a compound can be the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in lessening of a symptom of a disease or disorder such as depression.
• pharmaceutically acceptable salt(s), refers to salt(s) of acidic or basic groups that can be present in compounds of the disclosure and/or used in the compositions of the disclosure.
• a pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present disclosure upon administration to a patient, is capable of providing a compound of this invention or an active metabolite or residue thereof.
• Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluenesulfonate and pamoate (i.e., l,l'-methylene
• Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
• Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids.
• the compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
• the compounds disclosed herein can exist in a solvated form as well as an unsolvated form with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms.
• pharmaceutically acceptable solvents such as water, ethanol, and the like
• the compound is amorphous. In certain embodiments, the compound is a single polymorph. In various embodiments, the compound is a mixture of polymorphs. In particular embodiments, the compound is in a crystalline form.
• prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
• the transformation can occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit into the intestine, blood or liver).
• Prodrugs are well known in the art (see, e.g., Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255).
• a prodrug can be an ester formed by the replacement of the hydrogen atom of the carboxylic acid group with a group such as (Ci-C8)alkyl, (C2-Ci2)alkanoyloxy methyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- 1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
• alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms
• l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms
• l-methyl-l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms
• N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms
• di-N,N-(Ci-C2)alkylamino(C2-C 3 )alkyl such as ⁇ -dimethylaminoethyl
• carbamoyl-(Ci-C2)alkyl N,N-di(Ci-C2)alkylcarbamoyl-(Ci
• a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C6)alkanoyloxymethyl, l-((Ci-C6)alkanoyloxy)ethyl,
• N-(Ci-C6)alkoxycarbonylaminomethyl succinoyl, (Ci-C6)alkanoyl, a-amino(Ci-C4)alkanoyl, arylacyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH) 2 ,
• a prodrug can be formed, for example, by creation of an amide or carbamate, an N-acyloxyalkyl derivative, an (oxodioxolenyl) methyl derivative, an N-Mannich base, imine or enamine.
• a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. See, for example, Simplicio, et al, Molecules 2008, 13, 519 and references therein.
• compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.
• an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.
• compositions of the present disclosure and/or in methods of the present disclosure, unless otherwise understood from the context.
• embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments can be variously combined or separated without parting from the present teachings and disclosure(s).
• all features described and depicted herein can be applicable to all aspects of the disclosure(s) described and depicted herein.
• an element means one element or more than one element.
• molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context.
• substituents are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges.
• the term "Ci-6 alkyl" is specifically intended to individually disclose C 1; C 2 , C 3 , C 4 , C5, C 6 , C1-C6, C1-C5, C 1 -C 4 , Ci- C 3 , C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.
• an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40
• an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, and 20.
• phrases "optionally substituted with 1 -5 substituents" is specifically intended to individually disclose a chemical group that can include 0, 1, 2, 3, 4, 5, 0-5, 0-4, 0-3, 0-2, 0-1 , 1 -5, 1 -4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, 3-4, and 4-5 substituents.
• variable is defined as found elsewhere in the disclosure unless understood to be different from the context.
• definition of each variable and/or substituent, for example, C1-C6 alkyl, R 2 , R b , w and the like, when it occurs more than once in any structure or compound, can be independent of its definition elsewhere in the same structure or compound.
• Definitions of the variables and/or substituents in formulae and/or compounds herein encompass multiple chemical groups.
• the present disclosure includes embodiments where, for example, i) the definition of a variable and/or substituent is a single chemical group selected from those chemical groups set forth herein, ii) the definition is a collection of two or more of the chemical groups selected from those set forth herein, and iii) the compound is defined by a combination of variables and/or substituents in which the variables and/or substituents are defined by (i) or (ii).
• Disclosed compounds include a compound having the formula:
• R b is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and C 1-C6 alkyl
• R 1 is selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl
• R 2 is selected from the group consisting of hydrogen, halogen, and Ci-C alkyl.
• R 1 is hydrogen.
• R 1 is C1-C6 alkyl, for example, methyl (CH 3 ).
• R 2 is hydrogen. In certain embodiments, R 2 is C1-C6 alkyl, for example, methyl (CH 3 ).
• R b is hydrogen. In some embodiments, R b is C 1-C6 alkyl, for example, methyl (CH3).
• a disclosed compound has the formula:
• the compound is selected from the compounds delineated in the Examples.
• a disclosed compound has the formula:
• a disclosed compound has the formula:
• Disclosed compounds may provide for efficient cation channel opening at the NMDA receptor, e.g. may bind or associate with the glutamate site of the NMDA receptor to assist in opening the cation channel.
• the disclosed compounds may be used to regulate (turn on or turn off) the NMDA receptor through action as an agonist.
• a disclosed compound may bind to one NMDA subtype and not another.
• a disclosed compound may bind to one, or more than one NMDA subtype, and/or e.g. may have substantially less (or substantial no) binding activity to certain other NMDA subtypes.
• a disclosed compound e.g., compound A
• a disclosed compound binds to NR2A with substantially no binding to NR2D.
• a disclosed compound binds to NR2B and NR2D with substantially lower binding to NR2A and NR2C.
• the compounds as described herein may be glycine site NMDA receptor partial agonists.
• a partial agonist as used in this context will be understood to mean that at a low concentration, the analog acts as an agonist and at a high concentration, the analog acts as an antagonist.
• Glycine binding is not inhibited by glutamate or by competitive inhibitors of glutamate, and also does not bind at the same site as glutamate on the NMDA receptor.
• a second and separate binding site for glycine exists at the NMDA receptor.
• the ligand-gated ion channel of the NMDA receptor is, thus, under the control of at least these two distinct allosteric sites.
• Disclosed compounds may be capable of binding or associating with the glycine binding site of the NMDA receptor. In some embodiments, disclosed compounds may possess a potency that is 10-fold or greater than the activity of existing NMDA receptor glycine site partial agonists.
• the disclosed compounds may exhibit a high therapeutic index.
• the therapeutic index refers to the ratio of the dose that produces a toxicity in 50% of the population (i.e., TD 50 ) to the minimum effective dose for 50% of the population (i.e., ED 50 ).
• the therapeutic index (TD 5 o):(ED 5 o).
• a disclosed compound may have a therapeutic index of at least about 10: 1 , at least about 50: 1, at least about 100: 1 , at least about 200: 1, at least about 500: 1 , or at least about 1000: 1.
• formulations and compositions comprising a disclosed compound and optionally a pharmaceutically acceptable excipient are provided.
• a formulation includes a racemic mixture of one or more of the disclosed compounds.
• Formulations can be prepared in any of a variety of forms for use.
• the compounds can be prepared in a formulation suitable for oral administration, subcutaneous injection, or other methods for administering an active agent to a patient, who may be in need thereof, as are known in the pharmaceutical arts.
• pharmaceutical compositions of the disclosure can be suitable for delivery to the eye.
• Related methods can include administering a pharmaceutically effective amount of a disclosed compound or a pharmaceutical composition including a disclosed compound to a patient in need thereof, for example, to an eye of the patient, where administering can be topically, subconjunctivally, subtenonly, intravitreally, retrobulbarly, peribulbarly, intracomerally, and/or systemically.
• Amounts of a disclosed compound as described herein in a formulation may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
• Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• compositions typically must be sterile and stable under the conditions of manufacture and storage.
• the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
• the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
• Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
• the compounds can be administered in a time release formulation, for example in a composition which includes a slow release polymer.
• the compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
• Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, polylactic acid and polylactic, polygly colic copolymers (PLG). Many methods for the preparation of such formulations are generally known to those skilled in the art.
• Sterile injectable solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
• the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
• a compound may be formulated with one or more additional compounds that enhance the solubility of the compound.
• the condition can be a mental condition.
• a mental illness can be treated.
• a nervous system condition can be treated.
• a condition that affects the central nervous system, the peripheral nervous system, and/or the eye can be treated.
• neurodegenerative diseases can be treated.
• the methods include administering a compound to treat patients suffering from autism, anxiety, depression, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive-compulsive disorder (OCD), phobia, post-traumatic stress syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder (e.g., a withdrawal symptom, opiate addiction, nicotine addiction, and ethanol addition), a sleep disorder, a memory disorder (e.g., a deficit, loss, or reduced ability to make new memories), a learning disorder, urinary incontinence, multiple system atrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down's syndrome, fragile X syndrome, tuberous sclerosis, olivio- ponto-cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia,
• ADHD attention
• methods of treating a memory disorder associated with aging schizophrenia, special learning disorders, seizures, post-stroke convulsions, brain ischemia, hypoglycemia, cardiac arrest, epilepsy, Lewy body dementia, migraine, AIDS dementia,
• Huntington's chorea Parkinson's disease, early stage Alzheimer's disease, and Alzheimer's disease are provided.
• methods for treating schizophrenia are provided.
• paranoid type schizophrenia disorganized type schizophrenia (i.e., hebephrenic schizophrenia), catatonic type schizophrenia, undifferentiated type schizophrenia, residual type schizophrenia, post-schizophrenic depression, and simple schizophrenia
• Psychitic disorders such as schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, and psychotic disorders with delusions or hallucinations may also be treated using the compositions described herein.
• Paranoid schizophrenia may be characterized where delusions or auditory hallucinations are present, but thought disorder, disorganized behavior, or affective flattening are not.
• Delusions may be persecutory and/or grandiose, but in addition to these, other themes such as ashamedy, religiosity, or somatization may also be present.
• Disorganized type schizophrenia may be characterized where thought disorder and flat affect are present together.
• Catatonic type schizophrenia may be characterized where the patient may be almost immobile or exhibit agitated, purposeless movement. Symptoms can include catatonic stupor and waxy flexibility.
• Undifferentiated type schizophrenia may be characterized where psychotic symptoms are present but the criteria for paranoid, disorganized, or catatonic types have not been met.
• Residual type schizophrenia may be characterized where positive symptoms are present at a low intensity only.
• Post-schizophrenic depression may be characterized where a depressive episode arises in the aftermath of a schizophrenic illness where some low-level schizophrenic symptoms may still be present.
• Simple schizophrenia may be characterized by insidious and progressive development of prominent negative symptoms with no history of psychotic episodes.
• methods are provided for treating psychotic symptoms that may be present in other mental disorders, including, but not limited to, bipolar disorder, borderline personality disorder, drug intoxication, and drug-induced psychosis.
• methods for treating delusions e.g., "non-bizarre" that may be present in, for example, delusional disorder are provided.
• methods for treating social withdrawal in conditions including, but not limited to, social anxiety disorder, avoidant personality disorder, and schizotypal personality disorder are provided.
• the disclosure provides methods for treating a
• the neurodevelopmental disorder related to synaptic dysfunction can be Rett syndrome also known as cerebroatrophic hyperammonemia, MECP2 duplication syndrome (e.g., a MECP2 disorder), CDKL5 syndrome, fragile X syndrome (e.g., a FMR1 disorder), tuberous sclerosis (e.g., a TSCl disorder and/or a TSC2 disorder), neurofibromatosis (e.g., a NFl disorder), Angelman syndrome (e.g., a UBE3A disorder), the PTEN hamartoma tumor syndrome, Phelan-McDermid syndrome (e.g., a SHANK3 disorder), or infantile spasms.
• Rett syndrome also known as cerebroatrophic hyperammonemia, MECP2 duplication syndrome (e.g., a MECP2 disorder), CDKL5 syndrome, fragile X syndrome (e.g., a FMR1 disorder), tuberous sclerosis (e.g., a T
• the neurodevelopmental disorder can be caused by mutations in the neuroligin (e.g., a NLGN3 disorder and/or a NLGN2 disorder) and/or the neurexin (e.g., a NRXNl disorder).
• the neuroligin e.g., a NLGN3 disorder and/or a NLGN2 disorder
• the neurexin e.g., a NRXNl disorder
• neuropathic pain may be acute or chronic.
• the neuropathic pain may be associated with a condition such as herpes, HIV, traumatic nerve injury, stroke, post-ischemia, chronic back pain, post-herpetic neuralgia, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, spinal cord injury, sciatica, phantom limb pain, diabetic neuropathy such as diabetic peripheral neuropathy (DPN), and cancer chemotherapeutic- induced neuropathic pain.
• DPN diabetic peripheral neuropathy
• methods of the disclosure include a method of treating autism and/or an autism spectrum disorder in a patient need thereof, comprising administering an effective amount of a disclosed compound to the patient.
• a method for reducing the symptoms of autism in a patient in need thereof is provided, where the method includes administering an effective amount of a disclosed compound to the patient.
• the compound may decrease the incidence of one or more symptoms of autism such as eye contact avoidance, failure to socialize, attention deficit, poor mood, hyperactivity, abnormal sound sensitivity, inappropriate speech, disrupted sleep, and perseveration. Such decreased incidence may be measured relative to the incidence in the untreated individual or an untreated individual(s).
• Also provided herein is a method of modulating an autism target gene expression in a cell comprising contacting a cell with an effective amount of a compound described herein.
• the autism gene expression may be for example, selected from ABAT, APOE, CHRNA4, GABRA5,GFAP, GRIN2A, PDYN, and PENK.
• a method of modulating synaptic plasticity in a patient suffering from a synaptic plasticity related disorder comprising administering to the patient an effective amount of a compound.
• a method of treating Alzheimer's disease, or e.g., treatment of memory loss that e.g., accompanies early stage Alzheimer's disease, in a patient in need thereof comprising administering a compound.
• a method of modulating an Alzheimer's amyloid protein e.g., beta amyloid peptide, e.g. the isoform ⁇ . 42
• in-vitro or in-vivo e.g. in a cell
• a compound may block the ability of such amyloid protein to inhibit long-term potentiation in hippocampal slices as well as apoptotic neuronal cell death.
• a disclosed compound can provide neuroprotective properties to a Alzheimer's patient in need thereof, for example, a therapeutic effect on later stage Alzheimer's-associated neuronal cell death.
• the disclosed methods include treating a psychosis or a pseudobulbar affect ("PBA") that is induced by another condition such as a stroke, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis, traumatic brain injury, Alzheimer's disease, dementia, and/or Parkinson's disease.
• PBA pseudobulbar affect
• Such methods include administration of a pharmaceutically effective amount of a disclosed compound to a patient in need thereof.
• a method of treating depression comprising administering a compound described herein.
• the treatment may relieve depression or a symptom of depression without affecting behavior or motor coordination and without inducing or promoting seizure activity.
• Exemplary depression conditions that are expected to be treated according to this aspect include, but are not limited to, major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder (SAD), bipolar disorder (or manic depressive disorder), mood disorder, and depressions caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, and post-traumatic stress disorders.
• SAD seasonal affective disorder
• bipolar disorder or manic depressive disorder
• mood disorder and depressions caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, and post-traumatic stress disorders.
• patients suffering from any form of depression often experience anxiety.
• Various symptoms associated with anxiety include fear, panic, heart palpitations, shortness of breath, fatigue, nausea, and headaches among others
• a method of treating depression in a treatment resistant patient comprising a) optionally identifying the patient as treatment resistant and b) administering an effective dose of a compound to said patient.
• a compound described herein may be used for acute care of a patient.
• a compound can be administered to a patient to treat a particular episode (e.g., a severe episode) of a condition described herein.
• combination therapies comprising a disclosed compound in combination with one or more other active agents.
• a disclosed compound may be combined with one or more antidepressants, such as tricyclic antidepressants, MAO-I's, SSRI's, and double and triple uptake inhibitors and/or anxiolytic drugs.
• Exemplary drugs that may be used in combination with a compound include Anafranil, Adapin, Aventyl, Elavil, Norpramin, Pamelor, Pertofrane, Sinequan, Surmontil, Tofranil, Vivactil, Parnate, Nardil, Marplan, , Lexapro, Luvox, Paxil, Prozac, Zoloft, Wellbutrin, Effexor, Remeron, Cymbalta, Desyrel (trazodone), and Ludiomill.
• a compound may be combined with an antipsychotic medication.
• Non-limiting examples of antipsychotics include butyrophenones, phenothiazines, thioxanthenes, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, iloperidone, zotepine, sertindole, lurasidone, and aripiprazole. It should be understood that combinations of a compound and one or more of the above therapeutics may be used for treatment of any suitable condition and are not limited to use as antidepressants or antipsychotics.
• HATU (584 g, 1.536 mol), NH4CI (137 g, 2.56 mol) and diisopropylethylamine (708 mL, 3.841 mol) at 0 °C under nitrogen atmosphere.
• the reaction mixture was brought to RT and stirred for 8 h. After consumption of the starting material (by TLC), the reaction mixture was preceded between water (2 L) and CH 2 CI 2 (2 L) and stirred for 15 minutes. Organic layer was separated, washed with 2N HC1 solution (2xlL) and saturated NaHCC solution (2 L) and brine solution (2 L). Organic layer was dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure.
• reaction mixture was diluted with CH2CI2 (20 mL) and concentrated under reduced pressure. Obtained crude material was purified by silica gel column chromatography eluting with 4% MeOH/DCM to afford (2S,3R)-3-hydroxy-2-((S)-5-isobutyl-l-oxo-2,5-diazaspiro[3.4]octan-2- yl)butanamide (6 g) as thick syrup.
• the PEL assay measures the acquisition of positive (hedonic) 50-kHz ultrasonic vocalizations (USVs) to a social stimulus, heterospecific rough and tumble play stimulation. Heterospecific rough-and-tumble play stimulation was administered by the experimenter's right hand. Animals received 3 min of heterospecific rough-and-tumble play that consisted of alternating 15 sec blocks of heterospecific play and 15 sec of no-stimulation. High frequency ultrasonic vocalizations (USVs) were recorded and analyzed by sonogram with Avasoft SASlab Pro (Germany) as previously described by Burgdorf et al, "Positive emotional learning is regulated in the medial prefrontal cortex by GluN2B-containing NMDA receptors,"
• FIG. 1 shows the results of the rat PEL test. The results demonstrate that Compound A, when administered one hour prior to PEL testing, increases positive emotional learning as measured by rat USVs, thereby indicating an antidepressant effect.
• the bioavailablity of Compound A was investigated following PO administration. CSF, brain and plasma samples were analyzed following dosing with compound A (10 mg/ The following table indicates the bioavailablity and CSF/plasma and brain/plasma ratios.
• GLYX-13 a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator
• FIG. 2 depicts the potentiation of [ H]MK-801 binding for wild-type NMDAR2 subtypes for A. As shown in FIG. 2, Compound A is highly NR2A preferring with no binding to NR2D.
• Sprague Dawley rats were dosed intravenously with 2 mg/kg of Compound A.
• a second group of Sprague Dawley rats was dosed per os with 10 mg/kg of compound A.
• Plasma samples were drawn over a 24 h period and analyzed for Compound A.
• FIG. 3 presents the mean plasma concentration-time profile of Compound A following the single intraveneous (2 mg/kg) and oral (10 mg/kg) dose administration in male Sprague Dawley rats over the 24 hour period.
• Sprague Dawley rats were dosed per os with 10 mg/kg of Compound A. Plasma, brain, and CSF samples were analyzed at various time points over a 24 hour period.
• FIG. 4 displays the mean plasma, brain, and CSF concentration-time profile of Compound A following a single oral (10 mg/kg) dose administration in male Sprague Dawley rats over the 24 hour period.
• CS conditioned stimulus
• UCS tickle unconditioned stimulus
• FIG. 5 shows the results of the rat USVs test. The results demonstrate that Compound B increases positive emotional learning in the rat USVs test, thereby indicating an
• the bioavailablity of Compound B was investigated. CSF, brain and plasma samples were analyzed following dosing with Compound B. The following table indicates the bioavailablity and CSF/plasma and brain/plasma ratios.
• FIG. 6 depicts the potentiation of [ H]MK-801 binding for wild-type NMDAR2 subtypes for compound B.
• Compound B is highly NR2B and NR2D preferring with lower potency in NR2A and NR2C.
• Sprague Dawley rats were dosed intravenously with 2 mg/kg of Compound B.
• a second group of Sprague Dawley rats was dosed per os with 10 mg/kg of Compound B.
• Plasma samples were drawn over a 24 h period and analyzed for compound B.
• FIG. 7 depicts the mean plasma concentration-time profile of Compound B following a single intraveneous (2 mg/kg) and oral (10 mg/kg) dose administration in male Sprague Dawley rats over a 24 hour period.
• Sprague Dawley rats were dosed per os with 10 mg/kg of compound B. Plasma, brain, and CSF samples were analyzed at various time points over the 24 hour period.
• FIG. 8 depicts the mean plasma, brain, and CSF concentration-time profiles of Compound B following a single oral (10 mg/kg) dose administration in male Sprague Dawley rats over the 24 hour period.
• the in vitro MN (micronucleus) assay was performed for Compound A.
• the assay was also performed for Compound B. Cytotoxicity is presented as the % of control growth. A cytotoxicity value of less than 60% is flagged, and the compound is considered toxic at the respective concentration.
• the results of the in vitro MN assay for Compound A are shown in FIG. 9.
• the results of the in vitro MN assay for Compound B are shown in FIG. 10.
• the Ames assay was performed for each of Compound A and Compound B.
• hyphens (-) indicate negative results.
• the results of the Ames assay for Compound A are shown in FIG. 9.
• the results of the Ames assay for Compound B are shown in FIG. 10.
• a hERG assay was performed using Compound A to identify potential hERG channel interactions. Also, a hERG assay was performed using Compound B. For hERG, results showing an inhibition or stimulation higher than 50% are considered to represent significant effects on the test compound. The results of the hERG assay for Compound A are shown in FIG. 9 and the results of the hERG assay for Compound B are shown in FIG. 10. EXAMPLE 13
• Rats were first anesthetized using 3.5-4% isoflurane, then the ears were protected with 1.5 x 1.5 mm foam plugs (Pura-Fit ® , Moldex-Metric Inc., Culver City, California), and the rat was placed into a head access rodent thoracic restrainer (Stoelting, USA) to protect the body while allowing the head to move freely.
• An aluminum shock tube (183 x 61 cm; L-3 Applied Technologies, USA) was positioned 10 cm from the head of the rat.
• Rats received a single -42 PSI blast of helium generated by puncturing 0.014 inches of polyester film. Sham controls were placed outside of the blast radius. Animals were dosed with Compound A (10 mg/kg PO), Compound B (10 mg/kg PO) or 0.5% Na-CMC in 0.9% sterile saline vehicle (1 ml/kg PO) 1 h post-blast.
• PEL Positive emotional learning
• Heterospecific rough-and-tumble play was conducted as previously described by Burgdorf et al, "The long- lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus," Neuroscience 308:202-211, 2015.
• Heterospecific rough-and-tumble play stimulation was administered by the experimenter's right hand. Animals received 3 min of heterospecific rough-and-tumble play that consisted of alternating 15 sec blocks of heterospecific play and 15 sec of no-stimulation.
• This Example relates to the assessment of the anxiolytic effect of treatment in the stress- induced anxiety model, novelty induced hypophagia.
• This assay is also sensitive to the rapid acting antidepressants ketamine and GLYX-13 (Li et al., "mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists," Science 329:959-964, 2010; and Burgdorf et al, 2013). See also Bodnoff et al, "A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety," Psychopharmacology, 97:277-279, 1989.
• NIH novelty induced hypophagia
• Animals were food deprived overnight before testing, and lab chow was placed in the center chamber of an open field (40x40x20 cm) for 10 min under dim red lighting. Between testing each animal, feces and urine were removed from the apparatus. After NIH testing, the latency to eat in the animal's home cage was determined as a control to ensure the effect on eating is specific to the novel environment. Animals were videotaped, and latency (sec) for the animal to take the first bite of food was manually scored offline.
• ED 50 was defined as the dose (or log linear interpolation of dose) that exhibited a half maximal effect (average of the vehicle and maximally efficacious dose) from a log (dose) linear (NIH value) plot.
• the maximally efficacious dose was defined as the lowest dose that was statistically different from vehicle but statistically equivalent (per Fisher's PLSD; a set at 0.05) to the higher doses.
• FIGS. 13 and 14 The results are shown in FIGS. 13 and 14.
• Compound A produces an anxiolytic effect in the novelty -induced hypophagia (NIH) test in rats.
• Compound B produces an anxiolytic effect in the novelty -induced hypophagia (NIH) test in rats.
• Bennett model of mechanical analgesia is used to assess the analgesic effects of compounds as measured by paw withdrawal threshold.
• Bennett GJ, Xie YK "A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man," Pain 33: 87-107, 1988.
• Spared nerve injury surgery is performed on animals with testing for analgesic response once animals have recovered from surgery but still exhibit a low threshold of paw withdrawal after application of von frey filaments. Vehicle animals receive the surgery and then receive vehicle rather than test compound. Animals were tested 1 hr, 24 h and 1 wk post-test compound or vehicle administration.
• Rats were anesthetized using inhaled isoflurane (2.5%). Spared nerve injury surgery was performed as previously described (Bennett and Xie, 1988). An incision (-1.5 cm in length) was made with a scalpel blade dorsally through skin on the right hindlimb, parallel and posterior to femur. Using a small pointed hemostat, the biceps femoris and gluteus superficialis muscles were separated. Using curved blunt forceps, the common sciatic nerve was isolated and exposed. For the mechanical analgesia studies, the whole sciatic nerve was ligated.
• the nerve was loosely ligated with a square knot; 3 ligatures, 1 mm apart were placed on the nerve. The ligatures were tightened to the point that the suture did not slide up or down the nerve. This protocol resulted in a partial loss-of-function of the nerve.
• the common peroneal and tibial branches of the sciatic nerve were ligated and cut, and the sural branch was spared. See Decosterd I, Woolf CJ, "Spared nerve injury: an animal model of persistent peripheral neuropathic pain," Pain 87: 149- 158, 2000. Testing occurred 1-2 weeks post-surgery.
• rats were acclimated to the surface of a suspended wire mesh grid (1 cm X 1 cm, with the wire being 0.3 cm in diameter) for 15-20 min. Starting from the smallest, each Von Frey filament was pressed perpendicularly to the plantar surface of the affected
• a non-clinical in vivo pharmacology study was performed to measure antidepressant-like effects.
• a negative control (0.5% sodium carboxy methyl cellulose in 0.9% sterile saline vehicle) and a positive control (Compound D) were used to compare against Compound A and Compound B.
• the study allowed for the construction of a dose-response curve of the effects of each compound on the Porsolt forced swim test as assessed by the rats' response (reduced floating time) during a 5-minute swimming test.
• the Porsolt forced swim test adapted for use in rats was performed as described by Burgdorf et al, (The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus. Neuroscience 308:202-211 , 2015). Animals were placed in a 46 cm tall ⁇ 20 cm in diameter clear glass tube filled to 30 cm with tap water (23 ⁇ 1 °C) for 15 min on the first day (habituation) and 5 min on the subsequent test day.
• the EC5 0 was defined as the dose (or log linear interpolation of dose) that exhibited a half maximal effect (average of the vehicle and maximally efficacious dose) from a log (dose) linear plot.
• the maximally efficacious dose was defined as the lowest dose that was statistically different from vehicle but statistically equivalent (per Fisher's PLSD) to the higher doses.
• FIG. 17 The results for Compound A are shown in FIG. 17.
• Rats were dosed with Compound A (10-1000 ⁇ g/kg PO; blue circles or data points connected via lines), positive control Compound D (10 ⁇ g/kg PO; green circle or the data point at 10 ⁇ g/kg PO), or Na-CMC in 0.9% saline (1 ml/kg PO; black circles or data point at 1 ml/kg PO) 1 h before testing.
• Compound A produces an antidepressant-like effect as measured by decreased floating time in the Porsolt test compared to vehicle group 1 h post-dosing.
• FIG. 18 The results for Compound B are shown in FIG. 18.
• Rats were dosed with Compound B (0.1-10 ⁇ g/kg PO; blue circles or data points linked with line), positive control Compound D (10 ⁇ g/kg PO; green circle or data point at 10 ⁇ g/kg PO), or Na- CMC in 0.9% saline (1 ml/kg PO; black circles or data point at 1 ml/kg PO) 1 h before testing.
• Compound B produces an antidepressant-like effect as measured by decreased floating time in the Porsolt test compared to vehicle group 1 hour post-dosing.

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