USRE49340E1 - Use of known compounds as D-amino acid oxidase inhibitors - Google Patents

Use of known compounds as D-amino acid oxidase inhibitors Download PDF

Info

Publication number
USRE49340E1
USRE49340E1 US16/401,892 US201516401892A USRE49340E US RE49340 E1 USRE49340 E1 US RE49340E1 US 201516401892 A US201516401892 A US 201516401892A US RE49340 E USRE49340 E US RE49340E
Authority
US
United States
Prior art keywords
disease
schizophrenia
daao
drugs
desmethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US16/401,892
Other languages
English (en)
Inventor
Yufeng Jane Tseng
Yu-Li LIU
Chung-Ming Sun
Hai-Gwo Hwu
Chih-Min Liu
Wen-Sung LAI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
National Yang Ming Chiao Tung University NYCU
Original Assignee
National Health Research Institutes
National Taiwan University NTU
National Yang Ming Chiao Tung University NYCU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by National Health Research Institutes, National Taiwan University NTU, National Yang Ming Chiao Tung University NYCU filed Critical National Health Research Institutes
Priority to US16/401,892 priority Critical patent/USRE49340E1/en
Assigned to NATIONAL YANG MING CHIAO TUNG UNIVERSITY reassignment NATIONAL YANG MING CHIAO TUNG UNIVERSITY MERGER AND CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: NATIONAL CHIAO TUNG UNIVERSITY, NATIONAL YANG MING CHIAO TUNG UNIVERSITY
Application granted granted Critical
Publication of USRE49340E1 publication Critical patent/USRE49340E1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/24—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/26—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y104/00—Oxidoreductases acting on the CH-NH2 group of donors (1.4)
    • C12Y104/03—Oxidoreductases acting on the CH-NH2 group of donors (1.4) with oxygen as acceptor (1.4.3)
    • C12Y104/03003—D-Amino-acid oxidase (1.4.3.3)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B35/00—ICT specially adapted for in silico combinatorial libraries of nucleic acids, proteins or peptides
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/60—In silico combinatorial chemistry
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/60—In silico combinatorial chemistry
    • G16C20/64—Screening of libraries
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/902—Oxidoreductases (1.)
    • G01N2333/906—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.7)
    • G01N2333/90605—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.7) acting on the CH-NH2 group of donors (1.4)
    • G01N2333/90633—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.7) acting on the CH-NH2 group of donors (1.4) with oxygen as acceptor (1.4.3) in general
    • G01N2333/90638—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.7) acting on the CH-NH2 group of donors (1.4) with oxygen as acceptor (1.4.3) in general with a definite EC number (1.4.3.-)
    • G01N2333/90644—D-Amino acid oxidase (1.4.3.3)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/302—Schizophrenia

Definitions

  • the invention relates to D-amino acid oxidase (DAAO) inhibitors. Particularly, the invention relates to selection of known compounds as DAAO inhibitors.
  • DAAO D-amino acid oxidase
  • NMDA N-methyl-D-aspartic acid
  • the receptor is a heterotetramer composed of two structure subunits of NMDA receptor 1 (NR1) and NR2.
  • the extracellular domain of these two subunits were responsible for modulatory and ligand binding functions, where the NR1 binds the co-agonist glycine, and the NR2 binds the neurotransmitter glutamate.
  • the membrane channel domain is responsible for the entrance of calcium ions.
  • the receptor requires the binding of glutamate from NR2 subunit to activate the receptor, and requires the co-agonist of glycine binding for the efficient opening of the ion channel.
  • D-amino acid oxidase was found to be involved in the activation process of the NMDA receptor.
  • the substrates of DAAO especially the D-serine, may bind to the glycine site of the NMDA receptor as a co-agonist. This in turn may regulate the NMDA receptor in opening its calcium channel.
  • D-serine has been found to inhibit the ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated current in rat hippocampus neurons (Gong, X. Q.
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
  • DAAO was hypothesized to be implicated in the pathogenesis of schizophrenia.
  • NMDA receptor also involved in affective disorder (Kaster, M. P. et al., Pharmacological reports: PR 2012, 64 (3), 706-13)
  • Schizophrenia is a devastating mental disorder that afflicts approximately 1 percent of the worldwide population. The direct and indirect costs associated with this disorder make it extremely expensive (Abbott A. Nature, 2010; 468: 158-9).
  • schizophrenia is mainly characterized by positive symptoms, including delusions and hallucinations, negative symptoms, such as blunted emotions, anhedonia, and social isolation, and cognitive deficits such as the impairment of executive function, attention, and working memory.
  • the initial and most common hypothesis regarding pathophysiology of schizophrenia originated from the antipsychotic treatments is dopamine hypothesis, especially for the treatment of positive symptoms (Howes, O. D; Kapur, S. Bulletin, 2009, 35(3), 549-62; Madras, B.
  • NMDAR N-methyl-D-aspartate receptor
  • NMDARs are heteromeric complexes that contain NR1, NR2, and NR3 subunits. NMDARs also contain a glutamate recognition site in the NR2 subunit and a glycine modulatory site in the NR1 subunit. Both glutamate and glycine are agonists of the NMDARs (Clements J D, Westbrook G L.
  • D-amino acid oxidase D-amino acid oxidase
  • DAO shows genetic associations to the disorder in several but not all studies; (2) the expression and activity of DAO are increased in schizophrenia; and (3) the inactivation of DAO resulted in behavioral and biochemical effects in rodents, suggesting potential therapeutic benefits.
  • NMDA receptor enhancer has the following indications: (i) treatment for all symptom domains of schizophrenia and schizoaffective disorder, including negative, cognitive, depressive, positive and general psychopathology symptom domains (Tsai, G. E. and P. Y. Lin, Curr Pharm Des, 2010. 16(5): p. 522-37; and Singh, S. P. and V. Singh, CNS Drugs, 2011. 25(10): p. 859-85); (ii) treatment for depression (Huang, C. C., et al., Biol Psychiatry, 2013. 74(10): p.
  • D-serine is a full agonist at the allosteric glycine binding site of the NMDA receptor, and was reported to improve negative, cognitive symptoms, and symptoms poorly addressed by the standard D2 antagonist in schizophrenia (Ferraris, D. V. et al., Current pharmaceutical design 2011, 17 (2), 103-11) and in depression (Hashimoto, K et al., European Archives of Psychiatry and Clinical Neuroscience 2013). Inhibition of DAAO can increase the brain D-serine level directly therefore can be potentially used for the schizophrenia therapy (Miyamoto, S. et al., Molecular psychiatry 2012, 17 (12), 1206-27; Sacchi, S. et al., Current pharmaceutical design 2012; Ono, K. et al., Journal of neural transmission (Vienna, Austria: 1996) 2009, 116 (10), 1335-47) and even further for affective disorder.
  • Known inhibitors of DAAO include benzoic acid, pyrrole-2-carboxylic acids, and indole-2-carboxylic acids.
  • Indole derivatives and particularly certain indole-2-carboxylates have been described in the literature for treatment of neurodegenerative disease and neurotoxic injury.
  • EP 396124 discloses indole-2-carboxylates and derivatives for treatment or management of neurotoxic injury resulting from a CNS disorder or traumatic event or in treatment or management of a neurodegenerative disease.
  • U.S. Pat. Nos. 5,373,018; 5,374,649; 5,686,461; 5,962,496 and 6,100,289 disclose treatment of neurotoxic injury and neurodegenerative disease using indole derivatives.
  • WO 03/039540 disclose DAAO inhibitors, including indole-2-carboxylic acids, and methods of enhancing learning, memory and cognition as well as methods for treating neurodegenerative disorders.
  • Patent Application No. WO/2005/089753 discloses benzisoxazole analogs and methods of treating mental disorders, such as Schizophrenia.
  • compounds such as the AS057278 (5-methylpyrazole-3-carboxylic acid) (Adage, T. et al., Eur Neuropsychopharmacol 2008, 18 (3), 200-14), CBIO (6-chlorobenzo[d]isoxazol-3-ol) (Ferraris, D.
  • FIGS. 1 a- 1 d show structural analysis for 5-0-Desmethyl-Omeprazole.
  • (a) The comparison with 3-hydroxyquinolin-2 (1H)-one binding mode.
  • (b) 5-0 Desmethyl-Omeprazole bound with DAAO-FAD complex
  • (d) Residues for 5-0-Desmethyl-Omeprazole binding.
  • the green cartons showed DAAO structure.
  • the pink, blue and yellow sticks displayed FAD, 3-hydroxyquinolin-2(1H)-one and 5-0-Desmethyl-Omepratole, respectively.
  • the purple lines were the residues which interacted with 5-0-Desmethyl-Omeprazole.
  • the yellow dashed lines were hydrogen bonding interactions.
  • FIG. 2 shows the IC 50 of the selected drugs.
  • FIG. 3 shows that the injection of RS-D7 increases nociception function (A & B) and sensorimotor gating function (C) in mice.
  • FIG. 4 shows that the injection of RS-D7 alleviates sensorimotor gating deficit in ICR mice injected with methamphetamine (3 mg/kg).
  • FIG. 5 shows that the injection of RS-D7 alleviates MK-801 (0.2 mg/kg) induced behavioral deficits in (A) sucrose preference test, (B & C) hot plate test, and (D) prepulse inhibition in mice.
  • the invention is based on the idea of discovering the known drugs and compounds as potential DAAO inhibitors—drug repurposing, the structure-based virtual screening was performed with the drugbank database.
  • the invention utilizes virtual screening strategy to seek for current market drugs as anti-schizophrenia therapy—drug repurposing.
  • Drug repurposing strategy finds new uses other than the original medical indications of existing drugs. Finding new indications for such drugs will benefit patients who are in needs for a potential new therapy sooner since known drugs are usually with acceptable safety and pharmacokinetic profiles.
  • repurposing strategy was applied for discovering DAAO inhibitor as new schizophrenia therapy was performed with virtual screening on marketed drugs and its metabolites. The identified and available drugs and compounds were further confirmed with in vitro DAAO enzymatic inhibitory assay.
  • a and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • subject includes living organisms such as humans, monkeys, cows, sheep, horses, pigs, cattle, goats, dogs, cats, mice, rats, cultured cells, and transgenic species thereof.
  • subject is a human.
  • administering includes routes of administration which allow the active ingredient of the invention to perform their intended function.
  • treat refers to a method of reducing the effects of a disease or condition. Treatment can also refer to a method of reducing the underlying cause of the disease or condition itself rather than just the symptoms.
  • the treatment can be any reduction from native levels and can be, but is not limited to, the complete ablation of the disease, condition, or the symptoms of the disease or condition.
  • prevent means inhibition or averting of symptoms associated with the target disease.
  • terapéuticaally effective amount refers to that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing a desired therapeutic effect, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • neurodegenerative diseases e.g., Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis
  • neuropsychiatric diseases e.g. schizophrenia and anxieties, such as general anxiety disorder
  • exemplary neurological disorders include MLS (cerebellar ataxia), Huntington's disease, Down syndrome, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodegeneration, (e.g.
  • Neurodegenerative disorder also includes any undesirable condition associated with the disorder.
  • a method of treating a neurodegenerative disorder includes methods of treating loss of memory and/or loss of cognition associated with a neurodegenerative disorder. Such method would also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.
  • the invention provides a method of treating and/or preventing a disease associated with DAAO inhibition in a subject, comprising administering to the subject an effective amount of a compound selected from the group consisting of: esomeprazole, olanzapine.
  • the invention provides a method of inhibiting aberrant regulatory mechanism of glutamate transmission on N-methyl-D-aspartic acid (NMDA) receptor in a subject, comprising administering to the subject an effective amount of a compound selected from the group consisting of: esomeprazole, olanzapine.
  • NMDA N-methyl-D-aspartic acid
  • the invention provides a use of a compound selected from the group consisting of: esomeprazole, olanzapine, 5-O-desmethyl-omprazole, ( ⁇ )-trans 4-(4-Fluorophenyl)-3-(3-hydroxy-4-methoxyphenoxymethyl) piperidine (BRL 36583A), ( ⁇ )trans 4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl) piperidine-hydrochloride (BRL 36610A), amodiaquin, duloxetine, nalbuphine and N-desmethylclozapine, or a therapeutically acceptable salt, solvate, prodrug or isomer thereof, in the manufacture of a medicament for inhibiting aberrant regulatory mechanism of glutamate transmission on N-methyl-D-aspartic acid (NMDA) receptor in a subject.
  • NMDA N-methyl-D-aspartic acid
  • the invention provides a method of inhibiting hypo function of N-methyl-D-aspartate receptor (NMDAR)-mediated signaling pathway, in a subject, comprising administering to the subject an effective amount of a compound selected from the group consisting of: esomeprazole, olanzapine, 5-O-desmethyl-omprazole, ( ⁇ )-trans 4-(4-Fluorophenyl)-3-(3-hydroxy-4-methoxyphenoxymethyl) piperidine (BRL 36583A), ( ⁇ )trans 4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl) piperidine-hydrochloride (BRL 36610A), amodiaquin, duloxetine.
  • the invention provides a use of a compound selected from the group consisting of: esomeprazole, olanzapine, 5-O-desmethyl-omprazole, ( ⁇ )-trans 4-(4-Fluorophenyl)-3-(3-hydroxy-4-methoxyphenoxymethyl) piperidine (BRL 36583A), ( ⁇ )trans 4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl) piperidine-hydrochloride (BRL 36610A), amodiaquin, duloxetine, nalbuphine and N-desmethylclozapine, or a therapeutically acceptable salt, solvate, prodrug or isomer thereof, in the manufacture of a medicament for inhibiting hypofunction of N-methyl-D-aspartate receptor (NMDAR)-mediated signaling pathway in
  • the compounds of the invention are useful for treating or preventing any disease and/or condition, wherein modulation of D-serine levels, and/or its oxidative products, is effective in ameliorating symptoms. Inhibition of the enzyme can lead to increases in D-serine levels and a reduction in the formation of toxic D-serine oxidation products.
  • the invention provides methods for the treatment or prevention of neurological disorders and methods of enhancing learning, memory and/or cognition.
  • the invenion also provides methods for the treatment or prevention of the disease mediated by DAAO inhibition; preferably, symptom domains of schizophrenia and schizoaffective disorder, depression, Tourette Syndrome, Post-traumatic stress disorder (PTSD), Obsessive-compulsive disorder (OCD), analgesics, loss of memory and/or cognition associated with neurodegenerative diseases or loss of neuronal function characteristic of neurodegenerative diseases.
  • the symptom domains of schizophrenia and schizoaffective disorder include negative, cognitive, depressive, positive and general psychopathology symptom domains.
  • the disease associated with DAAO inhibition is mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease or schizophrenia.
  • the disease associated with DAAO inhibition is pain, ataxia or convulsion.
  • the compounds of the invention can be used for treating or preventing loss of memory and/or cognition associated with neurodegenerative diseases (e.g., Alzheimer's disease and schizophrenia) and for preventing loss of neuronal function characteristic of neurodegenerative diseases. Further, methods are provided for the treatment or prevention of pain, ataxia and convulsion.
  • the effective amount of the compound described herein ranges from 2 mg/kg body weight to 5 g/kg body weight; preferably, 10 mg/kg body weight to 3 g/kg body weight or 20 mg/kg body weight to 2 g/kg body weight.
  • a pharmaceutically acceptable carrier, diluent, excipient, and/or salt means that the carrier, diluent, excipient and/or salt must be compatible with the active ingredient, does not adversely affect the therapeutic benefit of the active ingredient, and is not deleterious to the recipient thereof.
  • Administration of the active ingredient or pharmaceutical compositions thereof for practicing the present invention can be by any method that delivers the compounds systemically and/or locally (e.g., at the site of the bone fracture, osteotomy, or orthopedic surgery). These methods include oral routes, parenteral routes, intraduodenal routes, etc.
  • the active ingredient or a pharmaceutical composition thereof can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the active ingredient or a pharmaceutical composition thereof include, but are not limited to, mineral oil. liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, sugars such as lactose and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active ingredient or a pharmaceutical composition thereof suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • additional therapeutic agents can be administered together with the active ingredient or a pharmaceutical composition thereof.
  • Those additional agents can be administered sequentially in any order, as part of a multiple dosage regimen, from the active ingredient or a pharmaceutical composition thereof (consecutive or intermittent administration).
  • those agents can be part of a single dosage form, mixed together with the active ingredient or a pharmaceutical composition thereof (simultaneous or concurrent administration).
  • a pharmaceutical composition useful in the invention can take the form of solutions, suspensions, tablets, pills, capsules, powders, granules, semisolids, sustained release formulations, elixirs, aerosols, and the like.
  • Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch, preferably potato or tapioca starch, and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • t the active ingredient or a pharmaceutical composition thereof of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol. glycerin and various like combinations thereof.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intramedullary and intraarticular injection and infusion.
  • a pharmaceutical composition for parenteral injection can comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
  • aqueous and non-aqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • carboxymethylcellulose and suitable mixtures thereof such as vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions useful in the present invention can also contain adjuvants such as, but not limited to, preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, such as for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • Administration by slow infusion is particularly useful when intrathecal or epidural routes are employed.
  • a number of implantable or body-mountable pumps useful in delivering compound at a regulated rate are known in the art. See, e.g., U.S. Pat. No. 4,619,652.
  • Suspensions in addition to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • aqueous or partially aqueous solutions are prepared.
  • compositions useful in the invention can also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline. employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the active ingredient or a pharmaceutical composition thereof with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the drugs.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the drugs.
  • compositions include, but are not limited to, a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type, including but not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin.
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate.
  • potassium hydrogen phosphate sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol. sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • Solid pharmaceutical excipients include, but are not limited to, starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • the invention provides a method for selection of a DAAO inhibitor, comprising selecting a drug database; removing compounds containing metal atoms and compounds with molecular weights outside the 100-700 g/mol range; selecting the compound candidates with interaction with more than three residues of Leu51, Gln53, Leu215, His217, Tyr 224, Tyr228, Ile230, Arg283 and Gly313 of DAAO and subjecting the selected compound candidates to an inhibitory activity assay.
  • Any drug database can be used in the method of the invention.
  • the compounds are reduced to a subset by removing molecules containing metal atoms and molecules with molecular weights outside the 100-700 g/mol range.
  • MSD was performed on the selected compounds. From the results of MDS, nearby the DAAO residues near each compound were analyzed. According to the literature. the active site of DAAO contained the following residues: Leu51, Gln53, Leu215, His217, Tyr 224, Tyr228, Ile230, Arg283 and Gly313.
  • the molecules with more than three residues mentioned above within 3 A distance nearby were considered candidates.
  • the DAAO inhibitory compounds mentioned herein are obtained by performing the selection method of the invention.
  • N-desmethylclozapine, nalbuphine, and amodiaquin were purchased from Sigma-Aldrich Co. LLC. (Sigma-Aldrich, USA).
  • Trishydrochloride was purchased from invitrogen (Life Technologies Corporation, USA).
  • 5-O-Desmethyl-Omeprazole and Olanzapine were purchased from Toronto Research Chemicals (Canada).
  • PM-BRL 36583A and PM-BRL 36610A were gift from GlaxoSmithKline (United Kingdom).
  • Duloxetine was purchased from Sequoia Research Products (United Kingdom). Black 96 well plates were purchased form Nunc (Thermo Scientific, USA).
  • the DAAO crystal structures was obtained from the Protein Data Bank (Schnell, E.; Sizemore, M.; Karimzadegan, S.; Chen, L.; Bredt, D. S.; Nicoll, R. A., Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc Natl Acad Sci USA 2002, 99 (21). 13902-7) (PDB id: 3G3E).
  • PDB id: 3G3E Total of 1463 compounds from DrugBank (DrugBank http://www.drugbank.ca/) and our in-house collections of drug metabolites and compounds were used for the virtual screening. The compounds were reduced to a subset by removing molecules containing metal atoms and molecules with molecular weights outside the 100-700 g/mol range.
  • a 1000-step energy minimization using the steepest descent algorithm was employed with an energy minimization convergence criteria of a between-step difference smaller than 1000 kJ mol ⁇ 1 nm ⁇ 1 .
  • the system was subjected to a 1 ns molecular dynamics simulation at constant temperature (300 K), pressure (1 atm), and a time step of 0.001 ps (1 fs) with the coordinates of the systems recorded every every 1000 steps.
  • the DAAO enzymatic activity assay was modified according to the report of Oguri et al (Oguri, S., Screening of d-amino acid oxidase inhibitor by a new multi-assay method. Food chemistry 2007, 100 (2), 616).
  • the DAAO activity was measured by using substrate D-alanine reaction produced hydrogen peroxide (H 2 O 2 ) to further react with 3-(4-hydroxyphenyl) propionic acid (HPPA).
  • HPPA 3-(4-hydroxyphenyl) propionic acid
  • the HPPA were oxidized by H 2 O 2 and peroxidase to become the fluorogenic dimer which was measured to represent the activity of DAAO.
  • the substrate of DAAO was prepared in 50 mM D-alanine (dissolved in 0.2 M Tris-HCl buffer, pH 8.3).
  • a 100 ul of D-alanine solution was mixed with 4 ul (in 100%) dimethyl sulfoxide, DMSO) of different concentrations of drugs ranging from 31.36 nM, 94.08 nM, 0.28 uM, 0.85 uM, 2.54 uM, 7.62 uM, 22.86 uM, 68.59 uM, 0.21 mM, 0.62 mM, 1.85 mM, 5.56 mM, 16.67 mM, and 50.00 mM with a final DMSO concentrations of 0.167% in each reaction concentration.
  • a 10 ul of D-alanine and drug mixture was incubated with 220 ul of Reaction Master Mix in black 96 well plate at 37° C. for 5 min.
  • the Reaction Master Mix contained 110 ul of 5 U/mL porcine kidney DAAO (Sigma-Aldrich, USA) solution (dissolved with 0.2 M Tris-HCl buffer, pH 8.3), 1.1 mL of 15 U/mL peroxidase solution (dissolved with 0.2 M Tris-HCl buffer, pH 8.3), 1.1 mL of 20 mM HPPA solution (dissolved with 0.2 M Tris-HCl buffer, pH 8.3), and 2.2 ml of 2 M Tris-HCl buffer (pH 8.3) for 110 reaction assays.
  • Fluorescence intensity (Fs) was measured at 405 nm by irradiation excitation at 320 nm. The higher is the DAAO enzymatic activity, the higher is the fluorescence intensity.
  • DAAO inhibitors were compared by using inhibitory concentrations which reduce 50% of DAAO activity (IC 50 ).
  • IC 50 value was calculated by GraphPad Prism, version 5 software (GraphPad Software, Inc., La Jolla, Calif.) (GraphPad Prism 5, GraphPad software Inc: California, USA) through nonlinear regression model.
  • GROMOS 53A6 force is field (Oostenbrink, C.; Soares, T A.; van der Vegt, N. F. A.; van Gunsteren, W. F., Validation of the 53A6 GROMOS force field. Eur Biophys J Biophy 2005, 34 (4), 273-284) and the SPC216-type water molecules were used to simulate the complex system. Na + or Cl ⁇ would be added if the systems were not the electrostatic neutrality conditions. From the results of MDS, nearby the DAAO residues near each compound were analyzed.
  • the active site of DAAO contained the following residues: Leu51, Gln53, Leu215, His217, Tyr 224, Tyr228, Ile230, Arg283 and Gly313.
  • the molecules with more than three residues mentioned above within 3 ⁇ distance nearby were considered candidates.
  • Nine candidates could be acquired from commercial sources for testing and proceed with in vitro study. Name and structure of the compounds with their IC 50 are listed in Table 1.
  • the compounds were tested in fluorescence intensity (Fs) measured at 405 nm by irradiation excitation at 320 nm.
  • Fs fluorescence intensity
  • the DAAO enzymatic activities after the incubation with different concentrations of sodium benzoate showed that the IC 50 (causing 50% of DAAO activity reduction of sodium benzoate concentration) is around 71.74 uM (95% confidence interval ranging from 62.67 uM to 82.13 uM).
  • we also performed the enzymatic assay to validate the IC 50 The IC 50 of each known drug were showed in Table 1 and the IC50 were plotted in FIG. 2 . The higher the DAAO enzymatic activity is, the higher the fluorescence intensity is.
  • FIG. 1 The relative binding poses and positions of 5-O-Desmethyl-Omeprazole and 3-hydroxyquinolin-2(1H)-one (Duplantier, A. J. et al., J Med Chem 2009, 52 (11), 3576-3585) (which obtained from PDB crystal structure) was displayed in FIG. 1 (a) .
  • the 3-hydroxyquinolin-2(1H)-one was close to FAD in FIG. 1 (a) .
  • the benzimidazole part of the 5-O-Desmethyl-Omeprazole was located near FAD, the binding pose was different from the compounds described above.
  • the pyridine ring of the 5-O-Desmethyl-Omeprazole locates in other region far from the FAD.
  • FIGS. 1 (b) and (d) the residues interacted with the 5-O-Desmethyl-Omeprazole and included in Leu51, Pro54, Leu56, Trp107, His217, Asp218, Tyr224 and Gly313.
  • Leu56, Trp107 and Tyr224 formed the hydrogen bonds with 5-O-Desmethyl-Omeprazole. From these analysis, we suggested that the 5-O-Desmethyl-Omeprazole had a dissimilar binding mode from the 3-hydroxyquinolin-2(1H)-one, and the hydrogen bonds also played an important role in the complex system.
  • animal model provides an important tool in pharmaceutical discovery and development efforts (Everitt J. I, Toxicologic Pathology. 2015, 43(1), 70-7). Indeed, animal models not only play an indispensable role in the discovery and verification of potential drugs/treatments but also provide a feasible approach to elucidate causal relationships between genes and related symptoms (Lai, W. S et al., Current Pharmaceutical Design, 2014, 20(32), 5139-50).
  • the healthy animal model can help to ensure the quality, potency, and safety of the therapeutic potential (Lebron, J.
  • amphetamine/methamphetamine administrations in mice provide a good model to further investigate the pathophysiology of schizophrenia.
  • focusing on the dopamine system has led to limited progress in understanding the mechanism of the cognitive dysfunction and negative symptoms of schizophrenia (Miyamoto, S et al., Molecular Psychiatry, 2012, 17, 1206-1227). Therefore, to improve understanding of the pathology and symptomatology (particularly cognitive and negative symptoms) of schizophrenia, the dysfunction of glutamate pathway is one of the prominent mechanisms behind the disease's pathophysiology (Egerton, A et al., Current Pharmaceutical Biotechnology, 2012, 13(8), 1500-1512; Moghaddam, B; Javitt, D, Neuropsychopharmacology, 2012, 37(1), 4-15).
  • NMDA receptor antagonists such as phencyclidine (PCP) and dizocilpine (MK-801), produce “schizophrenia-like” symptoms in healthy individuals (Javitt, D. C; Zukin, S. R, The American Journal of Psychiatry, 1991, 148, 1301-1308; Krystal, J. H et al., Archives of General Psychiatry, 1994, 51, 199-214), and dysregulated NMDA receptor subunits are seen in postmortem tissue from schizophrenia patients and animal models of NMDA antagonism (Gunduz-Bruce, H et al., Brain Research Reviews, 2009, 60, 279-286; Lisman, J.
  • PCP phencyclidine
  • MK-801 dizocilpine
  • MK-801 is a better NMDA antagonist to bind inside the ion channel of NMDA receptor thus preventing the flow of ions.
  • emerging evidence also exhibits the ability of MK-801 to induce cognitive deficits and negative symptoms of relevance to schizophrenia in mice (Neill, J. C; Barnes et al., Pharmacology & Therapeutics, 2010, 128(3), 419-32; Bubeniková-Valesová, V et al., Neuroscience & Biobehavioral Reviews, 2008. 32(5), 1014-23). It is worth taking advantage of MK-801 mouse model of schizophrenia to show phenomenological validity and is suitable for searching for new substances with antipsychotic effects.
  • the pharmacological animal model of schizophrenia is due in part to similarities in clinical presentation and response to treatment. These behavioral tasks have been evaluated with varying degrees of test validities for assessing schizophrenia-relevant behavioral deficits in mice. Different batches of male adult C57/B16 mice were used and the details of different behavioral tasks were described elsewhere.
  • mice hot plate test was used to assess basic pain and nociception function in mice. Compared with the WT controls, the latency of mouse first reaction (i.e., jump) was accelerated and the numbers of jump was increased on the 55° C. hot plate test after 40 mg/kg RS-D7 (i.p.) injection ( FIGS. 3 A and 3 B ). These results suggest that the injection of 40 mg/kg RS-D7 increase nociception function in mice.
  • RS-D7 i.p.
  • PPI Prepulse Inhibition
  • Methamphetamine is a potent psychostimulant that increases the amount of extracellular dopamine in the brain.
  • Methamphetamine (or amphetamine)-induced psychosis model has been well-established and useful for schizophrenia in laboratory animals.
  • the injection of 20 mg/kg RS-D7 (i.p.) induce a greater PPI in ICR mice with methamphetamine injection (3 mg/kg, i.p.), especially in 74 dB prepulse ( FIG. 4 ). This finding suggests that the injection of 20 mg/kg RS-D7 increased sensorimotor gating function in methamphetamine-treated mice.
  • MK-801 is a non-competitive NMDA receptor antagonist.
  • An injection and chronic injections of MK-801 provide a potential animal model to mimic both the negative and cognitive symptoms of schizophrenia.
  • C57/B16 Mice received an acute administration of MK-801 (0.2 mg/kg, i.p.) and the doses of MK-801 were chosen to avoid stereotypic behaviors in the open field.
  • a significant reduction of sucrose uptake was observed after acute MK-801 injection.
  • the injection of 20 mg/kg RS-D7 rescued the MK-801 induced deficit in mice ( FIG. 5 A ). This result suggests that acute RS-D7 injection alleviated MK-801-induced anhedonia in the sucrose preference test.
  • mice with acute MK-801 injection exhibited a profound reduction of acoustic PPI.
  • the injection of 40 mg/kg RS-D7 significantly alleviated MK-801 induced PPI deficit in these mice.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Psychiatry (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Theoretical Computer Science (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Library & Information Science (AREA)
  • Computing Systems (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Pain & Pain Management (AREA)
  • Microbiology (AREA)
  • Emergency Medicine (AREA)
US16/401,892 2014-04-30 2015-04-30 Use of known compounds as D-amino acid oxidase inhibitors Active USRE49340E1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/401,892 USRE49340E1 (en) 2014-04-30 2015-04-30 Use of known compounds as D-amino acid oxidase inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201461986480P 2014-04-30 2014-04-30
US15/125,716 US9868975B2 (en) 2014-04-30 2015-04-30 Use of known compounds as D-amino acid oxidase inhibitors
US16/401,892 USRE49340E1 (en) 2014-04-30 2015-04-30 Use of known compounds as D-amino acid oxidase inhibitors
PCT/US2015/028385 WO2015168346A1 (en) 2014-04-30 2015-04-30 Use of known compounds as d-amino acid oxidase inhibitors

Publications (1)

Publication Number Publication Date
USRE49340E1 true USRE49340E1 (en) 2022-12-20

Family

ID=54359315

Family Applications (2)

Application Number Title Priority Date Filing Date
US15/125,716 Ceased US9868975B2 (en) 2014-04-30 2015-04-30 Use of known compounds as D-amino acid oxidase inhibitors
US16/401,892 Active USRE49340E1 (en) 2014-04-30 2015-04-30 Use of known compounds as D-amino acid oxidase inhibitors

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US15/125,716 Ceased US9868975B2 (en) 2014-04-30 2015-04-30 Use of known compounds as D-amino acid oxidase inhibitors

Country Status (15)

Country Link
US (2) US9868975B2 (es)
EP (2) EP3498275B1 (es)
JP (2) JP2017524143A (es)
KR (2) KR102537686B1 (es)
CN (2) CN112773798B (es)
AU (1) AU2015253099B2 (es)
CA (1) CA2946153C (es)
DK (1) DK3137658T3 (es)
ES (2) ES2951736T3 (es)
IL (1) IL248567B (es)
MX (2) MX2016011551A (es)
PT (1) PT3137658T (es)
SG (2) SG11201607166XA (es)
TW (1) TWI675660B (es)
WO (1) WO2015168346A1 (es)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT3137658T (pt) * 2014-04-30 2022-05-05 Univ Nat Taiwan Uso de compostos conhecidos como inibidores do d-aminoácido oxidase
IL265108B2 (en) * 2016-09-14 2024-03-01 Yufeng Jane Tseng Novel mutated benzimidazoles as D-amino acid oxidase (DAAO) inhibitors
CN108143734A (zh) * 2018-02-09 2018-06-12 南京中医药大学 阿莫地喹及其药学上可接受的盐在制备用于治疗阿尔茨海默病的药物中的应用
CN110297839B (zh) * 2019-06-25 2022-04-12 中国人民解放军军事科学院军事医学研究院 药物适应症的查询方法、装置、计算机设备和存储介质
IL294231A (en) * 2021-06-23 2023-01-01 Yoda Pharmaceuticals Inc History of benzimidazole for the treatment and/or prevention of nlrp3-mediated diseases and disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090264653A1 (en) 2005-12-16 2009-10-22 Wilmin Bartolini Useful indole compounds

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4619652A (en) 1982-12-23 1986-10-28 Alza Corporation Dosage form for use in a body mounted pump
JPH0347123A (ja) 1989-05-05 1991-02-28 G D Searle & Co インドール―２―カルボキシレート化合物類を含有するｃｎｓ疾患治療用組成物
GB9208492D0 (en) 1992-04-16 1992-06-03 Glaxo Spa Heterocyclic compounds
GB9304500D0 (en) 1993-03-05 1993-04-21 Glaxo Spa Heterocyclic compounds
GB9321221D0 (en) 1993-10-14 1993-12-01 Glaxo Spa Heterocyclic compounds
DE69638114D1 (de) * 1995-11-13 2010-03-04 Inst Med Molecular Design Inc Verfahren zum entwurf einer physiologisch aktiven verbindung
CN1486180A (zh) * 2000-12-07 2004-03-31 纽热莫勒丘乐有限公司 用nmda受体拮抗物治疗神经精神病紊乱的方法
US20030162825A1 (en) 2001-11-09 2003-08-28 Sepracor Inc. D-amino acid oxidase inhibitors for learning and memory
WO2003097011A1 (en) * 2002-05-17 2003-11-27 Eisai Co., Ltd. Compositions and methods using proton pump inhibitors
CA2559105A1 (en) 2004-03-16 2005-09-29 Janssen Pharmaceutica N.V. Benzisoxazoles
ES2324354T3 (es) * 2005-07-29 2009-08-05 Rottapharm S.P.A. Combinacion terapeutica de itriglumida e inhibidores de la bomba de protones en el tratamiento de trastornos gastrointestinales y relacionados.
US20090306169A1 (en) * 2005-10-06 2009-12-10 Brandish Philip E Use of Fused Pyrrole Carboxylic Acids for the Treatment of Neurodegenerative and Psychiatric Diseases and D-Amino Acid Oxidase Inhibitors
CA2687128C (en) * 2006-05-10 2017-03-28 Laclede, Inc. Compositions and methods for enzymatic treatment of lung disorders
KR20090024823A (ko) 2006-06-30 2009-03-09 세프라코 아이엔시. Ｄ-아미노산 옥시다제의 융합된 헤테로사이클 억제제
US20090099248A1 (en) * 2007-01-18 2009-04-16 Sepracor Inc. Inhibitors of d-amino acid oxidase
EP2297167A1 (en) 2008-06-02 2011-03-23 Ironwood Pharmaceuticals, Inc. Selenophene and selenazole carboxylic acid derivatives
JP4462382B1 (ja) * 2009-04-23 2010-05-12 学校法人北里研究所 Ｄ−アスパラギン酸オキシダーゼおよびｄ−アミノ酸オキシダーゼに対する新規阻害剤
US20120035156A1 (en) * 2010-08-09 2012-02-09 Daniela Alberati Combination of glyt1 compound with antipsychotics
JO3115B1 (ar) * 2011-08-22 2017-09-20 Takeda Pharmaceuticals Co مركبات بيريدازينون واستخدامها كمثبطات daao
WO2013061161A2 (en) * 2011-10-28 2013-05-02 Green Bcn Consulting Services Sl New combination therapies for treating neurological disorders
KR101348984B1 (ko) * 2012-01-31 2014-01-10 전남대학교산학협력단 박테리아 시토크롬 ｐ450을 이용한 오메프라졸로부터 대사산물의 신규한 생산방법 및 이를 위한 조성물
PT3137658T (pt) * 2014-04-30 2022-05-05 Univ Nat Taiwan Uso de compostos conhecidos como inibidores do d-aminoácido oxidase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090264653A1 (en) 2005-12-16 2009-10-22 Wilmin Bartolini Useful indole compounds

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
Abelo, A. et al., Drug Metab. Dispos. 2000 vol. 28, pp. 966-972. *
Bromundt et al.: "Sleep-wake Cycles and Cognitive Functioning in Schizophrenia," British Journal of Psychiatry; Apr. 1, 2011, vol. 198, No. 04, pp. 269-276.
Burnet et al. "D-Amino Acid Oxidase Activity and Expression are Increased in Schizophrenia" Molecular Psychiatry vol. 13, pp. 658-660, 2008.
Haenisch et al.: "Risk of Dementia in Elderly Patients with the Use of Proton Pump Inhibitors," European Archives of Psychiatry and Clinical Neuroscience; Oct. 24, 2014, vol. 265, No. 5, pp. 419-428.
Heresco-Levy et al. "D-Serine Efficacy as Add-On Pharmacotherapy to Risperidone and Olanzapine for Treatment-Refractory Schizophrenia" Biological Psychiatry vol. 57, pp. 577-585, 2005.
Katane et al. "Identification of Novel D-Amino Acid Oxidase Inhibitors by In Silico Screening and Their Functional Characterization In Vitro" Journal of Medicinal Chemistry, 2012.
Khazaal et al.: "Eating and weight related cognitions in people with Schizophrenia: A case control study". Clinical Practice and Epidemiology in Mental Health; Oct. 31, 2006, vol. 2, No. 1.
Lewis, R., Hawley's Condensed Chemical Dictionary, 15th ed., 2007, excerpt p. 711. *
Li et al. "Pharmacokinetic Drug Interaction Profile of Omeprazole with Adverse Consequences and Clinical Risk Management" Therapeutics and Clinical Risk Management vol. 9, pp. 259-271, 2013.
Maderia et al. "Increased Brain D-Amino Acid Oxidase (DAAO) Activity in Schizophrenia" Schizophrenia Research vol. 101, pp. 76-83, 2008.
Novick et al. "SWEETLEAD: An In Silico Database of Approved Drugs, Regulated Chemicals, and Herbal Isolates for Computer-Aided Drug Discovery" PLOS ONE vol. 8, pp. 1-9, 2013.
Risbood, V. et al., . Pharm Prac. 2010 vol. 23, Poster Submission at p. 167. *
Sacchi et al. "Structure-Function Relationships in Human D-Amino Acid Oxidase" Amino Acids vol. 43, pp. 1833-1850, 2012.
Silva, T. et al., Mini-Rev. Med. Chem. 2005 vol. 5 pp. 893-914. *
Sparey et al. "The Discovery of Fused Pyrrole Carboxylic Acids as Novel, Potent D-Amino Acid Oxidase (DAO) Inhibitors" Bioorganic and Medicinal Chemistry Letters vol. 18, pp. 3386-3391, 2008.
Tsai et al. "D-Serine Added to Clozapine for the Treatment of Schizophrenia" American Journal of Psychiatry vol. 156, pp. 1822-1825, 1999.
Wagner, S. et al., Eur. J. Clin. Pharmacol. 2011 vol. 67, pp. 533-534. *
Yang et al.: "The DAO Gene is Associated with Schizophrenia and Interacts with Other Genes in the Taiwan Han Chinese Population," PLOS ONE; Mar. 28, 2013, vol. 8, Issue. 3, p. e60099.

Also Published As

Publication number Publication date
MX2016011551A (es) 2017-02-28
SG11201607166XA (en) 2016-09-29
KR20160147868A (ko) 2016-12-23
CN106687626A (zh) 2017-05-17
US20170037448A1 (en) 2017-02-09
MX2021000133A (es) 2021-03-25
WO2015168346A1 (en) 2015-11-05
AU2015253099A1 (en) 2016-09-15
EP3137658B1 (en) 2022-03-30
KR102537686B1 (ko) 2023-05-30
TWI675660B (zh) 2019-11-01
IL248567B (en) 2022-08-01
TW201610246A (zh) 2016-03-16
EP3498275B1 (en) 2023-06-07
AU2015253099B2 (en) 2019-07-18
EP3498275C0 (en) 2023-06-07
JP2017524143A (ja) 2017-08-24
NZ723652A (en) 2021-04-30
US9868975B2 (en) 2018-01-16
EP3498275A1 (en) 2019-06-19
IL248567A0 (en) 2016-12-29
JP2020112558A (ja) 2020-07-27
CN112773798A (zh) 2021-05-11
CA2946153C (en) 2022-06-14
DK3137658T3 (da) 2022-05-02
CN112773798B (zh) 2024-03-29
JP6941326B2 (ja) 2021-09-29
PT3137658T (pt) 2022-05-05
ES2911879T3 (es) 2022-05-23
EP3137658A4 (en) 2018-03-14
ES2951736T3 (es) 2023-10-24
SG10202102125SA (en) 2021-04-29
CN106687626B (zh) 2021-01-26
EP3137658A1 (en) 2017-03-08
CA2946153A1 (en) 2015-11-05
KR20220123738A (ko) 2022-09-08

Similar Documents

Publication Publication Date Title
JP6941326B2 (ja) 疾患をｄ−アミノ酸オキシダーゼ（ｄａａｏ）阻害により治療するための医薬組成物
Coyle et al. Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia
US20130225623A1 (en) Methods of Treating Psychiatric or Neurological Disorders with MGLUR Antagonists
Scarpa et al. M1 muscarinic acetylcholine receptors: A therapeutic strategy for symptomatic and disease-modifying effects in Alzheimer's disease?
JP2010510314A (ja) 精神遅滞、ダウン症候群、脆弱ｘ症候群および自閉症の治療方法
Hashimoto Glycine transporter-1: a new potential therapeutic target for schizophrenia
Hashimoto Glycine transport inhibitors for the treatment of schizophrenia
KR20170012449A (ko) 결정질 베타-d-니코틴아미드 리보시드의 제조 및 용도
JP2008538102A (ja) バーチャルドッキングアプローチを適用したプロテインキナーゼｂ阻害剤のスクリーニング方法並びにそれにより見出された化合物及び組成物
US20210169883A1 (en) Method of treating aggression with orexin receptor antagonists
TW201808269A (zh) 用於治療搔癢症及／或發癢之方法
WO2019068771A1 (en) USE OF SIGMA RECEPTOR LIGANDS AGAINST AGE-RELATED COGNITIVE DISORDERS
NZ723652B2 (en) Use of known compounds as d-amino acid oxidase inhibitors
US20090221610A1 (en) Compositions and Methods for Treating Cognitive Disorders
US10835532B2 (en) Muscarinic agonists as cognitive enhancers
Morrow et al. Glutamatergic approaches for the treatment of schizophrenia
Calcaterra ESTABLISHMENT AND UTILIZATION OF A DRUG DISCOVERY PLATFORM FOR KV11. 1-3.1, A NOVEL TARGET FOR THE TREATMENT OF SCHIZOPHRENIA

Legal Events

Date Code Title Description
FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO SMALL (ORIGINAL EVENT CODE: SMAL); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

AS Assignment

Owner name: NATIONAL YANG MING CHIAO TUNG UNIVERSITY, TAIWAN

Free format text: MERGER AND CHANGE OF NAME;ASSIGNORS:NATIONAL CHIAO TUNG UNIVERSITY;NATIONAL YANG MING CHIAO TUNG UNIVERSITY;REEL/FRAME:060741/0147

Effective date: 20210201