WO2000066110A1 - Glycine cleavage system inhibitors as potential antipsychotics - Google Patents

Glycine cleavage system inhibitors as potential antipsychotics Download PDF

Info

Publication number
WO2000066110A1
WO2000066110A1 PCT/EP2000/003456 EP0003456W WO0066110A1 WO 2000066110 A1 WO2000066110 A1 WO 2000066110A1 EP 0003456 W EP0003456 W EP 0003456W WO 0066110 A1 WO0066110 A1 WO 0066110A1
Authority
WO
WIPO (PCT)
Prior art keywords
glycine
cleavage system
pcp
glycine cleavage
schizophrenia
Prior art date
Application number
PCT/EP2000/003456
Other languages
French (fr)
Inventor
Michael Arlt
Gerd Bartoszyk
Original Assignee
Merck Patent Gmbh
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 Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to BR0010151-6A priority Critical patent/BR0010151A/en
Priority to AU47481/00A priority patent/AU4748100A/en
Priority to JP2000614995A priority patent/JP2002543124A/en
Priority to MXPA01010933A priority patent/MXPA01010933A/en
Priority to KR1020017013838A priority patent/KR20020008167A/en
Priority to CA002372073A priority patent/CA2372073A1/en
Priority to EP00929364A priority patent/EP1185259A1/en
Publication of WO2000066110A1 publication Critical patent/WO2000066110A1/en
Priority to NO20015247A priority patent/NO20015247L/en

Links

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • 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
    • A61P25/18—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

Definitions

  • the invention relates to inhibitors of the glycine cleavage system and their use as potential antipsychotic agents.
  • the invention relates furthermore to a process for treating humans having psychosis, psychosis associated with an illness, schizophrenia, Alzheimers disease or other related psychotic disorders.
  • Glycine is a neurotransmitter in the central nervous system.
  • strychnine sensitive glycine receptors exist, where glycine sen/es as an inhibitory neurotransmitter.
  • glycine binding site located at the NMDA receptor.
  • glycine sen/es as a excitatory coagonist.
  • glutamate and glycine is mandatory.
  • NMDA Antagonists such as phencyclidine (PCP) and related drugs (e.g.
  • ketamine or dizocilpine induce symptoms in human volunteers which are not distinguishable from schizophrenia (Luby et al., 1959; Rosenbaum et al., 1959; Bakker and Amini, 1961), i.e. they induce a spectrum of symptoms including the positive, negative and cognitive aspects of schizophrenia (Krystal et al., 1994; Mulhotra et al., 1996). In addition, PCP provokes an exacerbation of symptoms in patients suffering from schizophrenia (Lathi et al., 1995; Malhotra et al., 1997).
  • PCP-induced emotional, cognitive and behavioural changes represent not only a clinical model of schizophrenia (Luby et al., 1962), but moreover PCP-induced behavioural changes in mice and rats mimicking the symptoms of schizophrenia in these model organisms are now frequently used animal models for schizophrenia (e.g. Freed et al., 1984) and have been validated with many antischizophrenic drugs with different mechanisms of action (e.g. Jackson et al., 1993; Gleason et al., 1997; Vanover, 1997; Krebs-Thomson et al., 1998).
  • D-cycloserine The effects of D-cycloserine were evaluated in several clinical trial. In one clinical trial doses from 15 to 250mg/d of D-cycloserine were assessed. The results showed that the dose of 50 mg/d reduced negative symptoms in schizophrenic patients (Goff 1995). In another double blind, placebo-controlled clinical trial it was found that 50mg/d along with their effective dose of antipsychotics gave an improvement in negative symptoms (Goff 1999).
  • Glycine is not only a neurotransmitter but also one of the major sources of C-1 building blocks. It is catabolized by the Glycine Cleavage System (GCS) to yield carbon dioxide, ammonia and methylene tetrahydrofolate.
  • GCS Glycine Cleavage System
  • the GCS consists of four enzymes:
  • the invention relates to inhibitors of the glycine cleavage system and their use as potential antipsychotic agents. It could be shown that, for example, vaiporate and cysteamine are potential inhibitors.
  • the invention relates furthermore to a process for treating humans having psychosis, psychosis associated with an illness, schizophrenia, Alzheimers disease or other related psychotic disorders.
  • an inhibitor preferably vaiporate and / or cysteamine
  • the invention provides a process, wherein the psychotic disorder is schizophrenia, major depression, manic-depressive disorder, Alzheimers disease or post-traumatic stress syndrome.
  • the invention provides a process, wherein administering the glycine cleavage system inhibitor affects augmenting NMDA receptor-mediated neurotransmission. Furthermore, it is an object of this invention to provide the use of inhibitors of the glycine cleavage system for the manufacture of a medicament directed to psychotic disorders like schizophrenia, major depression, manic-depressive disorder, Alzheimers disease or post-traumatic stress syndrome.
  • the P-protein was characterized from chicken liver (1500g of liver yielded 8 mg of protein corresp. to 33.000 U). Its molecular weight is 208.000. It is a homodimer, each monomer carrying one molecule of pyridoxalphosphate (Hiraya, 1980). The monomers of the chicken and human P-protein have been cloned. Structural homology is 84. Disregarding changes Asp->Glu, Arg->Lys and Ser->Thr strucural homology is as high as 93% (Kume 1991). The homology between the chicken and the E. Coli enzyme is 53% (Kure 1997).
  • Valproate anticonvulsive drug, EMD 49461 is known to inhibit the GCS (Martin- Gallardo 1985).
  • the Ki is 0.59mM, 2mM in liver and brain mitochondria, respectively.
  • I. p. administration of 720 mg/kp in rats resulted in an elevation of glycine levels in blood, liver, brain and spinal cord to appr. 140% of control rats.
  • Cysteamine (EMD 247 714) is an known GCS inhibitor (IC50 appr. 60?M, Lowry 1986).
  • I. p. administration of 250 mg/kg Cysteamine in 8 day old rats caused an increase of glycine in the cortex to 360% of the control animals (Iwama 1997).
  • PCP-induced hyperlocomotion model we use a test apparatus consisting of a clear plexiglas box (45 cm x 45 cm) equiped with two series of equally spaced infrared beam lights controlling X-Y axes and connected to a microcomputer. Measured automatically are the distance (way) traveled [m], and the time spent with locomotion or resting [sec] in intervals of 30 min over a total of 90 minutes following PCP administration.
  • the known model substances for inhibition of the glycine cleavage system, valproate and cysteamine are administered parenterally before the PCP challenge (PCP 5 mg/kg administered intraperitoneally).
  • PCP at the indicated dose induces excessive locomotor behavior with an increase of about 200 - 250% measured by either locomotion distance or time compared to control animals.
  • Valproate and cysteamine were used at doses from 100 to 500 mg/ kg. Both valproate and cysteamine reduce PCP-induced hyperlocomotion at various doses tested (see figures) indicating an antischizophrenic action.
  • Dopamine antagonists are the classic antischizophrenic drugs, and conventional animal models to test for antischizophrenic drugs with a dopaminergic mechanism of action use the induction of stereotyped behaviours such as climbing behavior in mice by the application of dopamine-agonistic drugs such as apomorphine (Protais et al., 1976; Puech et al., 1978).
  • inhibitors of the glycine cleavage system directly for the treatment of psychotic disorders like schizophrenia, schizoid or schizotypal personality disorders, disorders associated with psychosis such as major or manic depression, Alzheimers disease and post-traumatic stress syndroms.
  • the inhibitors can be adminstered alone or together with usual antipsychotic drugs.
  • Fig. 1 depicts the effect of vaiporate (VAL) and cysteamin (CYS) on PCP induced hyperlocomotion, Upper panel: traveled distance, lower panel: locomotion time. Detailed description above.
  • Nankai et al. Prog Neuropsychopharmacol Biol Psychiatry 22, 1998, 35.

Abstract

The invention relates to inhibitors of the glycine cleavage system and their use as potential antipsychotic agents. The invention relates furthermore to a process for treating humans having psychosis, psychosis associated with an illness, schizophrenia, Alzheimer's disease or other related psychotic disorders.

Description

Glycine Cleavage System Inhibitors as Potential Antipsychotics
The invention relates to inhibitors of the glycine cleavage system and their use as potential antipsychotic agents. The invention relates furthermore to a process for treating humans having psychosis, psychosis associated with an illness, schizophrenia, Alzheimers disease or other related psychotic disorders.
BACKGROUND AND TECHNICAL FIELD OF THE INVENTION Glycine is a neurotransmitter in the central nervous system. There, strychnine sensitive glycine receptors exist, where glycine sen/es as an inhibitory neurotransmitter. In addition there is a glycine binding site located at the NMDA receptor. Here, glycine sen/es as a excitatory coagonist. For the full activation of the glycine receptor the presence of glutamate and glycine is mandatory. NMDA Antagonists such as phencyclidine (PCP) and related drugs (e.g. ketamine or dizocilpine) induce symptoms in human volunteers which are not distinguishable from schizophrenia (Luby et al., 1959; Rosenbaum et al., 1959; Bakker and Amini, 1961), i.e. they induce a spectrum of symptoms including the positive, negative and cognitive aspects of schizophrenia (Krystal et al., 1994; Mulhotra et al., 1996). In addition, PCP provokes an exacerbation of symptoms in patients suffering from schizophrenia (Lathi et al., 1995; Malhotra et al., 1997). PCP-induced emotional, cognitive and behavioural changes represent not only a clinical model of schizophrenia (Luby et al., 1962), but moreover PCP-induced behavioural changes in mice and rats mimicking the symptoms of schizophrenia in these model organisms are now frequently used animal models for schizophrenia (e.g. Freed et al., 1984) and have been validated with many antischizophrenic drugs with different mechanisms of action (e.g. Jackson et al., 1993; Gleason et al., 1997; Vanover, 1997; Krebs-Thomson et al., 1998). Amongst these animal models utilizing mice and rats, the most prominent models are PCP-induced hyperlocomotion to model the positive and negative symptoms of schizophrenia and PCP-induced disruption of prepulse inhibition revealing the cognition deficit symptoms of schizophrenia. Glycine, Glycine (Partial) Agonists and Schizophrenia Glycine and partial agonists at the glycine site have been evaluated in clinical trials (D'Souza 1995). In particular high doses of glycine gave very promising results (Zylberman 1995 and Heresco-Levy 1999). In two double blind, placebo controlled clinical studies it was shown that 0.4g/kg and 0.8g/kg glycine given orally along with their usual antipsychotic medication ameliorated negative symptoms by 15% and 30%, respectively. No changes were observed in side effects.
The effects of D-cycloserine were evaluated in several clinical trial. In one clinical trial doses from 15 to 250mg/d of D-cycloserine were assessed. The results showed that the dose of 50 mg/d reduced negative symptoms in schizophrenic patients (Goff 1995). In another double blind, placebo-controlled clinical trial it was found that 50mg/d along with their effective dose of antipsychotics gave an improvement in negative symptoms (Goff 1999).
Glycine and the Glycine Cleavage System
Glycine is not only a neurotransmitter but also one of the major sources of C-1 building blocks. It is catabolized by the Glycine Cleavage System (GCS) to yield carbon dioxide, ammonia and methylene tetrahydrofolate.
The GCS consists of four enzymes:
-glycine decarboxylase, P-protein,
-hydrogen carrier protein, H-protein
-aminomethyltransferase, T-protein, -dihydrolipoamide dehydrogenase, L-protein,
The following reaction scheme applies (Kikuchi 1980):
SUBSTITUTE SHEET (RULE 25)
Figure imgf000005_0001
In vitro it is possible to substitute the H-protein with lipoic acid (Hiraya 1980).
SUMMERY OF THE INVENTION
The invention relates to inhibitors of the glycine cleavage system and their use as potential antipsychotic agents. It could be shown that, for example, vaiporate and cysteamine are potential inhibitors. The invention relates furthermore to a process for treating humans having psychosis, psychosis associated with an illness, schizophrenia, Alzheimers disease or other related psychotic disorders.
Therefore, it is an object of the invention to provide a process for treating a psychotic disorder in a human patient which comprises administering to said human a sufficient amount of an inhibitor, preferably vaiporate and / or cysteamine, of the glycine cleavage system.
In detail, the invention provides a process, wherein the psychotic disorder is schizophrenia, major depression, manic-depressive disorder, Alzheimers disease or post-traumatic stress syndrome.
Furthermore, the invention provides a process, wherein administering the glycine cleavage system inhibitor affects augmenting NMDA receptor-mediated neurotransmission. Furthermore, it is an object of this invention to provide the use of inhibitors of the glycine cleavage system for the manufacture of a medicament directed to psychotic disorders like schizophrenia, major depression, manic-depressive disorder, Alzheimers disease or post-traumatic stress syndrome.
DESCRIPTION OF THE INVENTION Distribution
In chicken GCS activity was found in liver, kidney and brain but not in heart or spleen. P-protein mRNA was found in liver, kidney and brain, T- and H-protein activity appeared additionally in kidney and heart.
In the rat brain H- and T-protein mRNA were found in olfactory bulb, cerebrum, hippocampus, cerebellum, brainstem and spinal cord. P-protein mRNA was abundant in olfactory bulb, cerebrum, hippocampus and cerebellum. This parallels the distribution of NMDA receptors (Kure 1997).
P-Protein
The P-protein was characterized from chicken liver (1500g of liver yielded 8 mg of protein corresp. to 33.000 U). Its molecular weight is 208.000. It is a homodimer, each monomer carrying one molecule of pyridoxalphosphate (Hiraya, 1980). The monomers of the chicken and human P-protein have been cloned. Structural homology is 84. Disregarding changes Asp->Glu, Arg->Lys and Ser->Thr strucural homology is as high as 93% (Kume 1991). The homology between the chicken and the E. Coli enzyme is 53% (Kure 1997).
Known Inhibitors of the Glycine Cleavage System and Activity in Animal Models
Valproate (anticonvulsive drug, EMD 49461) is known to inhibit the GCS (Martin- Gallardo 1985). The Ki is 0.59mM, 2mM in liver and brain mitochondria, respectively. I. p. administration of 720 mg/kp in rats resulted in an elevation of glycine levels in blood, liver, brain and spinal cord to appr. 140% of control rats. Cysteamine (EMD 247 714) is an known GCS inhibitor (IC50 appr. 60?M, Lowry 1986). I. p. administration of 250 mg/kg Cysteamine in 8 day old rats caused an increase of glycine in the cortex to 360% of the control animals (Iwama 1997).
SUBSTITUTE SHEET (RULE 23) Other weak inhibitors are aminoacetonitrile and propargylamine (Benavides 1983).
For the PCP-induced hyperlocomotion model we use a test apparatus consisting of a clear plexiglas box (45 cm x 45 cm) equiped with two series of equally spaced infrared beam lights controlling X-Y axes and connected to a microcomputer. Measured automatically are the distance (way) traveled [m], and the time spent with locomotion or resting [sec] in intervals of 30 min over a total of 90 minutes following PCP administration. The known model substances for inhibition of the glycine cleavage system, valproate and cysteamine, are administered parenterally before the PCP challenge (PCP 5 mg/kg administered intraperitoneally). PCP at the indicated dose induces excessive locomotor behavior with an increase of about 200 - 250% measured by either locomotion distance or time compared to control animals. Valproate and cysteamine were used at doses from 100 to 500 mg/ kg. Both valproate and cysteamine reduce PCP-induced hyperlocomotion at various doses tested (see figures) indicating an antischizophrenic action.
Only limited data is available for the only more recently established model of PCP-induced disruption of prepulse inhibition (PPI). To our knowledge, only the glycine agonist R-(+)-HA-966 and the glycine transporter antagonists D- cycloserine have so-far investigated and demonstrated a reversal of PCP- induced PPI (Kretschmer and Koch, 1997; Furuya et al., 1998). In the hyperlocomotion model with PCP or related drugs used as challenge stimulants, the efficacy of glycine itself, the glycine agonist R-(+)-3-amino-1- hydroxypyrrolid-2-one (R-(+)-HA-966), the partial agonist D-cycloserine or the glycine transporter antagonist glycyldodecylamide (GDA) have been repeatedly demonstrated in rodents (e.g. Toth and Lajtha, 1986; Toth et al., 1986; Singh et al., 1990; Kretschmer et ai., 1992; Carlsson et al., 1994; Javitt et al., 1997; Nilsson et al., 1997; Javitt et al., 1999).
For the PCP-induced disruption of PPI we use a commercially available standard equipment (Coulboum Instruments, USA) consisting of a sound attenuated test box equiped with a startle response measuring unit connected to a microcomputer; a white noise generator applies a constant level of back ground noise during the experiment. After a habituation period, a series of 70 combinations of prepulses (no prepulse or 8 to 6 dB above back ground noise) and pulses (90 to 126 dB) is randomly applied to the rats. The known model substances for inhibition of the glycine cleavage system, valproate and cysteamine, are administered parenterally before the PCP challenge (PCP 1 - 5 mg/kg administered subcutaneously). In control animals, presentation of the prepulse inhibits the startle response elicited by the pulse alone. PCP at the indicated doses induces a disruption of PPI by a maximum of about 70% compared to control animals. The doses indicated above are used for valproate and cysteamine, administed before the PCP challenge. Both valproate and cysteamine reverse PCP-induced disruption of PPI at different prepulse/pulse combinations at various doses tested indicating an antischizophrenic action.
Although the complex interaction of glycine with the neurotransmitter dopamine is not yet fully understood, the counterbalancing effects (symmetric bilateral changes) of glycine and dopamine, at least in part via GABAergic and cholinergic interneurons, in the central nervous system are well known for long (e.g. Cheramy et al., 1978; Giorguieff et al., 1979; Leviel et al., 1979; Schmidt and Kretschmer, 1997; Nankai et al., 1998). Dopamine antagonists are the classic antischizophrenic drugs, and conventional animal models to test for antischizophrenic drugs with a dopaminergic mechanism of action use the induction of stereotyped behaviours such as climbing behavior in mice by the application of dopamine-agonistic drugs such as apomorphine (Protais et al., 1976; Puech et al., 1978).
Using the climbing test in mice, we previously found that the glycine transporter inhibitor GDA and the partial glycine agonist D-cycloserine inhibited apomorphine (1.25 mg/kg administered subcutaneously)-induced climbing behavior in mice. Therefore the model compound cysteamine at the doses indicated before are investigated in the climbing test in mice, too. Surprisingly again, cysteamine when given prior to the apomorphine challenge inhibit apomorphiπe-induced climbing at various doses with an ED50 value (dose which inhibits apomorphine- induced climbing by 50%) of 500 mg/ kg further indicating an antischizophrenic action.
From these findings it is suggested to use inhibitors of the glycine cleavage system directly for the treatment of psychotic disorders like schizophrenia, schizoid or schizotypal personality disorders, disorders associated with psychosis such as major or manic depression, Alzheimers disease and post-traumatic stress syndroms. The inhibitors can be adminstered alone or together with usual antipsychotic drugs.
Fig. 1 depicts the effect of vaiporate (VAL) and cysteamin (CYS) on PCP induced hyperlocomotion, Upper panel: traveled distance, lower panel: locomotion time. Detailed description above.
LITERATURE
Bakker and Amini, Compr. Psychiatry 2, 1961 , 269.
Benavides J., et al., Biochem. Pharmacol. 32, 1983, 287.
Carlsson et al., J Neural Transm - Gen Sect 95, 1994, 223.
Cheramy et al., Eur J Pharmacol 47, 1978, 141.
D'Souza D.C. et al., CNS Drugs Rev. 1 , 1995, 227.
Freed et al., Neuropharmacology 23, 1984, 175.
Furuya et al., Brain Res 781 , 1998, 227.
Giorguieff et al., J Physiol 75, 1979, 611.
Gleason et al., Psychopharmacology 129, 1997, 79.
Goff D.C. et al., Arch. Gen. Psychiatry 56, 1999, 21.
Goff, D.C. et al., Am. J. Psychiatry. 152, 1995, 1213.
Heresco-Levy U., Arch. Gen. Psychiatry 56, 1999, 29.
Hiraya et al., J. Biolog. Chem. 255, 1980, 11664.
Iwama H., et al., Biochem. Biophys. Res. Commun. 231 , 1997, 793.
Jackson et al., Pharmacol Biochem Behav 48, 465.
Javitt et al., Biol Psychiatry 45, 1999, 668.
Javitt et al., Neuropsychopharmacology 1997, 17, 202.
Kikuchi Goro, et al. Biochem. Soc. Transactions, 1980, 504. Krebs-Thomson et a., Neuropsychopharmacology 18, 1998, 339
Kretschmer and Koch, Psychopharmacology 130, 1997, 131.
Kretschmer et al., J Nezral Transm 87, 1992, 23.
Krystal et al., Arch Gen Psychiatry 51 , 1994, 199.
Kume A., et al., J. Biolog. Chem. 266, 1991 , 3323.
Kure S., et al., Jpn. J. Human Genet, 42, 1997, 13.
Lathi et al., Neuropsychopharmacology 13, 1995, 9.
Leviel et al., Brain Res 175, 1979, 259.
Luby et al., Am J Psychiatry 119, 1962, 61.
Luby et al., Arch Neurol Psychiatry 81 , 1959, 363.
Malhotra et al., Neuropsychopharmacology 14, 1996, 301.
Malhotra et al., Neuropsychopharmacology 17, 1997, 141.
Martin-Gallardo, et al., Biochem. Pharmacol. 34, 1985, 2877.
Nankai et al., Prog Neuropsychopharmacol Biol Psychiatry 22, 1998, 35.
Nilsson et al., J Neural Transm 104, 1997, 1195.
Pratais et al., Psychopharmacology 50, 1976, 1.
Puech et al., Eur J Pharmacol 50, 1978, 291.
Rosenbaum et al., Arch Gen Psychiatry 1, 1959, 651.
Schmidt and Kretschmer, Neurosci Biobehav Rev 21 , 1997, 381.
Singh et al., Proc Natl Acad Sci USA 87, 1990, 347.
Toth and Lajtha, Neurochem Res 11 , 1986, 393.
Toth et al., Res Commun Psychol Psychiatry Behav 11 , 1986, 1.
Vanover, Eur J Pharmacol 332, 1997, 115.
Zylberman I. et al., N.Y. Acad. Sci. 757, 1995, 487.

Claims

PATENT CLAIMS
1. Use of an inhibitor of the glycine cleavage system for the manufacture of a medicament for the treatment of a psychotic disorder in a human patient.
2. Use according to claim 1 , wherein the psychotic disorder is selected from schizophrenia, major depression, manic-depressive disorder, Alzheimers disease or post-traumatic stress syndrome.
3. Use according to claim 2, wherein the inhibitor affects augmenting NMDA receptor-mediated neurotransmission.
4. Use according to claim 1 - 3, wherein the inhibitor of the glycine cleavage system is selected from vaiporate and cysteamine.
PCT/EP2000/003456 1999-04-29 2000-04-17 Glycine cleavage system inhibitors as potential antipsychotics WO2000066110A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
BR0010151-6A BR0010151A (en) 1999-04-29 2000-04-17 Glycine cleavage system inhibitors as potential antipsychotics
AU47481/00A AU4748100A (en) 1999-04-29 2000-04-17 Glycine cleavage system inhibitors as potential antipsychotics
JP2000614995A JP2002543124A (en) 1999-04-29 2000-04-17 Glycine cleavage system inhibitors as potential antipsychotics
MXPA01010933A MXPA01010933A (en) 1999-04-29 2000-04-17 Glycine cleavage system inhibitors as potential antipsychotics.
KR1020017013838A KR20020008167A (en) 1999-04-29 2000-04-17 Glycine cleavage system inhibitors as potential antipsychotics
CA002372073A CA2372073A1 (en) 1999-04-29 2000-04-17 Glycine cleavage system inhibitors as potential antipsychotics
EP00929364A EP1185259A1 (en) 1999-04-29 2000-04-17 Glycine cleavage system inhibitors as potential antipsychotics
NO20015247A NO20015247L (en) 1999-04-29 2001-10-26 Glycemic system inhibitors as potential antipsychotics

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US13164799P 1999-04-29 1999-04-29
US60/131,647 1999-04-29
EP99108480 1999-04-30
EP99108480.7 1999-04-30

Publications (1)

Publication Number Publication Date
WO2000066110A1 true WO2000066110A1 (en) 2000-11-09

Family

ID=56290006

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/003456 WO2000066110A1 (en) 1999-04-29 2000-04-17 Glycine cleavage system inhibitors as potential antipsychotics

Country Status (12)

Country Link
US (1) US6395780B1 (en)
EP (1) EP1185259A1 (en)
JP (1) JP2002543124A (en)
KR (1) KR20020008167A (en)
AU (1) AU4748100A (en)
BR (1) BR0010151A (en)
CA (1) CA2372073A1 (en)
CZ (1) CZ20013786A3 (en)
MX (1) MXPA01010933A (en)
NO (1) NO20015247L (en)
PL (1) PL353180A1 (en)
WO (1) WO2000066110A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2398497A (en) * 2003-02-19 2004-08-25 Walcom Animal Science Composition for improving immunity of animals
WO2005067899A2 (en) * 2004-01-13 2005-07-28 Omega Bio-Pharma (I.P.2) Limited Methods for treating stress and affecting biological immune systems using a cysteamine compound
WO2005105066A2 (en) * 2004-04-30 2005-11-10 Universita' Degli Studi Di Milano Histone deacetylases inhibitors against hyperlipidaemias, atherosclerosis, cardiovascular diseases
US7786119B2 (en) 2004-04-01 2010-08-31 Cardiome Pharma Corp. Drug conjugates of ion channel modulating compounds
WO2013120086A1 (en) * 2012-02-10 2013-08-15 Whitehead Institute For Biomedical Research Inhibition of the glycine cleavage system for treatment of cancer

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1565185A4 (en) * 2002-11-07 2011-01-05 Technion Res & Dev Foundation Neuroprotective iron chelators and pharmaceutical compositions comprising them
WO2004093910A1 (en) * 2003-04-22 2004-11-04 Astellas Pharma Inc. REMEDY FOR CEREBRAL NEURODEGENERATIVE DISEASES USING PPARδ AGONIST
WO2005039548A2 (en) * 2003-10-15 2005-05-06 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
EP1686973A4 (en) 2003-11-25 2009-03-25 Technion Res & Dev Foundation Compositions and methods for treatment of cardiovascular disorders and diseases
US8097608B2 (en) * 2003-11-25 2012-01-17 Technion Research And Development Foundation Ltd. Methods for treatment of cardiovascular disorders and diseases
JP2007517049A (en) * 2003-12-29 2007-06-28 マクデビット、ジェイソン Compositions and methods for treating recurrent conditions
JP2005232148A (en) * 2004-02-03 2005-09-02 Technion Research & Development Foundation Ltd Use of propargylamine as neuroprotective agent
JP2008545663A (en) * 2005-05-27 2008-12-18 クイーンズ ユニバーシティ アット キングストン Treatment of protein folding disorders
FR2890563B1 (en) * 2005-09-09 2007-10-19 Servier Lab NOVEL ASSOCIATION BETWEEN AGOMELATIN AND A THYMOREGULATING AGENT AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING IT
US8263655B2 (en) * 2005-10-06 2012-09-11 Technion Research And Development Foundation Ltd Methods for treatment of renal failure
KR200453511Y1 (en) * 2009-12-29 2011-05-13 한국강성(주) micro USB connector plug
BR112012019374B1 (en) 2010-02-03 2022-01-11 Pharma Two B Ltd ORAL PHARMACEUTICAL COMPOSITION AND USE OF AN ACTIVE AGENT FOR THE PREPARATION OF AN ORAL PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005280A1 (en) * 1992-09-04 1994-03-17 Aws Shakir Mustafa Salim Compositions containing dimethylsulphoxide and a sulphydryl group releasing agent
WO1999049860A1 (en) * 1998-03-30 1999-10-07 The Endowment For Research In Human Biology, Inc. Agents and methods for modulation of zinc transfer by metallothionein

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005280A1 (en) * 1992-09-04 1994-03-17 Aws Shakir Mustafa Salim Compositions containing dimethylsulphoxide and a sulphydryl group releasing agent
WO1999049860A1 (en) * 1998-03-30 1999-10-07 The Endowment For Research In Human Biology, Inc. Agents and methods for modulation of zinc transfer by metallothionein

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; XP002146798, Database accession no. prev199699205075 *
DAVIS L.L. ET AL: "Valproate as an antidepressant in major depressive disorder", PSYCHOPHARMACOLOGY BULLETIN, vol. 32, 1996, pages 647 - 652, XP000917554 *
HAYES S.G. ET AL: "Long-term use of valproate in primary psychiatric disorders", JOURNAL OF CLINICAL PSYCHIATRY, vol. 50, 1989, pages 35 - 39, XP000917324 *
HOLTZER C.D. ET AL: "Valproate in the treatment of acute mania", JOURNAL OF PHARMACY TECHNOLOGY, vol. 12, 1996, pages 6 - 11, XP000917438 *
KECK P.E. ET AL: "Anticonvulsants and antipsychotics in the treatment of bipolar disorder", JOURNAL OF CLINICAL PSYCHIATRY, vol. 59, 1998, pages 74 - 81, XP000917401 *
MARK R. J. ET AL: "Anticonvulsants attenuate amyloid beta-peptide neurotoxicity, Ca2+ deregulation, and cytoskeletal pathology", NEUROBIOLOGY OF AGING, vol. 16, 1995, pages 187 - 198, XP000917338 *
MORINIGO A. ET AL: "Teatment of resistant schizophrenia with valproate and neuroleptic drugs", HILLSIDE JOURNAL OF CLINICAL PSYCHIATRY, vol. 11, 1989, pages 199 - 208, XP000917396 *
SCHNEIDER L.S. ET AL: "Mechanism of action and prospects for cognitive enhancing medications", MEDICAL CLINICS OF NORTH AMERICA, vol. 78, no. 4, 1994, pages 911 - 934, XP000917566 *
TAKAHASHI M. ET AL: "Case report of sodium valproate treatment of aggression associated with Alzheimer's disease", BRAIN AND NERVE (TOKYO), vol. 48, 1996, pages 757 - 760 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2398497A (en) * 2003-02-19 2004-08-25 Walcom Animal Science Composition for improving immunity of animals
WO2005067899A2 (en) * 2004-01-13 2005-07-28 Omega Bio-Pharma (I.P.2) Limited Methods for treating stress and affecting biological immune systems using a cysteamine compound
WO2005067899A3 (en) * 2004-01-13 2006-02-16 Omega Bio Pharma I P 2 Ltd Methods for treating stress and affecting biological immune systems using a cysteamine compound
US7786119B2 (en) 2004-04-01 2010-08-31 Cardiome Pharma Corp. Drug conjugates of ion channel modulating compounds
WO2005105066A2 (en) * 2004-04-30 2005-11-10 Universita' Degli Studi Di Milano Histone deacetylases inhibitors against hyperlipidaemias, atherosclerosis, cardiovascular diseases
WO2005105066A3 (en) * 2004-04-30 2006-05-18 Univ Degli Studi Milano Histone deacetylases inhibitors against hyperlipidaemias, atherosclerosis, cardiovascular diseases
WO2013120086A1 (en) * 2012-02-10 2013-08-15 Whitehead Institute For Biomedical Research Inhibition of the glycine cleavage system for treatment of cancer
US9493775B2 (en) 2012-02-10 2016-11-15 Whitehead Institute For Biomedical Research Inhibition of the glycine cleavage system for treatment of cancer

Also Published As

Publication number Publication date
MXPA01010933A (en) 2002-06-21
CA2372073A1 (en) 2000-11-09
NO20015247D0 (en) 2001-10-26
PL353180A1 (en) 2003-11-03
NO20015247L (en) 2001-10-26
US6395780B1 (en) 2002-05-28
EP1185259A1 (en) 2002-03-13
CZ20013786A3 (en) 2002-02-13
AU4748100A (en) 2000-11-17
JP2002543124A (en) 2002-12-17
BR0010151A (en) 2002-06-11
KR20020008167A (en) 2002-01-29

Similar Documents

Publication Publication Date Title
US6395780B1 (en) Cleavage system inhibitors as potential antipsychotics
Orr et al. Istradefylline reduces memory deficits in aging mice with amyloid pathology
Ben‐Menachem Mechanism of action of vigabatrin: correcting misperceptions
JP5363152B2 (en) Treatment of rejection and cognitive schizophrenia syndrome with glycine-trapping antagonists
Plaitakis Glutamate dysfunction and selective motor neuron degeneration inamyotrophic lateral sclerosis: A hypothesis
Mezler et al. LY-2140023, a prodrug of the group II metabotropic glutamate receptor agonist LY-404039 for the potential treatment of schizophrenia
Bruns et al. Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders
AU2007254677B2 (en) Treatment for attention-deficit hyperactivity disorder
Yu et al. BDNF mediates the protective effects of scopolamine in reserpine-induced depression-like behaviors via up-regulation of 5-HTT and TPH1
Toth et al. Pharmacological interference with metabotropic glutamate receptor subtype 7 but not subtype 5 differentially affects within-and between-session extinction of Pavlovian conditioned fear
Nam et al. KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson's disease
JP2013543482A (en) Treatment of diseases induced by L-dopa, dopamine agonists and / or dopamine activators
JP2023055770A (en) Dose regimen for use of ly3154207 in therapy of dopaminergic cns disorder
Vatankhah et al. AMN082—a metabotropic glutamate receptor type 7 allosteric agonist in the NAc facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats
US20240024268A1 (en) Methods for Dopamine Modulation in Human Neurologic Diseases
Aghaei et al. Peroxisome proliferator-activated receptor-γ activation attenuates harmaline-induced cognitive impairments in rats
Bezard et al. Rationale and development of tavapadon, a D1/D5-selective partial dopamine agonist for the treatment of Parkinson’s disease
Tsai Ultimate translation: developing therapeutics targeting on N-methyl-d-aspartate receptor
Horio et al. Effects of D-amino acid oxidase inhibitor on the extracellular D-alanine levels and the efficacy of D-alanine on dizocilpine-induced prepulse inhibition deficits in mice
Matsuoka et al. The glycine/NMDA receptor antagonist HA-966 impairs visual recognition memory in rhesus monkeys
WO1999063989A1 (en) Remedies for spinocerebellar ataxia and compositions for treating spinocerebellar ataxia
WO2020110128A1 (en) Combination of pridopidine and an additional therapeutic agent for treating drug induced dyskinesia
Le Marec et al. Behavioral and biochemical effects of L-tryptophan and buspirone in a model of cerebellar atrophy
US20210275512A1 (en) Pridopidine for treating drug induced dyskinesias
Alghenaim Elucidating the Dopaminergic Neurotoxicity of Kainic acid

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2000929364

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: PV2001-3786

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 15332001

Country of ref document: SK

ENP Entry into the national phase

Ref document number: 2372073

Country of ref document: CA

Ref document number: 2372073

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/2001/010933

Country of ref document: MX

Ref document number: 00806797.X

Country of ref document: CN

ENP Entry into the national phase

Ref document number: 2000 614995

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020017013838

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 47481/00

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: IN/PCT/2001/1220/KOL

Country of ref document: IN

WWP Wipo information: published in national office

Ref document number: 1020017013838

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: PV2001-3786

Country of ref document: CZ

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 2000929364

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: PV2001-3786

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 2000929364

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1020017013838

Country of ref document: KR