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WO1992017168A1 - Procede permettant d'empecher les lesions neuronales dues aux recepteurs de n-methyl-d-aspartate - Google Patents

Procede permettant d'empecher les lesions neuronales dues aux recepteurs de n-methyl-d-aspartate Download PDF

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Publication number
WO1992017168A1
WO1992017168A1 PCT/US1992/002699 US9202699W WO9217168A1 WO 1992017168 A1 WO1992017168 A1 WO 1992017168A1 US 9202699 W US9202699 W US 9202699W WO 9217168 A1 WO9217168 A1 WO 9217168A1
Authority
WO
WIPO (PCT)
Prior art keywords
medicament
compound
glutamate
mediated
nmda receptor
Prior art date
Application number
PCT/US1992/002699
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English (en)
Inventor
Stuart A. Lipton
Original Assignee
The Children's Medical Center Corporation
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 The Children's Medical Center Corporation filed Critical The Children's Medical Center Corporation
Publication of WO1992017168A1 publication Critical patent/WO1992017168A1/fr

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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
    • A61K31/13—Amines

Definitions

  • This invention relates to the treatment of nervous system disorders, particularly disorders mediated by the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor.
  • NMDA N-methyl-D-aspartate
  • Gluta ate has been implicated as a significant factor in the neurotoxicity associated with hypoxic- ischemic encephalopathy, seizures, trauma, and several degenerative neurological disorders such as the AIDS dementia complex and other neurological manifestations of AIDS, Huntington's disease and Parkinsonism (Hahn et al., Proc . Natl . Acad. Sci . USA £ -6556, 1988; Choi, Neuron 1:623, 1988; Rothman et al. , Trends Neurosci . 10:299, 1987; Meldrum et al., Trends Pharm . Sci . 11:379, 1990).
  • the invention features a method for reducing NMDA receptor-mediated neuronal damage in a mammal.
  • the method involves administering to the mammal a compound of the formula shown in Fig. 1, wherein R ⁇ includes an a ino group, and R 2 -R 17 are independently H or a short chain aliphatic group including 1-5 carbons, or a physiologically acceptable salt thereof, in a concentration effective to cause such reduction.
  • ⁇ is NH 2 ' anc tne compound is preferably amantadine; R 4 is a methyl group; R 10 is a methyl group; R 4 and R 10 are both methyl groups; R 4 and R 10 are both methyl groups and R ⁇ is NH 2 , and the compound is preferably me antine.
  • ⁇ may be
  • X ⁇ and X 2 are independently H or a short chain aliphatic group including between 1-5 carbons [i.e., either a methyl group or between 1-4 (-CH 2 ) groups and a terminal methyl group]; R 4 is a methyl group; R 10 is a methyl group; R 4 and R 10 are methyl groups; X ⁇ and X 2 are H and CH 3 , respectively, or X ⁇ and X 2 are CH 3 and H, respectively; and the compound is preferably rimantadine.
  • the mammal is a human infected with a human immune deficiency virus; the human manifests symptoms of the AIDS related complex or acquired immune deficiency syndrome; the neurotoxicity is mediated by an excitatory amino acid; and the neurotoxicity is mediated by glutamate, aspartate, homocysteic acid, cysteine sulphinic acid, ⁇ ysteic acid, quinolinate, or N-acetyl aspartyl glutamate.
  • NMDA receptor-mediated neuronal damage is meant any neuronal injury which resulting from stimulation or costimulation of the NMDA receptor.
  • excitatory amino acid is meant any amino acid which leads to the activation of an NMDA receptor- operated ionic channel.
  • Useful compounds of the instant invention include a tricyclic 10 carbon ring which includes at least one amino group at position R ⁇ of the general formula shown in Fig. 1.
  • the amino group may be attached directly to a ring carbon (as is the case for amantadine; see Fig. 2a) , or it may be attached to a carbon attached to the carbon ring (as is the case for rimantadine; see Fig. 2b) .
  • R 2 - R 17 are hydrogen atoms, methyl groups, or short chain aliphatic groups which include between 1-5 saturated carbons [i.e., 1-4 (-CH 2 ) groups and a terminal methyl group] , or any combination, thereof.
  • the neuroprotective potency of the compounds may be enhanced by substitutions of ring hydrogens.
  • methyl group substituants at positions R 4 and R 10 greatly enhance the ability and potency of the compound, memantine (shown in Fig. 2c) , to prevent glutamate- induced neuronal damage.
  • Memantine is neuroprotective in vitro at a concentration of 6 ⁇ M (see below) ; amantadine, a molecule unsubstituted at these positions, is effective at a concentration of approximately 200 ⁇ M.
  • the water solubility of compounds of the general formula shown in Fig. 1 may be increased by formulating the compound into a physiologically-acceptable salt, e.g., by reaction with HC1.
  • the preferred compounds of the invention i.e., amantadine, rimantadine, and memantine, and similar derivatives
  • amantadine, rimantadine, and memantine, and similar derivatives are water soluble and are able to pass readily through the blood brain barrier, facilitating a therapy which is both extremely rapid and unusually potent.
  • the preferred compounds also provide the advantage of a proven record of safe human administration (i.e., for treatment of viral infections or for treatment of Parkinson's disease, but not neuronal degeneration of Parkinsonism) .
  • amantadine has been approved for use by human patients, at least, in the United States.
  • Disorders which may be treated by the method of the invention include hypoxia-ischemic encephalopathy, seizures, stroke, AIDS dementia and other neurological manifestations of AIDS (see, e.g., USSN 571,949) and, generally, acute and chronic neurodegenerative disorders.
  • hypoxia-ischemic encephalopathy seizures, stroke, AIDS dementia and other neurological manifestations of AIDS (see, e.g., USSN 571,949) and, generally, acute and chronic neurodegenerative disorders.
  • Fig. 1 is the general formula of the compounds useful in the method of the invention.
  • Fig. 2 is a schematic representation of (a) amantadine, (b) rimantadine, and (c) memantine.
  • Fig. 3 is a graphical representation showing that memantine prevents glutamate-mediated retinal ganglion cell neurotoxicity.
  • the present invention is based on the finding that the amantadine derivative memantine (l-amino-3,5-dimethyl adamantine) reduces neuronal damage (see below) ; and that this reduction in damage is due to a block of NMDA receptor-operated channel activation by excitatory amino acids (such as glutamate-related compounds) using concentrations of memantine that are readily obtainable in human patients taking the drug (Wesemann et al., J. Neural Transmission (Supp.) 16:143, 1980).
  • An increased level of one or more glutamate-related compounds is associated with many neurodegenerative disorders (e.g., those listed above) , and amantadine derivatives are therefore useful for their treatment.
  • neuronal injury may result from stimulation of the NMDA receptor by other excitatory amino acids, such as aspartate, homocysteic acid, cysteine sulphinic acid, or cysteic acid, or from stimulation by excitatory peptides, such as N-acetyl aspartyl glutamate.
  • excitatory amino acids such as aspartate, homocysteic acid, cysteine sulphinic acid, or cysteic acid
  • excitatory peptides such as N-acetyl aspartyl glutamate.
  • Compounds most preferred in the invention are those which effect the greatest protection of neurons from NMDA receptor- mediated injury, e.g., that injury resulting from stimulation of the NMDA receptor by glutamate (as shown below) or other excitatory amino acids or stimulation by excitatory peptides, such as N-acetyl aspartyl glutamate.
  • glutamate as shown below
  • excitatory peptides such as N-acetyl aspartyl glutamate.
  • neuronal cell death may be assayed as follows. Under general anesthesia, the fluorescent dye granular blue (Mackromolecular Chemin, Umstadt, FRG) is injected as approximately a 2% (w/v) suspension in saline into the superior colliculus of 4- to 6-day-old Long-Evans rats (Charles River Laboratory, Wilmington, MA) . Two to 6 days later, the animals are sacrificed by decapitation and enucleated, and the retinas quickly removed.
  • the fluorescent dye granular blue Mackromolecular Chemin, Umstadt, FRG
  • the retinas are dissociated by mild treatment with the enzyme papain and cultured in Eagle's minimum essential medium (MEM, catalog #1090, Gibco, Grand Island, NY) supplemented with 0.7% (w/v) methylcellulose, 0.3% (w/v) glucose, 2mM glutamine, 1 ⁇ g/ml gentamicin, and 5% (v/v) rat serum, as described in Lipton et al. , J. Physiol . 3_8_5:361, 1987.
  • the cells are plated onto 75 mm 2 glass coverslips coated with poly-L- lysine in 35 mm tissue culture dishes.
  • the candidate amantadine derivative is added (e.g., in a series of concentrations ranging from InM - ImM) in the presence or absence of compounds which activate the NMDA receptor- operated channel complex, and in high calcium, low magnesium medium (lOmM CaCl 2 , 50 ⁇ M MgCl 2 ) to enhance NMDA- receptor neuotoxicity in this preparation (Hahn et al., Proc. Natl . Acad. Sci . USA £5:6556, 1988; Levy et al.. Neurology 40:852. 1990; Levy et al., Neurosci . Lett. 110:291, 1990) .
  • the degree of survival is compared to that in normal medium (1.8mM CaCl 2 , 0.8mM MgCl 2 ) , which minimizes NMDA receptor-mediated injury in this preparation (Hahn et al., cited above). Incubations last 16-24 h at 37°C in an atmosphere of 5% C0 2 /95% air. The ability of retinal ganglion cells to take up and cleave fluorescein diacetate to fluorescein is used as an index of their viability as described in detail in Hahn et al. (Proc. Natl . Acad. Sci . USA 5:6556, 1988). Dye uptake and cleavage generally correlate well with normal electrophysiological properties assayed with patch electrodes.
  • the cell-culture medium is exchanged for physiological saline containing 0.0005% fluorescein diacetate for 15-45 s, and then cells are rinsed in saline.
  • Retinal ganglion cell neurons that do not contain the fluorescein dye (and thus are not living) often remain visible under both phase-contrast and UV fluorescence optics, the latter because of the continued presence of the marker dye granular blue; other dead retinal ganglion cells disintegrate, leaving only cell debris.
  • the viable retinal ganglion cells display not only a blue color in the UV light but also a yellow-green fluorescence with filters appropriate for fluorescein.
  • the use of two exchangeable fluorescence filter sets permits the rapid determination of viable ganglion cells in the cultures.
  • the ganglion cells are often found as solitary neurons as well as neurons lying among other cells in small clusters.
  • An amantadine derivative may be tested for utility in the method of the invention using any type of neuronal cell from the central nervous system, as long as the cell can be isolated intact by conventional techniques.
  • retinal cultures are used above, hippocampal cortex neurons or any neuron containing NMDA receptors (e.g., neurons from other regions of the cortex) may also be used. Such neurons may be prenatal or postnatal.
  • retinal cultures can be produced from postnatal mammals; they are well-characterized and contain a central neuron, the retinal ganglion cell, that can be unequivocally identified with fluorescent labels.
  • a substantial portion of retinal ganglion cells in culture display both funptional synaptic activity and bear many, if not all, of the neurotransmitter receptors found in the intact retina.
  • Memantine Prevents NMDA Receptor-Mediated Neurotoxicity Using the assay described above, the amantadine derivative, memantine, was tested for its ability to increase survival of glutamate-treated retinal ganglion cells.
  • retinal ganglion cells were cultured in either normal medium (i.e., MEM containing 1.8mM CaCl 2 , 0.8mM MgCl 2 ) or in high calcium, low magnesium medium (i.e., lOmM CaCl 2 , 50 ⁇ m MgCl 2 ) .
  • MEM normal medium
  • lOmM CaCl 2 high calcium, low magnesium medium
  • the latter medium is known to enhance NMDA receptor-mediated neurotoxicity due to an endogenous glutamate receptor agonist (Hahn et al. , Proc. Natl .
  • Memantine HC1 was diluted in double-distilled water, filtered, and added to the growth media (to a final concentration of between l ⁇ M - 25 ⁇ M) .
  • the retinal cells were incubated for 16-20 hours at 37°C in a humidified atmosphere of 5% C0 2 and 95% air.
  • an endogenous glutamate-like agonist produces retinal cell neurotoxicity in the presence of elevated extracellular calcium concentrations (compare Fig. 3, columns 1 and 2).
  • glutamate- pyruvate transaminase GPT; 0.25 mg/ml; Boehringer- Mannheim, Indianapolis, IN
  • this enzyme specifically degrades endogenous glutamate by transaminating it to ⁇ -keto-glutarate in the presence of pyruvate.
  • the amantadine derivative, memantine prevented retinal ganglion cell death from the endogenous glutamate-related toxin in a dose-dependent manner (Fig. 3) .
  • Increased neuronal survival at 6 ⁇ M memantine (Fig. 3, column 4) reached statistical significance compared to the control (Fig. 3, column 1).
  • Doses of 25 ⁇ M memantine or greater may themselves be toxic in retinal cell preparations under these conditions.
  • All experiments depicted in Fig. 3 involving memantine treatment were repeated in triplicate and normalized to control cultures (i.e., normal medium lacking memantine). The values depicted represent mean + standard error of the mean (SEM) . An analysis of variance was used to test for significance; this analysis was followed by a Sheffe test for multiple comparison of means (Hahn et al., 1988, supra- .
  • memantine blocks neuronal cell death mediated by excessive stimulation of the NMDA receptor. Without being bound to any theory as to the mechanism whereby memantine exerts its neuroprotective effect, it is possible that memantine blocks the glutamate-induced increase in intracellular Ca 2+ at the NMDA receptor-associated ionic channel.
  • MK-801 docilpine; an NMDA-specific antagonist
  • the mode of action of memantine may be a non-competitive inhibition of Ca 2+ influx by blocking the NMDA receptor- operated channels. If so, inhibition by memantine is contingent upon prior activation of the receptor by the agonist. This has important consequences at the therapeutic level.
  • Normal NMDA receptor activation may be unaffected by the compounds of the invention while neuronal injury resulting from escalated glutamate levels following a stroke or trauma to the central nervous system might be effectively blocked (Karschin et al., J. Neurosci . .8:2895, 1988; Levy and Lipton, Neurology 4j0s852, 1990).
  • Memantine analogs have undergone clinical trials in the United States and in the Soviet Union using therapeutic doses for influenza A therapy. Those studies revealed only limited and reversible central nervous system side effects (Tominack et al.. Infect . Dis . Clin . N. Am.
  • amantadine and its derivatives may be administered by any of a number of routes in an amount sufficient to block glutamate's effect on the NMDA receptor.
  • the amantadine derivative may be included in a pharmaceutical preparation, using a pharmaceutical carrier (e.g., physiological saline); the exact formulation of the therapeutic mixture depends upon the route of administration.
  • the compound is administered orally or intravenously, but it may also be administered intrathecally or intravitreally.
  • the preferred compounds, amantadine, memantine, and rimantadine are administered at 100-500 ⁇ g/day, 5-80 mg/day, and 50-300 mg/day, respectively, in divided doses.
  • Any other compound, determined to be an effective neuroprotective agent by the assays described herein, is administered orally, intravenously, intrathecally, or intravitreally at 100 ⁇ g-500 mg/day in divided doses. Treatment may be repeated as necessary to prevent or alleviate neurological injury.
  • the compounds of the invention can be utilized to protect against a number of neurotoxic disorders caused by elevated levels of glutamate or related compounds. Such neurotoxic disorders include ischemia, hypoxia, hypoglycemia, epilepsy, Huntington's disease, and Alzheimer's disease and other neurodegenerative disorders.
  • the method of the invention is particularly preferred for the treatment of AIDS dementia and other neurological manifestations of the AIDS virus. The method may also be used for reduction of neuronal damage resulting from infection with other viruses which cause damage to the nervous system.
  • Other Embodiments are particularly preferred for the treatment of AIDS dementia and other neurological manifestations of the AIDS virus. The method may also be used for reduction of neuronal damage resulting from infection with other viruses which cause damage to the nervous system.
  • the method described herein is useful for reducing neuronal injury in any mammal having NMDA receptors. Treatment of neuronal damage in humans is the preferred utility; but the method may also be employed successfully for veterinary purposes.

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Abstract

Médicament devant être administré à un mammifère afin de réduire les lésions neuronales dues aux récepteurs de N-méthyl-D-aspartate. Ledit médicament comporte un composé répondant à la formule de la figure (I), dans laquelle R1 comprend un groupe amino et R2-R17 représentent, indépendamment les un des autres, H ou un groupe aliphatique à chaîne courte comportant de 1 à 5 carbones, ou son sel physiologiquement acceptable, dans une concentration suffisante pour provoquer ladite réduction.
PCT/US1992/002699 1991-04-04 1992-04-03 Procede permettant d'empecher les lesions neuronales dues aux recepteurs de n-methyl-d-aspartate WO1992017168A1 (fr)

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US68020191A 1991-04-04 1991-04-04
US680,201 1991-04-04

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998018457A1 (fr) * 1996-10-30 1998-05-07 Hanns Ludwig Utilisation d'amines d'adamantane ou de composes a structure analogue pour lutter contre le virus de meningo-encephalo-myelite zootique et pour assurer la prophylaxie et le traitement de pathologies affectives et d'autres troubles lies aux infections de la meningo-encephalo-myelite zootique chez l'homme et l'animal
EP0660707A4 (fr) * 1992-09-03 1998-05-13 Childrens Medical Center Procede de prevention contre les lesions neuronales dues au recepteur nmda.
FR2768624A1 (fr) * 1997-09-25 1999-03-26 Oreal Utilisation d'un inhibiteur d'acides amines excitateurs dans une composition cosmetique ou dermatologique pour peaux sensibles et composition obtenue
WO2000044371A1 (fr) * 1999-01-26 2000-08-03 Vernalis Research Limited Composes de 2-adamantanemethanamine destines au traitement d'anomalies de la transmission glutamatergique
EP1190711A1 (fr) * 2000-09-21 2002-03-27 Tinnitus Forschungs- und Entwicklungs GmbH Traitement de maladies avec des dérivés adamantanes
EP1190708A1 (fr) * 2000-09-21 2002-03-27 Tinnitus Forschungs- und Entwicklungs GmbH Utilisation médicale de substances
RU2196575C2 (ru) * 1999-07-30 2003-01-20 Научно-исследовательский институт фармакологии РАМН Вещество, обладающее психостимулирующим и антиастеническим действием
EP1201234A3 (fr) * 2000-09-21 2003-03-12 Tinnitus Forschungs- und Entwicklungs GmbH Traitement de maladies avec des dérivés adamantanes
WO2004009062A3 (fr) * 2002-07-19 2004-12-23 Khalid Iqbal Antagonistes du recepteur nmda et leur utilisation pour inhiber l'hyperphosphorylation de la proteine associee aux microtubules tau
WO2005079756A3 (fr) * 2004-02-13 2005-09-22 Neuromolecular Inc Methodes et compositions de traitement de troubles psychiatriques
WO2005092009A3 (fr) * 2004-03-19 2006-02-09 Axonyx Inc Inhibiteurs d'acetylcholinesterase et antagonistes de n-methyle-d-aspartate utiles dans le traitement de troubles cognitifs
WO2006119329A3 (fr) * 2005-05-02 2007-11-22 Combinatorx Inc Compositions et procedes pour traiter des maladies neurodegeneratives
WO2008036846A3 (fr) * 2006-09-22 2008-11-13 Braincells Inc Modulation induite par hmg-coa-réductase de la neurogenèse
US8901171B2 (en) 2010-01-27 2014-12-02 Takeda Pharmaceutical Company Limited Compounds for suppressing a peripheral nerve disorder induced by an anti-cancer agent

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US3328251A (en) * 1965-12-30 1967-06-27 Du Pont Pharmaceutical compositions and methods utilizing 2-aminoadamantane and its derivatives
US4122193A (en) * 1972-04-20 1978-10-24 Merz & Co. Drugs or medicines for influencing the central nervous system
US4351847A (en) * 1981-06-26 1982-09-28 Pennwalt Corporation Antiviral alpha, alpha-dialkyl adamantylethylamines
US5061703A (en) * 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3328251A (en) * 1965-12-30 1967-06-27 Du Pont Pharmaceutical compositions and methods utilizing 2-aminoadamantane and its derivatives
US4122193A (en) * 1972-04-20 1978-10-24 Merz & Co. Drugs or medicines for influencing the central nervous system
US4351847A (en) * 1981-06-26 1982-09-28 Pennwalt Corporation Antiviral alpha, alpha-dialkyl adamantylethylamines
US5061703A (en) * 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THE MERCK INDEX, 10 ed, 1985, no. A7, 373 and 8116. *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0660707A4 (fr) * 1992-09-03 1998-05-13 Childrens Medical Center Procede de prevention contre les lesions neuronales dues au recepteur nmda.
WO1998018457A1 (fr) * 1996-10-30 1998-05-07 Hanns Ludwig Utilisation d'amines d'adamantane ou de composes a structure analogue pour lutter contre le virus de meningo-encephalo-myelite zootique et pour assurer la prophylaxie et le traitement de pathologies affectives et d'autres troubles lies aux infections de la meningo-encephalo-myelite zootique chez l'homme et l'animal
AU722505B2 (en) * 1996-10-30 2000-08-03 Detlef Dietrich The use of adamantane amines or structurally similar compounds for combating borna disease virus and for the prevention and treatment of affective diseases and other disorders associated with BDV infections in humans and animals
FR2768624A1 (fr) * 1997-09-25 1999-03-26 Oreal Utilisation d'un inhibiteur d'acides amines excitateurs dans une composition cosmetique ou dermatologique pour peaux sensibles et composition obtenue
EP0904777A1 (fr) * 1997-09-25 1999-03-31 L'oreal Utilisation d'un inhibiteur d'acides aminés excitateurs dans une composition cosmétique ou dermatologique pour peaux sensibles et composition obtenue
US7601360B2 (en) 1997-09-25 2009-10-13 L'oreal Excitatory amino acid inhibitors for treating sensitive skins
US6616933B1 (en) 1997-09-25 2003-09-09 Societe L'oreal S.A. Excitatory amino acid inhibitors for treating sensitive skins
WO2000044371A1 (fr) * 1999-01-26 2000-08-03 Vernalis Research Limited Composes de 2-adamantanemethanamine destines au traitement d'anomalies de la transmission glutamatergique
US6531511B1 (en) 1999-01-26 2003-03-11 Vernalis Research Limited 2-adamantanemethanamine compounds for treating abnormalities in glutamatergic transmission
RU2196575C2 (ru) * 1999-07-30 2003-01-20 Научно-исследовательский институт фармакологии РАМН Вещество, обладающее психостимулирующим и антиастеническим действием
EP1201234A3 (fr) * 2000-09-21 2003-03-12 Tinnitus Forschungs- und Entwicklungs GmbH Traitement de maladies avec des dérivés adamantanes
WO2002024187A3 (fr) * 2000-09-21 2003-05-22 Tinnitus Traitement de pathologies au moyen de derives d'adamantane
EP1190708A1 (fr) * 2000-09-21 2002-03-27 Tinnitus Forschungs- und Entwicklungs GmbH Utilisation médicale de substances
EP1190711A1 (fr) * 2000-09-21 2002-03-27 Tinnitus Forschungs- und Entwicklungs GmbH Traitement de maladies avec des dérivés adamantanes
WO2004009062A3 (fr) * 2002-07-19 2004-12-23 Khalid Iqbal Antagonistes du recepteur nmda et leur utilisation pour inhiber l'hyperphosphorylation de la proteine associee aux microtubules tau
WO2005079756A3 (fr) * 2004-02-13 2005-09-22 Neuromolecular Inc Methodes et compositions de traitement de troubles psychiatriques
WO2005092009A3 (fr) * 2004-03-19 2006-02-09 Axonyx Inc Inhibiteurs d'acetylcholinesterase et antagonistes de n-methyle-d-aspartate utiles dans le traitement de troubles cognitifs
WO2006119329A3 (fr) * 2005-05-02 2007-11-22 Combinatorx Inc Compositions et procedes pour traiter des maladies neurodegeneratives
WO2008036846A3 (fr) * 2006-09-22 2008-11-13 Braincells Inc Modulation induite par hmg-coa-réductase de la neurogenèse
US8901171B2 (en) 2010-01-27 2014-12-02 Takeda Pharmaceutical Company Limited Compounds for suppressing a peripheral nerve disorder induced by an anti-cancer agent

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