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WO2001060357A1 - Nouvelle utilisation - Google Patents

Nouvelle utilisation Download PDF

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Publication number
WO2001060357A1
WO2001060357A1 PCT/SE2001/000292 SE0100292W WO0160357A1 WO 2001060357 A1 WO2001060357 A1 WO 2001060357A1 SE 0100292 W SE0100292 W SE 0100292W WO 0160357 A1 WO0160357 A1 WO 0160357A1
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Prior art keywords
neurons
compound
treatment
phenyl
use according
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PCT/SE2001/000292
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English (en)
Inventor
Ted Ebendal
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Ted Ebendal
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.)
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Publication date
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Priority to AU2001232578A priority Critical patent/AU2001232578A1/en
Publication of WO2001060357A1 publication Critical patent/WO2001060357A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3

Definitions

  • the present invention is directed to use of a compound for the manufacture of a medicament for potentiating neurotrophic effect on neurons. More particularly, the invention relates to use of the compound for the treatment of mammalian neurons afflicted with neurodegenerative disease or of neurons having been, or being, m the imminent risk of becoming damaged or injured. A method for potentiating neurotrophic effect on mammalian neurons is also presented.
  • neurotrophic factors are involved m the structural alterations which occur m response to injury and disease.
  • the clinical use of neurotrophic molecules has been reviewed by Eide,
  • Neurotrophic factors are found among several protein families of polypeptide growth factors, based on their amino acid sequence homology and/or their three- dimensional structure (MacDonald et al . , Cell 73, 1993, 421-424) .
  • neurotrophins including nerve growth factor, NGF; brain- derived neurotrophic factor, BDNF; neurotrophin-3, NT-3; and neurotrophin-4 , NT-4). These neurotrophic factors affect specific neuronal populations in the central nervous system.
  • MPKs mitogen-activated protein kinases
  • Erk extracellular signal-regulated kinases
  • Trk receptors activated by the neurotrophins have been shown to activate a phosphatidylinositol 3 (PI-3) kinase pathway, regarded as crucial for neuronal survival, and a MAPK pathway, commonly regarded as important for neuronal growth and elaboration of nerve processes (Dechant, Rodriguez-Tebar , and Barde, Progr. Neurobiol . 42: 347-352, 1994; Barbacid, J " . Neurobiol . 25: 1386-1403, 1994; Xia, Dickens, Raingeaud, Davis and Greenberg, Science 270: 1326-1331, 1995).
  • PI-3 phosphatidylinositol 3
  • MAPKs Mitogen-activated protein kinases
  • MEK MAPK/Erk kinases
  • Electroconvulsive treatment induces a rapid and transient phosphorylation of MEK substrates (Stratton et al . , J “ . Neurochem . 56, 1991, 147-152). Both MEK1 and MAPK immunoreactivities have been localised to neuron bodies and dendrites in dentate gyrus and CA3 region of the hippocampus as well as in the mossy fibre axons and CA3 apical dendrites of the stratum lucidum (Bhat et al . , J “ . Neurochem . 70, 1998, 558-571). In contrast, in the neocortex immunostaining was observed in both the nuclear and cytoplasmic compartments . Electroconvulsive treatment increased, within minutes, MAPK activity in the hippocampus.
  • K-252a is an indolocarbazole alkaloid isolated from Nocardiopsis : Kase, Iwahashi and Matsuda, J. Antibiot. (Tokyo), 39: 1059-1065, 1986
  • novel bis-N- substituted derivatives of staurosporine for treating diseased neuronal cells. It has also been observed that K-252 derivatives enhance neurotrophin-induced activity mediated by phosphorylation of Trk receptors, preferably the activity of neurotrophin-3, and that this will make these inhibitors useful to treat neurological disorders, either alone or in combination with NT-3 (U.S. patents 5,468,872; 5,516,772) .
  • MAPK/Erk kinase MAPK/Erk kinase 1
  • 4-diamino-2 , 3 -dicyano-1 4-bis [2-amino- phenylthio] butadiene
  • U0126 Another synthetic reversible inhibitor of MAPK/Erk kinase (MEK), 1 , 4-diamino-2 , 3 -dicyano-1 , 4-bis [2-amino- phenylthio] butadiene
  • U0126 Another synthetic reversible inhibitor of MAPK/Erk kinase (MEK), 1 , 4-diamino-2 , 3 -dicyano-1 , 4-bis [2-amino- phenylthio] butadiene
  • IC 50 was less than 1.0 ⁇ M and the compound was found to readily pass the cell membrane.
  • this compound exhibits a high degree of specificity for inhibition of MEK since a number of other tested serine/threonine kinases, including the MEK homologues known as p38 (a MAP kinase of 38000 Mw) and JNK (c-Jun N-terminal kinase) were not blocked by it (De Silva et al . , J “ . Immunol . 160, 1998, 4175-4181). Nor was protein kinase C inhibited (Favata et al . as above) .
  • NT-3 neurotrophic factor neurotrophin-3
  • R' and R" are individually chosen from thiophene, phenyl and phenyl substituted with at least one group selected from amino, hydroxy and carboxy, or of a pharmaceutically acceptable salt, solvate or isomer thereof, for the manufacture of a medicament for potentiating the neurotrophic effects on mammalian neurons of the neurotrophic factor neurotrophin-3 (NT-3) .
  • NT-3 neurotrophic factor neurotrophin-3
  • R' and R" are as mentioned above, or of pharmaceutically acceptable salts, solvates and isomers thereof, for the manufacture of a medicament for stimulating neural stem cell growth and differentiation in combination with the neurotrophic factor neurotrophin- 3 (NT-3) .
  • NT-3 neurotrophic factor neurotrophin- 3
  • a method for potentiating the neurotrophic effects on mammalian neurons of the neurotrophic factor neurotrophin-3 (NT-3) comprises administration, to a host in need of such treatment, an amount of the compound with the general formula:
  • a final aspect of the invention is a method for stimulating neural stem cell growth and differentiation in combination with the neurotrophic factor neurotrophin- 3 (NT-3) .
  • the method comprises administration, to a host in need of such treatment, an amount of the compound with the general formula:
  • R' and R" are as mentioned above, or of pharmaceutically acceptable salts, solvates and isomers thereof, effective for the treatment.
  • R' and R" in the formula are individually chosen from thiophene, phenyl and phenyl substituted with one or two amino groups or with one hydroxy or carboxy group in any of the positions 2 - 5.
  • R' and R" are thus for example chosen from 2-aminophenyl , 2-hydroxyphenyl , 4-hydroxyphenyl , 3- aminophenyl, 2 , 3 -diaminophenyl , 2 , 4-diaminophenyl and 4- aminophenyl .
  • R' and R" are identical.
  • the compound is 1 , 4-diamino-2 , 3-dicyano-l , 4-bis (2- aminophenylthio) butadiene .
  • the use of the compound and the method of treatment according to the present invention are particularly suited for the treatment of neurons afflicted with neurodegenerative disease, such as Parkinson's disease, Alzheimer's disease, Huntington' s disease or amyotrophic lateral sclerosis, or of neurons having been, or being, in the imminent risk of becoming damaged or injured by ischemia, stroke, hypoxia, hypoglycaemia, trauma, epilepsia or excitotoxicity . Further, the use of said compound and the method for treatment according to the present invention are suitable for replacement therapies.
  • neurodegenerative disease such as Parkinson's disease, Alzheimer's disease, Huntington' s disease or amyotrophic lateral sclerosis
  • the use of said compound and the method for treatment according to the present invention are suitable for replacement therapies.
  • MAPK kinase MAPK kinase
  • Neurotrophin-3 is a protein which belongs to a small family of NGF-like growth factors. Human DNA encoding NT-3 has been isolated and sequenced (Kaisho et al., FEBS Lett . 266, 1990, 187-191; Jones and Reichardt, Proc . Natl . Acad . Sci . USA 87, 1990, 8060-8064; Maisonpierre et al . Genomics 10, 1991, 558-568). The coding sequence is generally available and deposited with accession numbers M37763, X53655 and M61180 in the GenBank database.
  • the human NT-3 protein can be expressed isolated (Maisonpierre, Belluscio, Squinto, Ip, Furth, Lindsay and Yancopoulos, Science 247: 1446-1451, 1990) and has specific neurotrophic effects.
  • the NT-3 protein binds with preference to the signalling tyrosine kinase receptor TrkC, but also signals via the related NGF- receptor TrkA (Barbacid, J. Neurobiol . 25: 1386-1403, 1994) .
  • the sequence of human TrkC is known as GenBank accession numbers U05012 (McGregor et al . Genomics 22: 267-272, 1994), AJ224521 (Ichaso et al .
  • TrkA immunoreactivity has been shown m the adult basal forebram housing neurons afflicted m Alzheimer's disease (Lee et al . , Neurosci ence 83: 335-349, 1998) and in some other well localised groups of neurons (Holtzman et al., J. Neurosci .
  • TrkA mRNA in the brain is present in basal forebram neurons, in the interpeduncular nucleus and m some hmdbram nuclei (Gibbs and Pfaff, J " . Comp . Neurol . 341: 324-339, 1994).
  • TrkC in contrast, is more widely expressed in brain neurons. TrkC positive neurons are found in the olfactory system, neocortex, hippocampus, thalamic and hypothalamic nuclei, brainstem, cerebellum and spinal cord (Merlio et al . , Neuroscience 51: 513-532, 1992).
  • Neurotrophin-3 mRNA is expressed in hippocampal neurons and in cerebellum (Lauterborn et al . , Mol . Cell . Neurosci . 5: 46-62, 1994). Immunohistochemically, NT-3 has been localised to the basal forebrain, forebrain cortex, hippocampus, midbram nuclei, cerebellum, brainstem and spinal cord (Zhou and Rush, Brain Res . 643: 162-172, 1994; Friedman et al . , Neuroscience 84: 101-114, 1998) . The presence of NT-3 protein m the brain has been demonstrated by use of an enzyme immunoassay (S ⁇ derstr ⁇ m and Ebendal, Neurosci .
  • NT-3 has been shown to enhance sprouting of the corticospmal tract after spinal cord lesion (Schnell et al., Nature 367: 170-173, 1994). NT-3 also improves spatial learning abilities in aged rats (Fischer et al . Proc . Natl . Acad. Sci . USA 91: 8607-8611, 1994).
  • the potentiating effect of the compounds according to the invention can be used for promoting the survival and growth or regrowth of nerve processes of mammalian neurons, especially in humans, whether they be localised in the brain, spinal cord or peripheral nervous system.
  • the compounds may also find use to support survival and neurite outgrowth in nerve cells transplanted to patients. Such cells may be derived from the embryo. This has been brought into practice in connection with implantation of human embryonic mesencephalic tissue into the striatum of patients with Parkinson's disease or patients with MPTP- induced parkinsonism (Lindvall, Mov. Disord . Suppl . 1: 83-87, 1998).
  • transplanted cells may be derived from isolated neural stem cells (Frisen, Johansson, Lothian and Lendahl , Cell Mol . Life Sci . 54:935-945, 1998), whether being cultured or genetically modified in vitro (Weiss et al . , U. S. Patents 5,750,376 and 5,851,832).
  • Neurons in patients suffering from neurodegenerative diseases or having been subjected to neuronal lesions or ischemia, stroke, hypoxia, hypoglycemia, trauma, epilepsia or excitoxicity can be treated by provision of a dose of the compound effective for the treatment.
  • the effective dose will vary from case to case, and can be determined by the skilled man.
  • an effective dose of the compound according to the invention lies within the range 1 - 50 ⁇ M, preferably within 1 - 10 ⁇ M.
  • the potentiating effect of the compounds is efficient also with delayed administration.
  • the compounds according to the invention can be administered up to 24 hours after lesion of neurons, and the potentiating is still achieved. If the patient's endogenous levels of the neurotrophic factor are sufficient to allow signalling potentiated by the compound, no additional amount of the neurotrophic factor needs to be added.
  • An alternative strategy is to administer the compound and, in addition, provide the patient with NT-3. It is also possible to use biologically active proteins derived from NT-3, by e.g. exchange of conserved amino acid residues resulting in functional variants of these proteins.
  • the neurotrophic factor or the biologically active proteins derived therefrom are preferably used at doses resulting in concentrations of 5 - 500 ng/ml , most preferably 10-100 ng/ml, of these neurotrophic factors locally around the afflicted neurons.
  • the compounds, and optionally the neurotrophic factor can be administered by intracerebral , intravenous, intramuscular or subcutaneous routes.
  • the feasibility and efficacy of administering neurotrophic factors to human patients via different routes have been demonstrated.
  • Nerve growth factor (NGF) has been given directly to the human brain by continuous infusion via stereotactically implanted catheters in Parkinson patients (Sydow, Hansson, Young, Meyerson, Backlund, Ebendal, Farnebo, Freedman, Hamberger, Hoffer, Seiger, Str ⁇ mberg and Olson, Eur. J. Neurol .
  • NGF neurotrophic factor
  • Alzheimer patients Eriksdotter J ⁇ nhagen, Nordberg, Amberla, Backman, Ebendal, Olson, Seiger, Shigeta, Theodorsson, Viitanen, Winblad and Wahlund, Dement . Geriatr. Cogn . Disord . 9: 246-257, 1998.
  • NGF has been given subcutaneously to treat diabetic polyneuropathy (Apfel, Kessler, Adornato, Litchy, Sanders, Rask and the NGF Study Group, Neurology 51: 695- 702, 1998) .
  • Ciliary neurotrophic factor has also been given subcutaneously to pateints with ALS, amyotrophic lateral sclerosis (Miller, Petajan, Bryan, Armon, Barohn, Goodpasture, Hoagland, Parry, Ross, Stromatt and the rhCNTF ALS Study Group, Ann. Neurol . 39: 256-260, 1996) .
  • a further route of delivery of a trophic factor has been the intrathecal implantation of encapsulated, genetically engineered CNTF-producing cells to ALS patients (Aebischer, Schluep, Deglon, Joseph, Hirt, Heyd, Goddard, Hammang, Zurn, Kato, Regli and Baetge, Nature Medicine 2 : 696-699, 1996).
  • US 5,837,234 discloses bioartificial organ containing cells encapsulated in a' permselective polyether sulfone membrane. It is suggested that biologically active factors such as CNTF, NGF, GDNF can be produced.
  • Fig. 1 Photomicrographs showing the drastic improvement in nerve fibre outgrowth by 1 , 4-diamino-2 , 3- dicyano-1, 4-bis (aminophenylthio) butadiene (U0126) according to the invention in neurotrophin-3 (NT-3) stimulated nervous tissue.
  • Fig. la shows stimulation with NT-3 only (10 ng/ml)
  • Fig. lb after the addition of 1, 4-diamino-2 , 3-dicyano-l, 4-bis (aminophenylthio) butadiene at 1 ⁇ M.
  • Fig. 2 Graphic representation of mean stimulation scores using sympathetic (SYMP) and sensory neurons (NOD) . Stimulation was with NT-3 alone (10 ng/ml) or with NT-3 together with 1 , 4-diamino-2 , 3 -dicyano-1 , 4-bis (aminophenylthio) butadiene (U0126) (l ⁇ M) .
  • the compound 1 , 4-diamino-2 , 3-dicyano-l , 4-bis (2- aminophenylthio) butadiene (U0126) was purchased from Promega Corporation, Madison WI . It was dissolved in dimethylsulfoxide (DMSO) at 10 mM and stored frozen at -20 °C in aliquots. For tissue culture experiments, the compound was thawed and diluted 100-fold in distilled water and then further diluted 50 -fold in culture medium added in equal volume over the collagen gel matrix with explanted nervous tissue, yielding a final concentration of 1 ⁇ M of the compound.
  • DMSO dimethylsulfoxide
  • NT-3 was purchased from Austral Biologicals.
  • Ganglionic bioassays were carried out according to established methods (Ebendal, IBRO Handbook series: Methods in Neurosciences Vol .12 : 81-93. John Wiley, Chichester, 1989; Ebendal et al . , Nature 286: 25-28, 1980; Kullander et al . , J. Biol . Che . 272: 9300-9307, 1997) .
  • Ganglia containing sympathetic, sensory or parasy pathetic neurons were dissected under a stereomicroscope from the chicken embryo at day 9 of incubation.
  • the ganglia are put into a small drop of culture medium under sterile conditions, and are embedded in a collagen gel having a volume of 100 ⁇ l .
  • the collagen gel mixture sets within a minute after addition to the ganglia in plastic culture dishes, and results in a flat collagen gel drop where the culture medium is free to diffuse.
  • the neurotrophic factor is added in an additional 100 ⁇ l volume of culture medium (Eagle's Basal Medium supported with 1% fetal calf serum) .
  • the cultures are then incubated under humidified conditions in a carbon dioxide incubator at 37°C for two days. Thereafter, the resulting nerve fibre formation around the nerve cell explant is assessed in an inverted microscope equipped with darkfield and phase contrast optics .
  • NT-3 at 10 ng/ml was tested on sympathetic ganglia and a sparse nerve fibre outgrowth occured as described (Ernfors et al . , Proc . Na tl . Acad . Sci . USA 87, 1990, 5454-5458) .
  • the outgrowth response to NT-3 was drastically potentiated. The result is shown as a massive growth response in the form of a dense halo of nerve fibres around the nerve tissue explant (Fig. lb) .
  • Adding the compound at 50 ⁇ m to NT-3 had an inhibitory, apparently toxic, effect on the nerve cells.
  • Fig. 2 Mean scores for sympathetic ganglia cultured for 2 days are given. Tests performed in a separate test series are shown in Fig. 2. Tests performed at at least two different occasions, 4-20 ganglia scored in each group. Similar tests were performed using sensory nerve cells from the embryonic nodose ganglion (Fig.2) .
  • U0126 and PD184352 specifically inhibit MEK1 , they differ markedly in their capacity to potentiate neurotrophic-f ctor driven nerve outgrowth with U0126 being drastically superior. This difference in biological outcome in nerve cells is likely to reflect the profound chemical differences between these two compounds, probably leading to differences in details of the mechanisms of inhibition of the dual -speci icity kinase kinase MEK1.
  • U0126 was given 15 min before or 15 min after the traumatic brain injury. The rats were killed 2 weeks after the traumatic brain injury and U0126 infusion, for a microscopic evaluation of sections cut through the brain. In the rats receiving U0126 before or after the injury, the damaged brain area was preliminary reduced by 50% compared to the lesioned animals receiving the inactive control substance U0124. Thus, the volume estimation of spared bram tissue indicates that U0126 is at least as effective as the previous drugs tested such models (free radical scavengers etc.) . Furthermore, U0126 was highly effective also when administered after the traumatic bra injury.

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Abstract

L'invention concerne l'utilisation d'un composé de la formule (I) où R' et R'' sont choisis individuellement parmi thiophène, phényle et phényle substitué par au moins un groupe sélectionné parmi amino, hydroxy et carboxy ou un de leurs sels, solvats ou isomères pharmaceutiquement compatibles, afin de produire un médicament permettant de potentialiser les effets neurotrophiques du facteur neurotrophique neurotrophin-3 (NT-3) sur les neurones de mammifères, ou de stimuler la croissance de cellules embryonnaires neuronales et la différenciation en association avec le facteur neurotrophique neurotrophin-3 (NT-3). L'invention concerne également un procédé permettant de potentialiser les effets neurotrophiques de neurones de mammifères NT-3 ainsi qu'un procédé permettant de stimuler la croissance des cellules embryonnaires neuronales et la différenciation en association avec NT-3.
PCT/SE2001/000292 2000-02-18 2001-02-14 Nouvelle utilisation WO2001060357A1 (fr)

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AU2001232578A AU2001232578A1 (en) 2000-02-18 2001-02-14 New use

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SE0000532A SE0000532L (sv) 2000-02-18 2000-02-18 Ny användning
SE0000532-2 2000-02-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107485610A (zh) * 2016-06-12 2017-12-19 北京大学 咪康唑在预防血管破裂中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000028324A1 (fr) * 1998-11-10 2000-05-18 Mcgill University Procede d'identification de modulateurs de croissance neuronale

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000028324A1 (fr) * 1998-11-10 2000-05-18 Mcgill University Procede d'identification de modulateurs de croissance neuronale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOHAN V. DUNICA ET AL.: "MEK inhibitors: The chemistry and biological activity of U0126, Its analogs and cyclization products", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 8, 1998, pages 2839 - 2844 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107485610A (zh) * 2016-06-12 2017-12-19 北京大学 咪康唑在预防血管破裂中的应用
CN107485610B (zh) * 2016-06-12 2019-07-23 北京大学 咪康唑在预防血管破裂中的应用

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SE0000532D0 (sv) 2000-02-18
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