WO2014088106A1 - Agent prophylactique ou thérapeutique pour la fibromyalgie - Google Patents

Agent prophylactique ou thérapeutique pour la fibromyalgie Download PDF

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Publication number
WO2014088106A1
WO2014088106A1 PCT/JP2013/082878 JP2013082878W WO2014088106A1 WO 2014088106 A1 WO2014088106 A1 WO 2014088106A1 JP 2013082878 W JP2013082878 W JP 2013082878W WO 2014088106 A1 WO2014088106 A1 WO 2014088106A1
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msin3b
fibromyalgia
binding
pain
substance
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PCT/JP2013/082878
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English (en)
Japanese (ja)
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西村　善文
植田　弘師
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株式会社ＰＲＩＳＭ Ｐｈａｒｍａ
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Priority to JP2014551161A priority Critical patent/JPWO2014088106A1/ja
Publication of WO2014088106A1 publication Critical patent/WO2014088106A1/fr

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    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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 present invention relates to a prophylactic or therapeutic agent for fibromyalgia, and more particularly to a prophylactic or therapeutic agent for fibromyalgia containing a compound that binds to mSin3B.
  • Fibromyalgia an example of systemic pain syndrome, is particularly responsive to tender points, and is mainly caused by unexplained generalized pain and mental and neurological symptoms such as insomnia and depression. is there. There are 2% of the national population, and it has been reported that it is overwhelmingly affected among middle-aged and elderly women. Psychological factors due to physical trauma, stress, depression, and anxiety due to surgery and accidents are thought to be greatly involved in the background of the development of fibromyalgia, and as a result, from the lower brainstem nucleus to the dorsal horn Although the part by attenuation of the descending pain suppression system is said to be large, the initial cause site
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the current treatment mainly antidepressants, pharmacotherapy that orally administers anticonvulsants, Chinese herbal medicines, and psychotherapy such as psychotherapy, relaxation, and exercise therapy are performed.
  • amitriptyline, amoxapine, fluvoxamine, milnacipran and the like are used as the antidepressant administered orally.
  • the conventional treatment methods can improve fibromyalgia symptoms to some extent, there are problems that the treatment effects are not sufficient or cannot be completely cured.
  • Patent Document 1 an extract of inflamed tissue inoculated with vaccinia virus (for example, neurotropin) is effective for fibromyalgia (see Patent Document 1).
  • vaccinia virus for example, neurotropin
  • Patent Document 1 there is a need for a therapeutic agent for fibromyalgia that can effectively treat fibromyalgia but has a better therapeutic effect and fewer side effects. ing.
  • chronic pain due to nerve damage is a complex pain with a mixture of positive symptoms (pain hypersensitivity and allodynia (strong pain induced by tactile stimulation)) and negative symptoms (hyperperception). Symptoms are present. Moreover, since this abnormal pain shows resistance to an anti-inflammatory drug and morphine, it is regarded as intractable pain.
  • Patent Document 2 the effect of the mSin3B binding compound is not pain suppression, but is a therapeutic effect for negative symptoms related to pain such as paradoxical pain bluntness, and for positive symptoms such as pain hypersensitivity and allodynia. Did not show any efficacy at all (unpublished).
  • the known neuropathic pain is not systemic pain but specific to the impaired side. That is, neuropathic pain can identify a site of injury (injury) on the pain transmission pathway.
  • fibromyalgia the disease responsible site is not specified.
  • systemic administration of morphine is neuropathic pain and has an analgesic effect 10 times weaker than that of normal mice, but is not effective at all in fibromyalgia (100 times or more).
  • the neuropathic pain model was the same as that in normal mice, but was completely ineffective in the fibromyalgia model (see Non-Patent Documents 7 and 8).
  • fibromyalgia and neuropathic pain are diseases with the same pain, but are considered to be completely different diseases because differences in onset mechanism and drug effects are observed.
  • the inventors of the present invention have clarified that the repeated stress-induced chronic pain model is a good model for systemic pain syndrome including fibromyalgia (see Patent Document 3), and further using this model in clinical practice.
  • therapeutic agents used antidepressants
  • systemic pain and psychological factors have a close pharmacological correlation, and certain antidepressants are spinal cord subarachnoid.
  • it can be used as a therapeutic agent for fibromyalgia by internal administration (see Patent Document 4).
  • such therapeutic agents include milnacipran, paroxetine, amitriptyline and mianserin.
  • intrathecal administration of these antidepressants with spinal cord is highly invasive, continuous administration to patients is heavy, and the degree of satisfaction with the therapeutic effect for fibromyalgia is not yet sufficient, and fibromyalgia There was a need for new drugs.
  • An object of the present invention is to provide a prophylactic / therapeutic agent for fibromyalgia having an excellent prophylactic / therapeutic effect.
  • the present inventors created an ICS (Intermittent Cold Stress) model mouse as an animal experiment model of fibromyalgia.
  • ICS Intermittent Cold Stress
  • the inventors of the present invention when a compound that specifically binds to mSin3B, which is a corepressor that specifically binds to the neuroselective transcription repressor NRSF, gave a thermal stimulus in the ICS model mouse, The disappearance of analgesia was found to be observed.
  • the present invention has been completed based on these findings.
  • the gist of the present invention is as follows.
  • a prophylactic or therapeutic agent for fibromyalgia comprising a substance capable of binding to mSin3B.
  • a prophylactic / therapeutic agent for fibromyalgia having an excellent prophylactic / therapeutic effect can be provided.
  • FIG. 1 shows the STD (saturation transfer difference) (compound / mSin3B: 400 ⁇ M / 10 ⁇ M) of 3,5-dimethylpiperidyl 3-methyl-4-nitrophenyl ketone (Example 1).
  • FIG. 2 shows the STD (saturation transfer difference) of 1- [4- (difluoromethoxy) phenyl] -2- (3,5-dimethylpiperidyl) ethane-1-one (compound / mSin3B: 400 ⁇ M / 10 ⁇ M) ( Example 1).
  • FIG. 3 shows the test schedule (upper part) and results (lower part) of the pain-related behavior evaluation test of the ICS model mouse (Example 3).
  • “- ⁇ -Control-Veh” is a control group (non-stressed mouse) vehicle administration group
  • - ⁇ -ICS-155 is an ICS model mouse compound 155 administration group
  • - ⁇ -ICS-A28 is The ICS model mouse compound A28 administration group
  • the present invention provides a preventive or therapeutic agent for fibromyalgia containing a substance capable of binding to mSin3B. Details will be described below.
  • Fibromyalgia Fibromyalgia is a disease that causes severe pain throughout the body, and the classification standard proposed by the American College of Rheumatology in 1990 is currently used worldwide as a diagnostic method. According to this standard, pain is observed in any of the five parts of the upper body and lower body, the right and left bodies, and the spine and sternum from the umbilicus, and they persist for at least 3 months, or When a gentle load of 4 kg is applied to the prescribed 18 points of tender points throughout the body and pain is felt at 11 or more points, it is referred to as fibromyalgia.
  • Treatment of fibromyalgia means to completely cure the pathophysiology of fibromyalgia, to suppress the progression and worsening of symptoms without complete cure, or to stop the progression of the pathology, or It means improving part or all of the pathological condition and leading to the direction of healing.
  • Prevention of fibromyalgia means preventing, suppressing or delaying the onset of fibromyalgia pathology.
  • An “effective amount for treating fibromyalgia” is sufficient to effect such treatment for fibromyalgia when administered to an animal to treat fibromyalgia. Means quantity.
  • An “effective amount for preventing fibromyalgia” is sufficient to achieve such prophylaxis for fibromyalgia when administered to an animal to prevent fibromyalgia. Means quantity.
  • MSin3B is a corepressor that specifically binds to the neuroselective transcription repressor NRSF / REST, and the N-terminal transcription repression domain of NRSF / REST is histone deacetylase (HDAC) via the corepressor mSin3B.
  • HDAC histone deacetylase
  • C-terminal domain HDAC is recruited via CoREST, and the chromatin structure is inactivated via histone deacetylation, thereby suppressing transcription (Proc. Natl Acad. Sci. USA, 96, 13691-13696 (1999)).
  • mSin3B has four PAH domains (PAH1 to 4) with different binding partners and an HDAC synthesis action domain (HID).
  • PAH1 forms a complex with the N-terminal transcriptional repression domain of NRSF / REST (J. Mol. Biol., 314, 903-915 (2005)).
  • the molecular biological relationship between mSin3B (particularly the combined action of mSin3B and NRSF / REST) and fibromyalgia is not known at the time of filing of the present application.
  • the substance that can bind to mSin3B in the present invention may be any substance as long as it can specifically bind to mSin3B.
  • the binding site (domain) is not particularly limited, but a substance that can bind to the PAH1 domain of mSin3B is preferable.
  • the binding of mSin3B binding compound and mSin3B is known per se binding assay (radio binding assay etc.), NMR method (chemical shift mapping method, NMR titration method, STD (Saturation transfer difference) -NMR (saturation transfer difference NMR) method) However, it can be confirmed by the STD-NMR method described later.
  • the mSin3B binding compound of the present invention is not limited as long as it binds to mSin3B, but preferably inhibits mSin3B. “Inhibition of mSin3B” is not particularly limited as long as it can suppress the function of mSin3B and change the expression of a gene involved in mSin3B.
  • the interaction between mSin3B and NRSF / REST Inhibiting the transcriptional repressive action by inhibiting, inhibiting the transcriptional repressive action by inhibiting the interaction between mSin3B and HDAC, inhibiting the interaction between mSin3B and MeCP2 (methylated DNA is And binding to the transcriptional repressing factor MeCP2 and further binding to mSin3 leads to HDAC function activation).
  • the mSin3B binding compound binds to the PAH1 domain and inhibits the formation of a complex of mSin3B and NRSF / REST, thereby inhibiting the transcriptional repressing action.
  • NRSF neuro-restrictive sirencer factor
  • the mSin3B binding compound of the present invention preferably has a human medulloblastoma cell line growth inhibitory activity.
  • Medulloblastoma is the most malignant childhood brain tumor, and the expression level of NRSF / REST is very high in medulloblastoma cells.
  • Recombinant protein REST-VP16 which antagonizes NRSF / REST and activates the target gene of NRSF / REST, induces apoptosis by promoting the expression of neural genes and further activating the caspase cascade.
  • NRSF / REST has the potential to be a target molecule for therapeutic drugs for medulloblastoma (Nature Med., 7, 826-831 (2000)).
  • the growth inhibitory activity against the human medulloblastoma cell line of the mSin3B binding compound of the present invention can be measured, for example, by the method described in WO2011 / 099502. Further, it is disclosed in the same literature that an mSin3B binding compound exhibits a growth inhibitory action against a human medulloblastoma cell line.
  • the mSin3B-binding compound of the present invention is not particularly limited as long as it is defined above.
  • an antibody having an affinity for mSin3B polyclonal antibody, monoclonal antibody
  • a compound described in WO2011 / 099502 Pharmaceutically acceptable salts thereof, pharmaceutically acceptable esters thereof, and the like (hereinafter, the compound may be referred to as “mSin3B-binding compound of the present invention”).
  • Model mouse for fibromyalgia In order to prove that the mSin3B binding compound of the present invention is useful for prevention or treatment of fibromyalgia, an ICS (Intermittent Cold Stress) model mouse was used as an animal experimental model of fibromyalgia. This model mouse has been shown to develop systemic hyperalgesia in the long term (several weeks) after stress. Thermal pain hypersensitivity, mechanical allodynia, and pain against chemicals found in the Writing acetate test It exhibits generalized abnormal pain against various stimuli such as hypersensitivity and hypersensitivity caused by electrical stimulation.
  • ICS Intermittent Cold Stress
  • the present inventors have already published a constant cold stress (CCS) model as a control model (which is always left at 4 degrees without repeated temperature changes), and in this model, abnormal pain only lasts for several days. (Mol Pain. 2008 Nov 6; 4:52).
  • CCS constant cold stress
  • the SART model mouse as an autonomic nerve modulation model subjected to low-temperature stress at 1 hour intervals may only maintain abnormal pain within one week. I know (unpublished).
  • symptoms similar to fibromyalgia such as long-term generalized hypersensitivity for several weeks and allodynia are observed.
  • ICS model mice used in the present invention is very useful as an animal experimental model of fibromyalgia.
  • the preventive or therapeutic effect on fibromyalgia of an mSin3B binding compound using an ICS model mouse can be evaluated based on a known pain-related behavior evaluation method.
  • the pain-related behavior evaluation methods include the Hargreaves test (Thermal Paw Withdrawal test: thermal stimulation pain test method), the Paw Pressure test, the electrical stimulation-induced pain withdrawal (EPW) test, and the chemical stimulation test. Law.
  • the Hargreaves test is for evaluating a pain threshold for thermal stimulation, and can be performed by a known method (for example, Inoue et al., Nature Medicine, 10: 712-718, 2004) or in conformity thereto. Specifically, it can be carried out by the method described in Examples below.
  • the mSin3B-binding compound of the present invention can be used as a pharmaceutical preparation (eg, injection, capsule, tablet, powder, granule, etc.) formulated by a conventional method as a human or animal (eg, mouse, rat, hamster, rabbit, cat). , Mammals such as dogs, cows, sheep, monkeys).
  • the dosage, administration method, and frequency of administration can be appropriately changed depending on symptoms, age, and the like.
  • carriers such as distilled water and physiological saline may be used.
  • carriers such as distilled water and physiological saline may be used.
  • capsules tablets, powders, granules, starch, lactose, sucrose, calcium carbonate Excipients such as starch paste, gum arabic, gelatin, sodium alginate, carboxymethylcellulose, hydroxypropylcellulose and other binders, magnesium stearate, talc and other lubricants, starch, agar, crystalline cellulose, calcium carbonate Disintegrants such as sodium bicarbonate and sodium alginate may be used.
  • the active ingredient content in the formulation can vary between 1 and 99% by weight.
  • the active ingredient when taking the form of tablets, capsules, granules, powders, etc., it is preferable to contain 5 to 80% by weight of the active ingredient, and in the case of injections, it contains 1 to 10% by weight of the active ingredient. It is preferable to do so. Although it does not specifically limit as an administration method, Oral administration, intraperitoneal administration, etc. are mentioned.
  • Example 1 Measurement of binding ability to mSin3B by STD-NMR The experiment was conducted under the following STD-NMR measurement conditions. 1. Samples (1) Protein: 15 by the method described in Example 1 of N-mSin3B (WO2006 / 030722, prepared 15 N-mSin3B (15 N-labeled body PAH1 domain mSin3B (a.a.28-107)) was used. (2) Ligand: 3,5-dimethylpiperidyl 3-methyl-4-nitrophenyl ketone (purchased from SPECS), 1- [4- (difluoromethoxy) phenyl] -2- (3,5- Dimethylpiperidyl) ethane-1-one (purchased from Enamine) was used.
  • Sample preparation (1) The sample volume required for measurement was 500 ⁇ L. (2) The protein concentration was 10 ⁇ M and the ligand concentration was 400 ⁇ M. (3) The solvent was 100 mM phosphate buffer-pH 7.2 (5% d-DMSO), and the protein and the ligand were mixed.
  • Example 2 Preparation of fibromyalgia model mouse An ICS model mouse was prepared by repeating the room temperature at room temperature (24 ° C) and low temperature (4 ° C) every 30 minutes during the day and at low temperature at night. did. Specific breeding conditions and environmental temperature are as follows. (1) On day 0, the mouse to be used was moved to a refrigerator under low temperature conditions at 16:30, and was reared until 10:00 on the next day. (2) It moved to room temperature at 10:00 of the following day (the 1st day), and was reared alternately by low temperature condition and room temperature condition every 30 minutes until 16:30 thereafter. After 16:30, the animals were raised under low temperature conditions until 10:00 the next morning. (3) On the second day, the animals were reared in the same manner as on the first day, and transferred to room temperature at 10:00 on the third day. (4) The control group (non-stressed mice) was kept at room temperature for 3 days.
  • mice In this mouse, symptoms similar to fibromyalgia were observed, such as long-term generalized hypersensitivity that lasted for several weeks and also induced allodynia. As described above, this symptom is completely different from neuropathic pain produced by partial nerve ligation or the like.
  • crushed solid feed for general experiments MF, Oriental, Tokyo
  • free sterilized purified water solidified with agar as water
  • the mice were bred under constant humidity (55 ⁇ 5%) under light / dark 12 hours (light hours 8-20 hours).
  • Example 3 Therapeutic effect of mSin3B binding compound A compound that binds to mSin3B was administered to the ICS model mouse obtained in Example 2 to determine whether the mSin3B binding compound has a therapeutic effect on fibromyalgia. It investigated by conducting the behavioral analysis test about pain.
  • the mSin3B binding compounds used in this example are as follows: 3,5-dimethylpiperidyl 3-methyl-4-nitrophenyl ketone (compound 155) (purchased from SPECS) and 1- [4- (difluoromethoxy) phenyl] -2- (3,5-dimethylpiperidyl) ethane- 1-one (compound A28) (purchased from Enamine).
  • Hargreaves test thermo paw test: thermal stimulation pain test method
  • ICS model mice were placed in plastic cages placed on glass plates and allowed to adapt in the same environment for over 30 minutes. Thermal stimulation was projected from the bottom of the glass plate to the center of the hind limb footpad, and the latency until the mouse showed a hind limb escape response (Paw Withdrawal Latency: PWL) was measured and evaluated.
  • a drug solution dissolved in saline was intraperitoneally administered at 5 mg / kg.
  • the pain threshold measurement of P5, P6, P8 and P10 was performed before drug administration. Pain thresholds were measured at P5, P6, P8, P10, P12, P14 and P16. The latency and strength were measured three times or more and the average value was adopted. Further, an interval of 10 minutes was left before measuring the next threshold value.
  • FIG. 3 shows the test schedule, and the lower part shows the results of the Hargreaves test.
  • the vertical axis PWL Paw Withdrawal Latency
  • the horizontal axis indicates the day when the ICS stress has been applied.
  • the number of days elapsed as the day (P1) is shown.
  • “- ⁇ -Control-Veh” is a control group (non-stressed mouse) vehicle administration group
  • - ⁇ -ICS-155 is an ICS model mouse compound 155 administration group
  • a substance capable of binding to mSin3B is useful as a prophylactic and / or therapeutic agent for fibromyalgia.
  • This application is based on patent application No. 2012-267599 filed in Japan, the contents of which are incorporated in full herein. While the invention has been presented or described with reference to preferred embodiments thereof, various changes in form and detail have been made herein without departing from the scope of the invention as encompassed by the appended claims. It will be appreciated by those skilled in the art. All patents, patent publications and other publications shown or referenced herein are incorporated by reference in their entirety.

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Abstract

L'invention concerne une substance capable de se lier à mSin3B, ladite substance présentant un effet analgésique sur une souris ICS (intermittent cold stress, stress au froid intermittent) qui est un modèle animal expérimental de fibromyalgie, et, par conséquent qui est utile comme agent prophylactique ou thérapeutique pour la fibromyalgie.
PCT/JP2013/082878 2012-12-06 2013-12-06 Agent prophylactique ou thérapeutique pour la fibromyalgie WO2014088106A1 (fr)

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JP2014551161A JPWO2014088106A1 (ja) 2012-12-06 2013-12-06 線維筋痛症の予防または治療薬

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JP2012267599 2012-12-06

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006030722A1 (fr) * 2004-09-15 2006-03-23 Yokohama City University Sequence d'acides amines essentielle pour l'expression de genes neurospecifiques
JP2011074018A (ja) * 2009-09-30 2011-04-14 Toray Ind Inc 線維筋痛症の治療剤又は予防剤
WO2011099502A1 (fr) * 2010-02-10 2011-08-18 公立大学法人横浜市立大学 Utilisation d'un composé se liant à msin3b qui se lie, de façon spécifique, au facteur silenceur de la spécification neuronale nrsf
WO2011125836A1 (fr) * 2010-03-31 2011-10-13 東レ株式会社 Agent thérapeutique ou agent prophylactique pour la fibromyalgie

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006030722A1 (fr) * 2004-09-15 2006-03-23 Yokohama City University Sequence d'acides amines essentielle pour l'expression de genes neurospecifiques
JP2011074018A (ja) * 2009-09-30 2011-04-14 Toray Ind Inc 線維筋痛症の治療剤又は予防剤
WO2011099502A1 (fr) * 2010-02-10 2011-08-18 公立大学法人横浜市立大学 Utilisation d'un composé se liant à msin3b qui se lie, de façon spécifique, au facteur silenceur de la spécification neuronale nrsf
WO2011125836A1 (fr) * 2010-03-31 2011-10-13 東レ株式会社 Agent thérapeutique ou agent prophylactique pour la fibromyalgie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YOSHIFUJI MATSUMOTO: "Sen'i Kintsusho: Gainen to Chiryo", THE JOURNAL OF THE JAPANESE SOCIETY OF INTERNAL MEDICINE, vol. 95, no. 3, 10 March 2006 (2006-03-10), pages 510 - 515 *

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