WO2019004321A1 - アルツハイマー病の予防及び/又は治療剤 - Google Patents
アルツハイマー病の予防及び/又は治療剤 Download PDFInfo
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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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- 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
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- the present invention relates to a preventive and / or therapeutic agent for Alzheimer's disease. More specifically, the present invention relates to a preventive and / or therapeutic agent for Alzheimer's disease, which comprises a peptide type ergot alkaloid.
- AD Alzheimer's disease
- a ⁇ amyloid ⁇
- APP amyloid precursor protein
- Non-patent Document 1 drug repositioning, ie, diversion of existing drugs, is regarded as important for AD treatment.
- the existing medicines have already accumulated a great deal of clinical information on safety and pharmacokinetics (such as Chembl database), and safety has been established. Therefore, although there are no clinical symptoms, intervention as a preemptive treatment for the AD preparatory group determined as positive by amyloid test can be expected.
- Valsartan an antihypertensive drug
- Liraglutide an antidiabetic drug
- An object of the present invention is to provide a novel and effective means for preventing and / or treating Alzheimer's disease and the like.
- the present inventors first induced differentiation of cerebral cortex neurons from induced pluripotent stem cells (iPS cells) established from patients with familial AD. Using this neuron, we constructed an experimental system to monitor the metabolic dynamics of amyloid beta protein (amyloid beta: A ⁇ ), which is a pathogen of AD. Using this experimental system, screening analysis of existing drug libraries was performed to search for drugs that reduce A ⁇ production. As a result of the search, it has been found that the addition of bromocriptine mesylate reduces the production of A ⁇ , and that analogous compounds of bromocriptine also decrease the production of A ⁇ . As a result of further studies based on these findings, the present inventors have completed the present invention.
- iPS cells induced pluripotent stem cells
- R 1 represents a hydrogen atom or a halogen atom
- R 2 and R 3 each independently represent a linear or branched alkyl group having 1 to 5 carbon atoms or an aryl group having 6 to 10 carbon atoms.
- a method of preventing and / or treating Alzheimer's disease in said mammal which comprises administering an effective amount of the compound shown by or a salt thereof.
- Formula (I) for use in the prevention and / or treatment of Alzheimer's disease :
- R 1 represents a hydrogen atom or a halogen atom
- R 2 and R 3 each independently represent a linear or branched alkyl group having 1 to 5 carbon atoms or an aryl group having 6 to 10 carbon atoms.
- Alzheimer's disease for which there has been no effective preventive or therapeutic agent.
- those containing an existing drug whose safety has been confirmed as the active ingredient are less likely to cause side effects.
- FIG. 1 shows the results of the action of reducing A ⁇ production by dopamine receptor stimulation using dopamine hydrochloride, SKF38393, bromocriptine or PD168077.
- FIG. 2 shows the results of the action to reduce A ⁇ production by non-ergot system type 2 dopamine receptor agonists (Talipexole, Pramipexole, Ropinirole).
- FIG. 3 shows the results of the action of decreasing A ⁇ production by ergot system type 2 dopamine receptor agonists (Cabergoline, Pergolide).
- the present invention provides a preventive and / or therapeutic agent for Alzheimer's disease (hereinafter also referred to as "the medicament of the present invention"), which is characterized by containing a peptide type ergot alkaloid.
- peptide-type ergot alkaloid (hereinafter sometimes abbreviated as “the compound of the present invention”) is also called ergopeptine, and is located at the same position as the amide group of lysergic acid derivative in the ergolin ring. It means a derivative to which three peptides etc. are added. This structure contains proline and two other alpha amino acids, which are linked by cyclol.
- the structural formula of the peptide type ergot alkaloid used in the present invention is shown as the following formula (I) or (II).
- R 1 represents a hydrogen atom or a halogen atom
- R 2 and R 3 each independently represent a linear or branched alkyl group having 1 to 5 carbon atoms or an aryl group having 6 to 10 carbon atoms.
- the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- a fluorine atom As shown in the examples described below, from the viewpoint of decreasing the A ⁇ 42 / 40 ratio, the modification of the bromo group at the 2-position within the ergolin ring structure of the compound of the present invention is preferred, and a bromine atom is preferred as the halogen atom.
- alkyl group examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, 2-pentyl, 3-pentyl and the like
- R 2 is preferably a methyl group and an isopropyl group
- R 3 is preferably an isopropyl group, an isobutyl group and a sec-butyl group.
- the aryl group may, for example, be a phenyl group, a benzyl group, a tolyl group, an o-xylyl group or a naphthyl group, preferably a benzyl group.
- the structure possessed by the peptide-type ergot alkaloid shown by the formula (I) or the formula (II) is important for the action of decreasing the amount of A ⁇ production. Therefore, the peptide-type ergot alkaloid which can be used in the present invention is not particularly limited as long as it is represented by the formula (I) or the formula (II), but as a specific example, for example, the amino acid at the R 2 position is valine And ergotamines in which the amino acid at the R 2 position is alanine.
- ergotoxins examples include ergocristine (ergocristine), dihydroergocristine (dihydroergocristine), ergocornin (ergocornine), dihydroergocornine (dihydroergocornine), ⁇ -ergocryptine ( ⁇ -ergocryptine) as shown in Table 1.
- Bromocriptine which is a compound in which the hydrogen atom of R 1 of the compound is substituted with a bromine atom, dihydro ⁇ -ergocryptine, --ergocryptine ( ⁇ -ergocryptine),
- ergotamines include ergotamine, dihydrogotamine, dihydroergotamine, ergovaline, dihydroergovaline, and ⁇ -ergosine ), Dihydro ⁇ -ergosine (dihydro ⁇ -ergosine) , ⁇ -ergosine ( ⁇ -ergosine), dihydro ⁇ -ergosine (dihydro ⁇ -ergosine) and the like.
- ⁇ -ergocriptine, bromocriptine, ergocristine, dihydroergocristine, ergotamine and dihydroergotamine are preferable.
- the compounds of the present invention can be commercially available products or can be produced by methods known per se for each compound.
- distributors of each compound in the United States can be known by Drugs @ FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm) or the like.
- bromocriptine can be produced according to the method described in, for example, US Pat. No. 3,752,814, US Pat. No. 3,752,888 or the like, or a method analogous thereto, and other compounds may be produced similarly. it can.
- the compounds of the present invention include not only the free form, but also pharmacologically acceptable salts thereof.
- the pharmacologically acceptable salt varies depending on the type of compound, but, for example, alkali metal salt (sodium salt, potassium salt etc.), alkaline earth metal salt (calcium salt, magnesium salt etc.), aluminum salt, ammonium salt etc.
- base addition salts such as organic base salts such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, or mesilates
- Inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, citrate, oxalate, acetate, formate, propionate, benzoate , Trifluoroacetate, maleate, tartrate, methanesulfonate, benzene sulfone Salts, acid addition salts such as salts of organic acids such as p-toluenesulfonic acid salt.
- the compound of the present invention has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, either one isomer or a mixture is also included in the compound.
- an optical isomer is present in any of the compounds listed in Table 1, an optical isomer resolved from a racemate is also included in the compound.
- separation methods eg, concentration, solvent extraction, column chromatography, recrystallization etc.
- optical resolution methods eg, fractional recrystallization method, chiral column method, diastereomer method etc. Or the like
- the compounds of the present invention may be crystals, and single crystals or crystal mixtures are encompassed in the compounds of the present invention.
- the crystals can be produced by crystallization using a crystallization method known per se.
- the compound of the present invention may be a solvate (eg, hydrate etc.) or a non-solvate (eg, non hydrate etc.), both of which are encompassed in the compound of the present invention Ru.
- AD Alzheimer's disease
- familial AD the causative gene is not particularly limited, and includes genes of amyloid precursor protein (Amyloid Precursor Protein; APP), presenilin 1 (Presenilin 1; PSEN 1), presenilin 2 (Presenilin 2; PSEN 2), etc. It may be any known causative gene.
- dup APP mutation As such APP mutations, dup APP mutation, APP KM670 / 671NL mutation, APP D678N mutation, APP E682K mutation, APP A692G mutation, APP E693K mutation, APP E693Q mutation, APP E693Q mutation, APP E693G mutation, APP E693del (APP E693 ⁇ ) mutation, APP D694 N mutation, APP L705 V mutation, APP A 713 T mutation, APP T 714 A mutation, APP T 714 I mutation, APP V 715 M mutation, APP V 715 A mutation, APP I 716 V mutation, APP I 716 F mutation, APP I 716 T mutation, APP V 717 I mutation and the like.
- each preparation can be administered to the same subject simultaneously or at different times.
- the medicament of the present invention can be obtained by orally mixing the compound of the present invention, which is the active ingredient, as it is or in a mixture with a pharmaceutically acceptable carrier, excipient, diluent, etc. Or it can be administered parenterally.
- compositions for oral administration may be in solid or liquid dosage forms, specifically tablets (including coated tablets, film coated tablets), pills, granules, powders, capsules (including soft capsules), syrups Agents, emulsions, suspensions and the like.
- a composition for parenteral administration for example, injections, suppositories, etc. are used, and injections include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, drip injection etc.
- a dosage form may be included.
- excipients for example, sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol, corn starch, potato starch, alpha starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, silicate derivatives such as magnesium metasilicate aluminium; phosphate such as calcium hydrogen phosphate; carbonated Carbonates such as calcium; inorganic excipients such as sulfates such as calcium sulfate), lubricants (eg, stearic acid, calcium stearate, metal stearates such as magnesium stearate; talc; Colloidal silica; bead wax, wax like gay wax Acid, adipic acid, sulfuric acid salt such as sodium sulfate, glycol, fumaric acid, sodium benzo
- the dose of the compound of the present invention which is the active ingredient of the medicament of the present invention, may vary depending on various conditions such as the type of compound, the condition to be administered, age, body weight, and drug receptivity.
- the amount may be increased or decreased depending on the symptoms.
- dosages can be appropriately selected for each compound within the range where safety is confirmed. For example, information on compound safety can be obtained from DailyMed (http://dailymed.nlm.nih.gov/dailymed/index.cfm) operated by the National Library of Medicine.
- the medicament of the present invention may be any of the other drugs such as BACE inhibitor IV, JNJ-40418677, Semagacestat, compounds known to improve A ⁇ pathology such as Acitretin, Sulfide slindac, Imanitib, Flurbiprofen, Donepezil, Rivastigmine, Galanthamine, It may be used in combination with existing AD therapeutic agents such as Memantin, and compounds having the action of decreasing A ⁇ , such as Cilostazol, Cromolyn, Fluvastatin, Probucol, Topiramate, etc. found by the present inventors.
- preferred combinations include the compound of the present invention, the combination of Cromolyn and Topiramate, or the combination of the compound of the present invention, Cilostazol and Probucol.
- the medicament of the invention and these other agents can be administered simultaneously, sequentially or separately.
- the prophylactic and / or therapeutic methods for administering an effective amount of the compound of the present invention or the medicament of the present invention to a mammal are also included in the present invention.
- mammals include mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans), preferably humans.
- the effective amount, dose and other matters are as described above.
- mice were induced to differentiate from iPS cells established from familial Alzheimer's disease patients having a G384A heterozygous mutation in the presenilin 1 gene, and were used in the assay.
- human iPS cells were differentiated into cerebral cortical neurons by introducing Neurogenin 2 gene into iPS cells and adding doxycycline for transient expression for 5 days.
- a ⁇ assay Cerebral cortical neurons were seeded at 100,000 cells / well in a 96-well plate (CORNING Inc. Edge plate), and on the third day, the whole medium was changed, and at that time compounds of various concentrations were added . After 48 hours, the medium was collected, centrifuged at 400 g for 5 minutes to prevent contamination of dead cells, and stored at -80 ° C. until A ⁇ measurement. For measurement of trace A ⁇ in culture supernatant, SECTOR Imager 2400 (Meso Scale Discovery, USA) was used as a detection device, and SULFO-TAG labeled antibody was detected and quantified by electrochemiluminescence.
- Example 1 Search for a drug that decreases A ⁇ production Highly purified cerebral cortex neurons from induced pluripotent stem cells (iPS cells) established from patients with familial Alzheimer's disease (AD) Differentiation was induced by a highly reproducible rapid method. Using this neuron, we constructed an experimental system to monitor the metabolic dynamics of amyloid beta protein (amyloid beta: A ⁇ ), which is a pathogen of AD.
- a ⁇ amyloid beta protein
- the AD patient-derived cerebral cortical neurons have a G384A heterozygote mutation in the causative gene for familial AD, so production of the A ⁇ 42 subtype known as toxic A ⁇ is increased, and the most abundant A ⁇ 40 sub The ratio ratio A ⁇ 42/40 to type production is high.
- Bromocriptine is approved as a treatment for Parkinson's disease because it has an agonistic action on dopamine receptors (DR). The following study was conducted to determine whether the dopamine receptor stimulating action works to reduce A ⁇ production, or whether the structure of bromocriptine itself reduces A ⁇ production with a mechanism that does not mediate dopamine receptors.
- Talipexole B-HT 920 dihydrochloride
- Pramipexole dihydrochloride Pramipexole dihydrochloride
- Rupinirole hydrochloride was added to cerebral cortical neurons at concentrations of 0.0016, 0.008, 0.04, 0.2, 1, 5, 25 ⁇ M, respectively, as non-ergot system D2R agonists.
- none of the compounds altered A ⁇ production (FIG. 2).
- Cabergoline and Pergolide mesylate were added to cerebral cortical neurons at concentrations of 0.0016, 0.008, 0.04, 0.2, 1, 5 and 25 ⁇ M as ergot system D2R agonists.
- Cabergoline showed 25 ⁇ M
- Pergolide mesylate showed an action to reduce A ⁇ production at 5, 25 ⁇ M (FIG. 3).
- the ergot system D2R agonist bromocriptine has a peptide type alkaloid structure in which three peptides of proline, valine and leucine are linked to an ergoline ring structure.
- the peptide type alkaloid structure is known to have various similar compounds in combination of three peptides linked to an ergolin ring skeleton and to have different physiological activities. It was examined whether the action to reduce A ⁇ production of bromocriptine is commonly found in these structures, and which structure among similar structures is useful for the action to reduce A ⁇ production.
- bromocriptine structure described in the SMILES format was read into the ChEMBL database (https://www.ebi.ac.uk/chembl/), and a similarity search was performed (http: // www. ebi.ac.uk/chebi/userManualForward.do).
- a compound having high similarity is searched from 1,928,903 compounds registered in DB: ChEMBL_version 21 based on Tanimoto coefficient, and a cutoff is determined as 80% or more, and commercially available alpha-ergocryptine, ergocristine, ergotamine tartrate, The dihydroergocristine mesylate and dihydroergotamine mesylate were extracted, and the action to reduce A ⁇ production was examined (Table 3).
- the compounds of the present invention are useful for the prevention and / or treatment of Alzheimer's disease.
- drugs that have already been marketed as pharmaceuticals for other diseases have clinical and non-clinical data such as safety, etc., and a library of peripheral compounds already exists, so it is inexpensive and quick.
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Abstract
Description
しかし、これらの調節薬は、ADモデルマウスを用いた前臨床試験において大きな成功を得たにもかかわらず、ヒトへ転用した場合、多くの臨床試験において失敗に終わっている。
従って、薬物の安全性の解決と先制治療(早期治療)がAβを標的とする薬剤を有効とするためには重要であると考えらえる。
[1]式(I):
R1は、水素原子又はハロゲン原子を示し;
R2及びR3は、それぞれ独立して、炭素数1~5の直鎖若しくは分岐状のアルキル基又は炭素数6~10のアリール基を示す。〕
で示される化合物又はその塩を含有してなる、アルツハイマー病の予防及び/又は治療剤。
[2]R1が臭素原子である、[1]に記載の剤。
[3]R2がメチル基又はイソプロピル基であり、R3がイソプロピル基、イソブチル基、sec-ブチル基又はベンジル基である、[1]又は[2]に記載の剤。
[4]前記化合物がα-エルゴクリプチン、ブロモクリプチン、エルゴクリスチン、ジヒドロエルゴクリスチン、エルゴタミン及びジヒドロエルゴタミンからなる群より選択される少なくとも1種の化合物又はその塩である、[1]に記載の剤。
[5]前記化合物がブロモクリプチン又はその塩である[4]に記載の剤。
[6]前記アルツハイマー病がプレセニリン1の変異に起因する、[1]~[5]のいずれかに記載の剤。
[7] 哺乳動物に対して、式(I):
R1は、水素原子又はハロゲン原子を示し;
R2及びR3は、それぞれ独立して、炭素数1~5の直鎖若しくは分岐状のアルキル基又は炭素数6~10のアリール基を示す。〕
で示される化合物又はその塩の有効量を投与することを特徴とする、該哺乳動物におけるアルツハイマー病の予防及び/又は治療方法。
[8]アルツハイマー病の予防及び/又は治療における使用のための、式(I):
R1は、水素原子又はハロゲン原子を示し;
R2及びR3は、それぞれ独立して、炭素数1~5の直鎖若しくは分岐状のアルキル基又は炭素数6~10のアリール基を示す。〕
で示される化合物又はその塩。
R1は、水素原子又はハロゲン原子を示し;
R2及びR3は、それぞれ独立して、炭素数1~5の直鎖若しくは分岐状のアルキル基又は炭素数6~10のアリール基を示す。
このようなAPP変異としては、dup APP 変異、APP KM670/671NL 変異、APP D678N 変異、APP E682K 変異、APP A692G 変異、APP E693K 変異、APP E693Q 変異、APP E693G 変異、APP E693del(APP E693Δ) 変異、APP D694N 変異、APP L705V 変異、APP A713T 変異、APP T714A 変異、APP T714I 変異、APP V715M 変異、APP V715A 変異、APP I716V 変異、APP I716F 変異、APP I716T 変異、APP V717I 変異などが挙げられる。
プレセニリン1変異としては、PSEN1 A79V 変異、PSEN1 V82L 変異、PSEN1 ΔI83/M84 変異、PSEN1 L85P 変異、PSEN1 V89L 変異、PSEN1 C92S 変異、PSEN1 V94F 変異、PSEN1 V96F 変異、PSEN1 V97L 変異、PSEN1 F105I 変異、PSEN1 F105L 変異、PSEN1 L113Q 変異、PSEN1 L113P 変異、PSEN1 Intron4; InsTAC 変異、PSEN1 Y115H 変異、PSEN1 Y115D 変異、PSEN1 Y115C 変異、PSEN1 T116N 変異、PSEN1 T116I 変異、PSEN1 P117A 変異、PSEN1 P117S 変異、PSEN1 P117R 変異、PSEN1 P117L 変異、PSEN1 E120K 変異、PSEN1 E120D 変異、PSEN1 E123K 変異、PSEN1 N135D 変異、PSEN1 N135S 変異、PSEN1 A136G 変異、PSEN1 F139V 変異、PSEN1 F139K 変異、PSEN1 F139T 変異、PSEN1 F139I 変異、PSEN1 I143F 変異、PSEN1 I143N 変異、PSEN1 I143T 変異、PSEN1 F146L 変異、PSEN1 F146V 変異、PSEN1 F146I 変異、PSEN1 T147I 変異、PSEN1 L153V 変異、PSEN1 Y154N 変異、PSEN1 Y154C 変異、PSEN1 InsFI 変異、PSEN1 H163Y 変異、PSEN1 H163R 変異、PSEN1 W165G 変異、PSEN1 W165C 変異、PSEN1 L166del 変異、PSEN1 L166H 変異、PSEN1 L166P 変異、PSEN1 L166R 変異、PSEN1 ΔI167変異、PSEN1 ΔI168 変異、PSEN1 S169P 変異、PSEN1 S169L 変異、PSEN1 S170F 変異、PSEN1 L171P 変異、PSEN1 L173W 変異、PSEN1 L173F 変異、PSEN1 L174F 変異、PSEN1 L174R 変異、PSEN1 F177L 変異、PSEN1 F177S 変異、PSEN1 S178P 変異、PSEN1 G183V 変異、PSEN1 E184D 変異、PSEN1 G206S 変異、PSEN1 G206D 変異、PSEN1 G206A 変異、PSEN1 G206V 変異、PSEN1 G209R 変異、PSEN1 G209E 変異、PSEN1 G209V 変異、PSEN1 I213L 変異、PSEN1 I213F 変異、PSEN1 I213T 変異、PSEN1 H214D 変異、PSEN1 H214Y 変異、PSEN1 G217D 変異、PSEN1 L219F 変異、PSEN1 L219P 変異、PSEN1 Q222R 変異、PSEN1 Q222H 変異、PSEN1 Q223R 変異、PSEN1 L226F 変異、PSEN1 L226R 変異、PSEN1 I229F 変異、PSEN1 A231T 変異、PSEN1 A231V 変異、PSEN1 F233L 変異、PSEN1 F233V 変異、PSEN1 F233T 変異、PSEN1 F233I 変異、PSEN1 L235V 変異、PSEN1 L235P 変異、PSEN1 F237I 変異、PSEN1 F237L 変異、PSEN1 T245P 変異、PSEN1 A246E 変異、PSEN1 L248R 変異、PSEN1 L250V 変異、PSEN1 L250S 変異、PSEN1 Y256S 変異、PSEN1 A260V 変異、PSEN1 V261L 変異、PSEN1 V261F 変異、PSEN1 L262F 変異、PSEN1 C263R 変異、PSEN1 C263F 変異、PSEN1 P264L 変異、PSEN1 G266S 変異、PSEN1 P267S 変異、PSEN1 P267L 変異、PSEN1 R269G 変異、PSEN1 R269H 変異、PSEN1 L271V 変異、PSEN1 V272A 変異、PSEN1 E273A 変異、PSEN1 T274R 変異、PSEN1 R278K 変異、PSEN1 R278T 変異、PSEN1 R278I 変異、PSEN1 R278S 変異、PSEN1 E280A 変異、PSEN1 E280G 変異、PSEN1 L282V 変異、PSEN1 L282F 変異、PSEN1 L282R 変異、PSEN1 P284S 変異、PSEN1 P284L 変異、PSEN1 A285V 変異、PSEN1 L286V 変異、PSEN1 L286P 変異、PSEN1 Δ9 変異、PSEN1 Δ9Finn 変異、PSEN1 869-22_869-23ins18 変異、PSEN1 T291P 変異、PSEN1 R358Q 変異、PSEN1 S365A 変異、PSEN1 S365Y 変異、PSEN1 R377F 変異、PSEN1 G378E 変異、PSEN1 G378V 変異、PSEN1 L381V 変異、PSEN1 G384A 変異、PSEN1 F386S 変異、PSEN1 S390I 変異、PSEN1 V391F 変異、PSEN1 L392V 変異、PSEN1 L392P 変異、PSEN1 G394V 変異、PSEN1 N405S 変異、PSEN1 A409T 変異、PSEN1 C410Y 変異、PSEN1 V412I 変異、PSEN1 L418F 変異、PSEN1 L420R 変異、PSEN1 L424V 変異、PSEN1 L424F 変異、PSEN1 L424H 変異、PSEN1 L424R 変異、PSEN1 A426P 変異、PSEN1 A431E 変異、PSEN1 A431V 変異、PSEN1 A434C 変異、PSEN1 L435F 変異、PSEN1 P436S 変異、PSEN1 P436Q 変異、PSEN1 I439V 変異、PSEN1 ΔT440 変異などが挙げられる。
プレセニリン2変異としては、PSEN2 R71W 変異、PSEN2 A85V 変異、PSEN2 T122P 変異、PSEN2T122R 変異、PSEN2 N141I 変異、PSEN2 V148I 変異、PSEN2 F174V 変異、PSEN2 S175C 変異、PSEN2 Y231C 変異、PSEN2 Q228L 変異、PSEN2 F239V 変異、PSEN2 F239I 変異、PSEN2 T430F 変異、PSEN2 D439A 変異などが挙げられる。
1.神経細胞の作製
プレセニリン1遺伝子にG384Aヘテロ接合変異を持つ家族性アルツハイマー病患者から樹立したiPS細胞から、大脳皮質神経細胞を分化誘導しアッセイに用いた。大脳皮質神経細胞分化誘導するため、iPS細胞にNeurogenin2遺伝子を導入し、ドキシサイクリンを添加して5日間一過的に発現させることにより、ヒトiPS細胞を大脳皮質神経へと分化させた。
表2の化合物は全て、DMSOに25 mMで溶解し使用した。
大脳皮質神経細胞を、96 well plate(CORNING社Edge plate)に、10万細胞/wellで播種したのち3日目に、培地を全量交換し、その際に各種各濃度の化合物を添加した。48時間後に培地を回収し、400 g 5分間の遠心処理により死細胞の混入を防ぎ、-80℃で、Aβ測定まで保存した。
培養上清中の微量Aβ測定には、SECTOR Imager 2400(Meso Scale Discovery, U.S.A)を検出装置として使用し、SULFO-TAG標識抗体を電気化学発光法により検出し定量化した。-80℃で凍結していた培養上清25 μLを氷上で解凍し、Human (6E10) Abeta 3-Plex Base Kit(Meso Scale Discovery, U.S.A)のキットプロトコルに従い、Aβ1-40, 1-42の培養上清中濃度をそれぞれ測定した。
家族性アルツハイマー病(Alzheimer’s disease: AD)患者より樹立した人工多能性幹細胞(induced pluripotent stem cell: iPS細胞)から、大脳皮質神経細胞を高純度かつ再現性の高い迅速法で分化誘導した。この神経細胞を用いて、ADの病原物質であるアミロイドベータ蛋白(amyloid beta: Aβ)の代謝動態をモニタリングする実験系を構築した。このAD患者由来大脳皮質神経細胞は、家族性ADの原因遺伝子であるPSEN1にG384Aヘテロ接合体変異を持つため、毒性Aβとして知られるAβ42サブタイプの産生が増加し、最も存在量の多いAβ40サブタイプの産生に対する比率ratio Aβ42/40が高い。この実験系を用いて、既存薬ライブラリーのスクリーニング解析を実施し、Aβ産生を減少させる薬剤を探索した。探索の結果、ブロモクリプチン(bromocriptine mesylate)添加が、Aβの産生を減らすことを見出した(図1)。Aβ低下作用は、Aβ40よりもAβ42サブタイプの産生を効率的に低下させ、結果としてAβ42/40比率を低下させた(図1)。
ブロモクリプチンは、ドパミン受容体(dopaminergic receptor: DR)に対してアゴニスト作用を持つことから、パーキンソン病治療薬として認可されている。ドパミン受容体刺激作用がAβ産生低下に働くかどうか、あるいはブロモクリプチンの構造自体がドパミン受容体を介さない作用機序でAβ産生を低下させるかどうかを決定するため、以下の検討を行った。
ブロモクリプチンはDRのうち、2型DR(dopamine receptor type 2: D2R)に高い親和性を持ち、D2R選択性が高い。そこで、D2R以外のDRサブタイプを刺激することでAβ産生が変化するかどうか検討した。1型及び5型に選択的なDRアゴニストであるSKF38393、4型DRに選択的DRアゴニストであるPD168077、さらに非選択的DRアゴニストであるドパミン塩酸塩を、それぞれ0.0016, 0.008, 0.04, 0.2, 1, 5, 25 μMの濃度で大脳皮質神経細胞に添加した。しかし、いずれの化合物もAβ産生を変化させなかった(図1)。この結果から、1型DR、4型、5型DRの刺激は、Aβ産生に関与しないことが特定された。
次に、ブロモクリプチンのAβ産生低下作用は、D2Rアゴニスト作用によるものか、D2R刺激経路以外によるものかを探索した。ブロモクリプチンはその構造骨格の特性から麦角系D2Rアゴニストとして分類される。一方で、麦角構造を持たない非麦角系D2Rアゴニストも同様にパーキンソン病治療薬として広く臨床応用されているが、ブロモクリプチンとは化合物構造が大きく異なる。非麦角系D2Rアゴニストとして、Talipexole (B-HT 920 dihydrochloride)、Pramipexole dihydrochloride、Ropinirole hydrochlorideを、それぞれ0.0016, 0.008, 0.04, 0.2, 1, 5, 25 μMの濃度で大脳皮質神経細胞に添加した。しかし、いずれの化合物もAβ産生を変化させなかった(図2)。
一方で、麦角系D2Rアゴニストとして、Cabergoline、Pergolide mesylateを、0.0016, 0.008, 0.04, 0.2, 1, 5, 25 μMの濃度で大脳皮質神経細胞に添加した。すると、Cabergolineは25 μMで、Pergolide mesylateは5, 25 μMでAβ産生低下作用を示した(図3)。
麦角系D2Rアゴニストであるブロモクリプチンは、エルゴリン環構造にプロリン・バリン・ロイシンの3つのペプチドが結合したペプチド型アルカロイド構造を持つ。ペプチド型アルカロイド構造は、エルゴリン環骨格に結合した3つのペプチドの組合せで様々な類似化合物が存在し異なる生理活性を持つことが知られている。ブロモクリプチンのAβ産生低下作用が、これらの構造に共通して見られるか、また類似構造のうちどの構造がAβ産生低下作用にとって有用であるか検討した。
さらに、ペプチド型アルカロイド構造に含まれる3つのペプチドの組み合わせについては、Aβ産生低下作用の軽重に大きな影響はなく、ergocristine(プロリン・バリン・フェニルアラニン)、ergotamine tartrate(プロリン・アラニン・フェニルアラニン)、dihydroergocristine mesylate(プロリン・バリン・フェニルアラニン)、dihydroergotamine mesylate(プロリン・アラニン・フェニルアラニン)は同様にAβ産生低下作用を示した。
Claims (8)
- R1が臭素原子である、請求項1に記載の剤。
- R2がメチル基又はイソプロピル基であり、R3がイソプロピル基、イソブチル基、sec-ブチル基又はベンジル基である、請求項1又は2に記載の剤。
- 前記化合物がα-エルゴクリプチン、ブロモクリプチン、エルゴクリスチン、ジヒドロエルゴクリスチン、エルゴタミン及びジヒドロエルゴタミンからなる群より選択される少なくとも1種の化合物又はその塩である、請求項1に記載の剤。
- 前記化合物がブロモクリプチン又はその塩である、請求項4に記載の剤。
- 前記アルツハイマー病がプレセニリン1の変異に起因する、請求項1~5のいずれか1項に記載の剤。
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