WO2021235293A1 - Ｃｕｇリピート配列の結合剤 - Google Patents

Ｃｕｇリピート配列の結合剤 Download PDF

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WO2021235293A1
WO2021235293A1 PCT/JP2021/018079 JP2021018079W WO2021235293A1 WO 2021235293 A1 WO2021235293 A1 WO 2021235293A1 JP 2021018079 W JP2021018079 W JP 2021018079W WO 2021235293 A1 WO2021235293 A1 WO 2021235293A1
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compound
group
repeat
cug
disease
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French (fr)
Japanese (ja)
Inventor
和彦 中谷
惇 松本
竜政 岡本
主税 堂野
亜沙子 清家
雅之 中森
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University of Osaka NUC
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Osaka University NUC
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Priority to US17/925,225 priority Critical patent/US20230193265A1/en
Priority to JP2022524409A priority patent/JPWO2021235293A1/ja
Priority to EP21809693.1A priority patent/EP4154886A4/en
Publication of WO2021235293A1 publication Critical patent/WO2021235293A1/ja
Anticipated expiration legal-status Critical
Priority to JP2026001566A priority patent/JP2026065050A/ja
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a novel CUG repeat sequence binder and the like.
  • Repeat disease is a hereditary neurological disorder that develops due to an abnormal elongation of a repeating (repeat) sequence of three bases on a gene.
  • myotonic dystrophy type 1 which is a type of repeat disease
  • DM1 myotonic dystrophy type 1
  • DMPK myotonic dystrophy protein kinase
  • the onset cause of DM1 is a decrease in protein function due to binding and aggregation of RNA having a CUG repeat sequence (CUG repeat RNA), which is transcribed from an abnormally elongated CTG repeat sequence, to an RNA-binding protein. It is believed that.
  • Non-Patent Documents 1 to 3 a molecule that dissociates RNA-binding protein from an aggregate of CUG repeat RNA and RNA-binding protein by binding to CUG repeat RNA is a useful molecular tool for research on DM1 treatment.
  • An object of the present invention is to provide a novel CUG repeat sequence binder.
  • Another object of the present invention is to provide a novel therapeutic and / or preventive agent for repeat diseases.
  • the inventors have also found a novel compound containing a specific structural unit. Further, they have found that such a novel compound is good even in light of the above-mentioned specific index, and further studied to complete the present invention.
  • Binder of CUG repeat sequence (binder to CUG repeat sequence) comprising compound A having a resonance unit of 10 RU or greater as measured by surface plasmon resonance at a concentration of 25 nM, an RNA immobilization amount of 401 RU at (CUG) 9.
  • a therapeutic and / or prophylactic agent for repeat diseases comprising Compound A having a resonance unit of 10 RU or greater as measured by surface plasmon resonance at a concentration of 25 nM, an RNA immobilization amount of 401 RU at (CUG) 9.
  • Compound A which has a resonance unit of 10 RU or more as measured by surface plasmon resonance at a concentration of 25 nM and an RNA immobilization amount of 401 RU of (CUG) 9, as a therapeutic and / or prophylactic agent for repeat diseases.
  • [17] A method for treating and / or preventing repeat disease, wherein compound A having a resonance unit of 10 RU or more as measured by surface plasmon resonance at a concentration of 25 nM and an RNA immobilization amount of (CUG) of 9 is administered to animals including humans.
  • a novel binder for a CUG repeat sequence can be provided.
  • Such agents can ameliorate splicing abnormalities due to repeat disease (eg, DM1 and the like).
  • a novel therapeutic and / or preventive agent for repeat disease can be provided. Since such agents can bind to the CUG repeat sequence, they treat diseases caused by CUG repeats, which are transcripts of abnormally stretched CTG repeats (or diseases caused by abnormal stretches of CTG repeats, CTG repeat diseases). And / or can be prevented. Moreover, since such an agent can bind to the CUG repeat sequence, it can treat and / or prevent a disease (CAG repeat disease) caused by abnormal elongation of CAG repeat, which is a complementary strand of CTG repeat.
  • CAG repeat disease a disease caused by abnormal elongation of CAG repeat
  • a novel compound can be provided.
  • a novel therapeutic and / or prophylactic agent for repeat diseases may be provided.
  • Example 1 It is the SPR measurement result in Example 1. It is the SPR measurement result in Example 2. It is a figure showing the normal splicing in Atp2a1 (sarcoplasmic reticulum Ca 2+ / ATPase gene) and the splicing in a DM1 patient. It is an evaluation result in Example 3. This is the evaluation result in Reference Example 1. It is a figure showing the normal splicing in Clcn1 (muscle-specific chloride channel gene) and the splicing in a DM1 patient. It is an evaluation result in Example 4. This is the evaluation result in Reference Example 2.
  • the agent of the present invention is compound A having a resonance unit (hereinafter, may be simply referred to as “index A”) measured by surface plasmon resonance at a concentration of 25 nM and an RNA immobilization amount of (CUG) of 9 of 401 RU or more. including.
  • index A a resonance unit measured by surface plasmon resonance at a concentration of 25 nM and an RNA immobilization amount of (CUG) of 9 of 401 RU or more.
  • the measurement of surface plasmon resonance may be carried out at a compound concentration of 25 nM and an RNA immobilization amount of (CUG) 9 of 401 RU, or by calculation using values measured at other compound concentrations and / or RNA immobilization amounts. It may be calculated.
  • the resonance unit measured at the compound concentration Y (nM) and the RNA immobilization amount Z (RU) of (CUG) 9 is W (RU)
  • the formula W ⁇ (401 / Z) ⁇ (25 / Y) is used.
  • Compound concentration 25 nM, (CUG) 9 RNA immobilization amount 401 RU resonance unit can be calculated.
  • Surface plasmon resonance can be measured, for example, by the method described below.
  • a surface plasmon resonance measuring device for example, BIAcore T200 (manufactured by GE Healthcare) can be used.
  • the sensor chip for surface plasmon resonance measurement for example, a sensor chip coated with streptavidin can be used.
  • a measurement buffer for surface plasmon resonance measurement for example, a HEPES buffer (for example, a sodium chloride solution of a HEPES buffer such as a 500 mM sodium chloride solution of a 10 mM HEPES buffer) can be used.
  • the compound A among the compounds having the index A of 10 RU or more, if the response curve of surface plasmon resonance does not show abrupt dissociation but shows dissociation after maintaining a bound state to some extent. , CUG repeat binding can be better achieved.
  • the agent of the present invention can function as a binder for CUG repeat sequences, a therapeutic and / or preventive agent for repeat diseases, and the like.
  • the agent of the present invention may have one or more compounds A.
  • the index A is usually 10 RU or more, and preferably 11 RU or more (for example, 12 RU or more, 13 RU or more, etc.).
  • the index A is 10 RU or more
  • normal splicing is likely to be performed in Atp2a1 (sarcoplasmic reticulum Ca 2+ / ATPase gene) or the like, and thus it can be effective in the treatment and / or prevention of repeat diseases.
  • the skeleton capable of forming a hydrogen bond complementary to uracil, the aromatic ring (and the type of its substituent), the number of these, and the like are likely to be factors that increase the value of the index A. ..
  • a compound having a skeleton or the like that causes such a factor is suitably used (or used) as a skeleton (or a raw material or a precursor, for example, JM608 described later) or the like that constitutes a part of the compound A in addition to the compound A. ) It is possible.
  • Examples of the compound A include those having a hydrogen bonding group (for example, a proton donor, a proton acceptor, etc.).
  • the hydrogen bond group may be a hydrogen bond donor (or a proton donor), a hydrogen bond acceptor (or a proton acceptor), or the like.
  • Compound A may have one or more hydrogen bonding groups. Further, the compound A may have one or more hydrogen bonding groups.
  • the hydrogen bond donor group (or proton donor) is a group having an H atom bonded to an atom having a high electronegativity (for example, an atom having an electronegativity of 3 or more in polling such as an N atom or an O atom). It may be there.
  • Examples of the hydrogen bond donating group include -NH- group, -NH 2 group, -OH and the like.
  • the number of hydrogen bond donor groups may be, for example, one or more (for example, two or more), preferably three or more.
  • the hydrogen bond accepting group may be a group having an atom having an unshared electron pair (for example, an N atom, an O atom, etc.) (for example, a carbonyl group, etc.).
  • the number of hydrogen bond accepting groups may be, for example, one or more, preferably two or more.
  • a compound having a skeleton capable of forming a hydrogen bond complementary to uracil is preferably mentioned.
  • the number of hydrogen bonds may be, for example, one or more, preferably two or more, and more preferably three or more.
  • Compound A may be positively charged (cationic) when dissolved in water.
  • the molecule of compound A may be basic.
  • the basic group of the compound A may be, for example, an amino group or the like.
  • the number of basic groups is not particularly limited, and is, for example, 1 or more (for example, 1 to 10, 1 to 7, 1 to 5, 1 to 3, etc.), 2 or more (for example, 2 to 2 to 3). 10 pieces, 2 to 7 pieces, 2 to 5 pieces, 2 to 3 pieces, etc.) may be used.
  • Examples of the compound A include those having an amide bond (-CONH-), those having an aromatic ring, those having a structure of the following formula (1) in which an amide bond and an aromatic ring are bonded, and the like.
  • Equation (1) (In the formula, Z represents an aromatic ring.)
  • Z may be an aromatic ring, a hydrocarbon-based aromatic ring, or a heterocycle.
  • the number of members of Z is not particularly limited and may be, for example, 3 to 12 (for example, 4 to 12). Further, Z may be a monocyclic ring or a condensed ring.
  • the heteroatom is not particularly limited, and examples thereof include a nitrogen atom, an oxygen atom, a sulfur atom and the like, and preferably a nitrogen atom, an oxygen atom and the like.
  • the heterocycle may have one or more heteroatoms. Further, in the heterocycle, the number of heteroatoms is not particularly limited, and may be, for example, one or more (for example, 1 to 5, 1 to 3, etc.).
  • the bonding location of the heteroatom is not particularly limited.
  • Z may have a substituent.
  • the substituent is not particularly limited, and is, for example, an alicyclic group, an aromatic ring group, a hydrocarbon group [for example, an alkyl group (for example, a C 1-5 alkyl group such as a methyl group or an ethyl group), an alkenyl group (for example).
  • C 2-5 alkenyl group such as ethyl group and propenyl group
  • alkynyl group for example, C 2-5 alkynyl group such as ethynyl group and propynyl group
  • amino group, nitro group and the like can be mentioned.
  • Those having a ring structure (for example, an alicyclic group, an aromatic ring group, etc.) are preferable.
  • the ring structure may be a hydrocarbon system or a heterocycle.
  • the number of ring members is not particularly limited and may be, for example, 3 to 10 (for example, 4 to 8 or the like).
  • the number of substituents in Z may be one or two or more. Further, the substituent may be one kind or two or more kinds.
  • the position of the substituent is not particularly limited, but it is preferably bonded to a carbon atom.
  • Specific examples of the compound A having the structure of the formula (1) include compounds having one or more structural units of the following formula (1A) (wherein R 1 represents a substituent). ..
  • R 1 is not particularly limited, and examples thereof include a substituent of Z exemplified above.
  • the R 1, preferably, an aromatic Hajime Tamaki (e.g., a hydrocarbon aromatic ring group, aromatic heterocyclic group, etc.), an alkynyl group (e.g., ethynyl group, such as C 2-5 alkynyl group such as propynyl group), amino Groups, nitro groups and the like can be mentioned.
  • a repeat sequence for example, CUG repeat
  • compound A bound to the repeat sequence and a base pair for example, a GC base pair in CUG repeat
  • Aromatic ring groups are particularly preferable from the viewpoint that compound A can be easily immobilized on a repeat sequence (or RNA having a repeat sequence) due to its properties and bulkiness.
  • heteroaromatic ring group examples include a pyridinyl group, a pyrimidinyl group, a pyrazinyl group, a pyrrolyl group, a furanyl group and the like.
  • hydrocarbon-based aromatic ring group examples include an aryl group (for example, a phenyl group, a tolyl group, a xylyl group, a naphthyl group, etc.).
  • R 1 may further have a substituent (a).
  • the number of substituents (a) may be one or two or more. Further, the substituent (a) may be one kind or two or more kinds.
  • the position of the substituent (a) is not particularly limited, but it is preferably bonded to a carbon atom.
  • substituent (a) examples include the substituent in the above-exemplified Z, and the compound A can be added to the repeat sequence (or the RNA having the repeat sequence) by having a certain degree of rigidity and bulkiness.
  • an alicyclic heterocyclic group for example, a group derived from an alicyclic amine or the like is preferable.
  • R 1 for example, the following structure (group) and the like can be mentioned.
  • X represents a substituent (a) and n represents an integer of 0 or 1 or more.
  • n 2 or more, the substituents may be the same or different substituents.
  • the upper limit of the number n of the substituent (a) can be selected according to the type of the group (aromatic ring group) to be substituted. For example, the upper limit may be 4 when the group to be substituted is pyridyl, and may be 3 when the group to be substituted is frill (franyl).
  • n may be typically 0 to 3, preferably 0 to 2, more preferably 0 or 1, and particularly 1.
  • R 1 preferably, the following structure (group) and the like can be mentioned.
  • the number of the structural units of the formula (1A) may be one or more in the compound A, but two of them from the viewpoint of easily satisfying the index A and the like.
  • the above for example, 2 to 5 pieces, etc.), 3 or more pieces, etc. are preferable.
  • each structural unit may be directly bonded or may be bonded via a linking group.
  • the linking group is not particularly limited, but is, for example, a heteroatom-containing group [for example, an ether group (-O-), a thioether group (-S-), a carbonyl group (-CO-), a thiocarbonyl group (-CS-). ), Imino group (-NH-), amide group (-NCO-), carbamoyl group (-NCOO-), etc.], hydrocarbon group ⁇ eg, saturated or unsaturated hydrocarbon group [eg, alkylene or alkylidene group (eg, alkylene or alkylidene group).
  • C 1-10 alkylene or alkylidene group such as methylene group, ethylene group, trimethylene group, propylene group, tetramethylene group
  • cycloalkylene or cycloalkylidene group for example, cyclopropylene group, cyclobutylene group, cyclohexylene group, etc.
  • C 3-10 cycloalkylene or cycloalkylidene group alkenylene group (eg, C 2-10 alkenylene group such as vinylene group), etc.]
  • arylene group eg, C 6-10 arylene group such as phenylene group
  • the molecular weight of compound A is not particularly limited, but may be, for example, 200 or more, preferably 300 or more, and more preferably 400 or more.
  • Compound A having the structural unit of the formula (1A) can be produced by using a known organic synthesis method.
  • the method for linking each structural unit is not particularly limited, and the compound A can be linked using a known organic synthesis method.
  • the present invention also includes novel compounds.
  • the novel compound include a compound in which Z is a complex condensed ring in the above formula (1), a compound having one or more structural units of the above formula (1A), and the like.
  • the compound having one structural unit of the formula (1A) can be a raw material of the compound having two or more of the structural units. The compound does not have to satisfy the index A of 10 RU or more.
  • the method for measuring surface plasmon resonance is not particularly limited, and may be measured by a conventional method.
  • Examples of the surface plasmon resonance measuring device include BIAcore T200 (manufactured by GE Healthcare) described in Examples described later.
  • examples of the sensor chip include a sensor chip (SA chip) coated with streptavidin.
  • examples of the measurement buffer include a HEPES buffer (for example, a sodium chloride solution of a HEPES buffer such as a 500 mM sodium chloride solution of a 10 mM HEPES buffer).
  • a HEPES buffer for example, a sodium chloride solution of a HEPES buffer such as a 500 mM sodium chloride solution of a 10 mM HEPES buffer.
  • examples of the activation buffer include 50 mM NaOH and 1M NaCl buffers.
  • Examples of the repeat disease targeted by the agent of the present invention include diseases caused by abnormal elongation of CTG repeat (CTG repeat disease) [for example, muscle tonic dystrophy type 1 and Huntington's disease-like disease 2 (Huntington's disease-like 2). ), Spinal cerebral degeneration type 8, Fuchs endothelial corneal dystrophy, etc.], Diseases caused by abnormal elongation of CAG repeat (CAG repeat disease) [For example, Huntington's disease, spinal muscle atrophy (spinal) And bulbar muscle attack), spinal cord cerebral degeneration type 2 etc.] and the like.
  • CTG repeat disease for example, muscle tonic dystrophy type 1 and Huntington's disease-like disease 2 (Huntington's disease-like 2).
  • CAG repeat disease Diseases caused by abnormal elongation of CAG repeat
  • CAG repeat disease Huntington's disease, spinal muscle atrophy (spinal) And bulbar muscle attack
  • spinal cord cerebral degeneration type 2 etc. and the like.
  • the target repeat disease may be one type or two or more types.
  • the form of the agent of the present invention is not particularly limited, but may be, for example, an injection, an eye drop, or the like.
  • the agent of the present invention is an injection or an eye drop
  • the agent of the present invention is, if necessary, various commonly used additives (eg, pH adjuster, buffer) in addition to compound A. , Stabilizer, isotonic agent, local anesthetic, etc.) may be contained.
  • Injections or eye drops can be prepared by a conventional method by adding various additives to compound A.
  • Examples of the pH adjuster and buffer include sodium citrate, sodium acetate, sodium phosphate, sodium phosphate and the like.
  • Examples of the stabilizer include sodium metabisulfite, ethylenediaminetetraacetic acid (EDTA), thioglycolic acid, thiolactic acid and the like.
  • Examples of the local anesthetic include procaine hydrochloride, lidocaine hydrochloride and the like.
  • Examples of the tonicity agent include sodium chloride, glucose and the like.
  • the additive may be used alone or in combination of two or more.
  • the content of compound A is not particularly limited and may be appropriately set according to the dose range, the number of doses, and the like.
  • the administration method of the agent of the present invention is not particularly limited, and examples thereof include intravenous administration, intramuscular administration, subcutaneous administration, intrathecal administration, and nasal administration.
  • the dose range of the agent of the present invention is not particularly limited, and is appropriately set according to the administration form, administration method, type of disease, subject properties (body weight, age, medical condition, presence / absence of use of other drugs, etc.) and the like. You can do it.
  • r (CUG) 9 manufactured by Thermo Fisher Scientific Inc.
  • HEPES buffer 10 mM HEPES and 500 mM NaCl
  • the r (CUG) 9 immobilized on the surface of the sensor chip was 401RU.
  • the surface plasmon resonance was measured using a BIAcore T200 SPR system (manufactured by GE Healthcare).
  • r (CUG) 9 the one having the following arrangement was used.
  • Example 1 To carry out the single cycle kinetics (SCK) method, the surface of the sensor chip was prepared by flowing HBS-EP + buffer at 30 ⁇ L / min for 120 seconds at 25 ° C., and then compound JM608 was added at a concentration of 0.063 ⁇ M. , 0.125 ⁇ M, 0.25 ⁇ M, 0.50 ⁇ M and 1.0 ⁇ M in HBS-EP + buffer, and the resulting solution was applied to the sensor surface at 30 ⁇ L / min per cycle for 60 seconds each. , Sequentially injected. The obtained SPR response curve was analyzed using BIAcore T200 evaluation software (version 2.0). The results are shown in FIG.
  • Example 2 SPR measurement was carried out in the same manner as in Example 1 except that compound JM642 was used instead of compound JM608 and the compounds JM642 were sequentially injected so as to have concentrations of 6 nM, 13 nM, 25 nM, 50 nM and 100 nM. The results are shown in FIG.
  • Example 2 the resonance units at each compound concentration of 25 nM are shown in Table 2.
  • Example 1 the measured value (1.9 RU) at a compound concentration of 63 nM was used, and the resonance unit at a compound concentration of 25 nM was calculated by the formula 1.9 RU ⁇ (25 nM / 63 nM).
  • RNA extraction from tissue, cDNA synthesis, and polymerase chain reaction were performed by Ann. Clin. Transl. Neurol. The method described in 2016, 3, 42-54 was performed.
  • the PCR product was separated by agarose gel electrophoresis and the gel was stained with GelRed (manufactured by Biotium). Gels were imaged using a Typhoon laser fluoroimager (manufactured by GE Healthcare) and gel bands were quantified using ImageQuant (manufactured by GE Healthcare).
  • total RNA extraction, cDNA synthesis, and PCR were performed on mice under the same conditions as above except that JM642 was not administered, and normal mice, and the PCR product was electrophoresed in the same manner as above. rice field. The results are shown in FIG.
  • exon 22 is taken up (residual) under normal splicing (Wild Type in FIG. 3), but Exon 22 is not taken up in DM1 patients.
  • FIG. 4 when the compound JM642 was administered to the DM1 mouse model, the residual rate of Exon22 (ex22) in Atp2a1 was high.
  • Example 3 (residual rate 70%) is the same as Reference Example 1 (residual rate 30%).
  • the splicing abnormality of DM1 could be further improved.
  • Example 4 Evaluation of Clcn1 (muscle-specific chloride channel gene) Evaluation was carried out in the same manner as in Example 3 except that Clcn1 was used instead of Atp2a1. The results are shown in FIG.
  • Exon7a is not taken up by normal splicing (Wild Type), but Exon7a is taken up in DM1 patients.
  • Wild Type normal splicing
  • Exon7a is taken up in DM1 patients.
  • FIG. 7 when compound JM642 was administered to the DM1 mouse model, the skip rate of Exon7a (ex7a) in Clcn1 was high.
  • Example 4 skip rate 70%
  • Reference Example 2 skip rate 60%
  • the splicing abnormality of DM1 could be further improved.
  • an agent or the like useful as a therapeutic and / or preventive agent for repeat diseases.

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US17/925,225 US20230193265A1 (en) 2020-05-20 2021-05-12 Cug repeat sequence binding agent
JP2022524409A JPWO2021235293A1 (https=) 2020-05-20 2021-05-12
EP21809693.1A EP4154886A4 (en) 2020-05-20 2021-05-12 CUG REPEAT SEQUENCE BINDER
JP2026001566A JP2026065050A (ja) 2020-05-20 2026-01-07 Ｃｕｇリピート配列の結合剤

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JPWO2022230924A1 (https=) * 2021-04-30 2022-11-03

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140050778A1 (en) * 2010-12-28 2014-02-20 University Of Rochester Nucleic acid binding compounds, methods of making, and use thereof
US20160206753A1 (en) * 2013-08-29 2016-07-21 The Scripps Research Institute Modularly assembled small molecules for the treatment of myotonic dystrophy type 1
JP2019514938A (ja) * 2016-04-27 2019-06-06 サミュメッド リミテッド ライアビリティ カンパニー イソキノリン−３イル−カルボキサミドならびにその調製および使用の方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080194557A1 (en) * 2007-01-18 2008-08-14 Joseph Barbosa Methods and compositions for the treatment of pain, inflammation and cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140050778A1 (en) * 2010-12-28 2014-02-20 University Of Rochester Nucleic acid binding compounds, methods of making, and use thereof
US20160206753A1 (en) * 2013-08-29 2016-07-21 The Scripps Research Institute Modularly assembled small molecules for the treatment of myotonic dystrophy type 1
JP2019514938A (ja) * 2016-04-27 2019-06-06 サミュメッド リミテッド ライアビリティ カンパニー イソキノリン−３イル−カルボキサミドならびにその調製および使用の方法

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
ANN. CLIN. TRANSL. NEUROL., vol. 3, 2016, pages 42 - 54
BIOORG. MED. CHEM. LETT., vol. 26, 2016, pages 3761 - 3764
CHEM. EUR. J., vol. 22, 2016, pages 14881 - 14889
CHEM. EUR. J., vol. 24, 2018, pages 18115 - 18122
LÓPEZ-MORATÓ MARTA, BROOK JOHN DAVID, WOJCIECHOWSKA MARZENA: "Small Molecules Which Improve Pathogenesis of Myotonic Dystrophy Type 1", FRONTIERS IN NEUROLOGY, vol. 9, 349, 18 May 2018 (2018-05-18), pages 1 - 12, XP055875495, DOI: 10.3389/fneur.2018.00349 *
MATSUMOTO JUN, NAKAMORI MASAYUKI, OKAMOTO TATSUMASA, MURATA ASAKO, DOHNO CHIKARA, NAKATANI KAZUHIKO: "The Dimeric Form of 1,3- Diaminoisoquinoline Derivative Rescued the Mis- splicing of Atp2al and Clcnl Genes in Myotonic Dystrophy Type 1 Mouse Model", CHEMISTRY-A EUROPIAN JOURNAL, vol. 26, no. 63, 11 November 2020 (2020-11-11), DE, pages 14305 - 14309, XP055875497, ISSN: 0947-6539, DOI: 10.1002/chem.202001572 *
REDDY KAALAK, JENQUIN JANA R., CLEARY JOHN D., BERGLUND J. ANDREW: "Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 20, no. 16, 4017, 17 August 2017 (2017-08-17), pages 1 - 20, XP055875496, DOI: 10.3390/ijms20164017 *
SCIENCE, vol. 289, 2000, pages 1769 - 1772
See also references of EP4154886A4
VO TAM; PAUL ANANYA; KUMAR ARVIND; BOYKIN DAVID W; WILSON W DAVID: "Biosensor-surface plasmon resonance: A strategy to help establish a new generation RNA-specific small molecules", METHODS, vol. 167, 2019, pages 15 - 27, XP085831363, ISSN: 1046-2023, DOI: 10.1016/j.ymeth.2019.05.005 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2022230924A1 (https=) * 2021-04-30 2022-11-03
WO2022230924A1 (ja) * 2021-04-30 2022-11-03 国立大学法人大阪大学 筋強直性ジストロフィー１型治療薬
JP7461687B2 (ja) 2021-04-30 2024-04-04 エディットフォース株式会社 筋強直性ジストロフィー１型治療薬
JP2024069430A (ja) * 2021-04-30 2024-05-21 エディットフォース株式会社 筋強直性ジストロフィー１型治療薬
JP7854207B2 (ja) 2021-04-30 2026-05-01 エディットフォース株式会社 筋強直性ジストロフィー１型治療薬

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