JPWO2022159712A5 - - Google Patents

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Publication number

JPWO2022159712A5

JPWO2022159712A5 JP2023544331A JP2023544331A JPWO2022159712A5 JP WO2022159712 A5 JPWO2022159712 A5 JP WO2022159712A5 JP 2023544331 A JP2023544331 A JP 2023544331A JP 2023544331 A JP2023544331 A JP 2023544331A JP WO2022159712 A5 JPWO2022159712 A5 JP WO2022159712A5

Authority

JP

Japan

Prior art keywords

modified oligonucleotide

seq

modified

nucleobases

sugar moiety

Prior art date

2025-01-24

Legal status (The legal status 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 status listed.)

Pending

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• 108091034117 Oligonucleotide Proteins 0.000 claims description 173
• 239000002777 nucleoside Substances 0.000 claims description 124
• 150000001875 compounds Chemical class 0.000 claims description 122
• 125000003835 nucleoside group Chemical group 0.000 claims description 102
• 125000003342 alkenyl group Chemical group 0.000 claims description 56
• 125000000217 alkyl group Chemical group 0.000 claims description 32
• RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 31
• FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 26
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
• 230000000692 anti-sense effect Effects 0.000 claims description 25
• 239000003795 chemical substances by application Substances 0.000 claims description 25
• 125000002619 bicyclic group Chemical group 0.000 claims description 23
• 239000008194 pharmaceutical composition Substances 0.000 claims description 21
• 102100021158 Double homeobox protein 4 Human genes 0.000 claims description 19
• 101000968549 Homo sapiens Double homeobox protein 4 Proteins 0.000 claims description 19
• 230000000295 complement effect Effects 0.000 claims description 17
• 150000003833 nucleoside derivatives Chemical class 0.000 claims description 16
• 201000010099 disease Diseases 0.000 claims description 13
• 208000035475 disorder Diseases 0.000 claims description 13
• JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Chemical class Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 12
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical group P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims description 10
• 239000002953 phosphate buffered saline Substances 0.000 claims description 10
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
• 150000004713 phosphodiesters Chemical class 0.000 claims description 8
• -1 6-palmitamidohexyl Chemical group 0.000 claims description 7
• 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 claims description 6
• 102100034343 Integrase Human genes 0.000 claims description 6
• 101710203526 Integrase Proteins 0.000 claims description 6
• 230000004048 modification Effects 0.000 claims description 6
• 238000012986 modification Methods 0.000 claims description 6
• 108020004707 nucleic acids Proteins 0.000 claims description 6
• 150000007523 nucleic acids Chemical class 0.000 claims description 6
• 102000039446 nucleic acids Human genes 0.000 claims description 6
• LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical group CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 5
• 208000037149 Facioscapulohumeral dystrophy Diseases 0.000 claims description 5
• 230000003213 activating effect Effects 0.000 claims description 5
• 208000008570 facioscapulohumeral muscular dystrophy Diseases 0.000 claims description 5
• 150000003839 salts Chemical class 0.000 claims description 5
• 125000006538 C11 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 208000010428 Muscle Weakness Diseases 0.000 claims description 4
• 206010028289 Muscle atrophy Diseases 0.000 claims description 4
• 206010028372 Muscular weakness Diseases 0.000 claims description 4
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
• 201000000585 muscular atrophy Diseases 0.000 claims description 4
• 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 4
• 208000024891 symptom Diseases 0.000 claims description 4
• 230000008685 targeting Effects 0.000 claims description 4
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
• 239000011575 calcium Substances 0.000 claims description 3
• 229910052791 calcium Inorganic materials 0.000 claims description 3
• 150000001768 cations Chemical class 0.000 claims description 3
• 239000011777 magnesium Substances 0.000 claims description 3
• 229910052749 magnesium Inorganic materials 0.000 claims description 3
• 239000011591 potassium Substances 0.000 claims description 3
• 229910052700 potassium Inorganic materials 0.000 claims description 3
• 239000011734 sodium Substances 0.000 claims description 3
• 229910052708 sodium Inorganic materials 0.000 claims description 3
• 208000035657 Abasia Diseases 0.000 claims description 2
• 108091030071 RNAI Proteins 0.000 claims description 2
• 101150084233 ago2 gene Proteins 0.000 claims description 2
• FBWJHGIUUCOZRM-UHFFFAOYSA-N cyclopropylphosphonic acid Chemical compound OP(O)(=O)C1CC1 FBWJHGIUUCOZRM-UHFFFAOYSA-N 0.000 claims description 2
• 230000001934 delay Effects 0.000 claims description 2
• ZTWTYVWXUKTLCP-UHFFFAOYSA-L ethenyl-dioxido-oxo-$l^{5}-phosphane Chemical compound [O-]P([O-])(=O)C=C ZTWTYVWXUKTLCP-UHFFFAOYSA-L 0.000 claims description 2
• 230000001815 facial effect Effects 0.000 claims description 2
• 230000009368 gene silencing by RNA Effects 0.000 claims description 2
• 210000003205 muscle Anatomy 0.000 claims description 2
• 201000006938 muscular dystrophy Diseases 0.000 claims description 2
• 230000001668 ameliorated effect Effects 0.000 claims 1
• 238000000034 method Methods 0.000 description 13
• 210000004027 cell Anatomy 0.000 description 6
• 239000000126 substance Substances 0.000 description 3
• UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
• RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
• 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
• 229930024421 Adenine Natural products 0.000 description 1
• GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
• 229960000643 adenine Drugs 0.000 description 1
• 239000003814 drug Substances 0.000 description 1
• 210000005260 human cell Anatomy 0.000 description 1
• 238000004519 manufacturing process Methods 0.000 description 1
• 210000000663 muscle cell Anatomy 0.000 description 1
• 229940113082 thymine Drugs 0.000 description 1