JP2021502095A5 - - Google Patents

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Publication number

JP2021502095A5

JP2021502095A5 JP2020525951A JP2020525951A JP2021502095A5 JP 2021502095 A5 JP2021502095 A5 JP 2021502095A5 JP 2020525951 A JP2020525951 A JP 2020525951A JP 2020525951 A JP2020525951 A JP 2020525951A JP 2021502095 A5 JP2021502095 A5 JP 2021502095A5

Authority

JP

Japan

Prior art keywords

pharmaceutical composition

modified oligonucleotide

modified

nucleoside

oligomer

Prior art date

2018-11-09

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.)

Granted

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• 239000002777 nucleoside Substances 0.000 claims description 142
• 150000001875 compounds Chemical class 0.000 claims description 109
• 108091034117 Oligonucleotide Proteins 0.000 claims description 64
• 235000000346 sugar Nutrition 0.000 claims description 44
• 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 28
• 239000008194 pharmaceutical composition Substances 0.000 claims description 23
• LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 21
• UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 16
• RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 16
• 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 claims description 10
• 229930024421 Adenine Natural products 0.000 claims description 8
• GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 8
• 229960000643 adenine Drugs 0.000 claims description 8
• 230000004770 neurodegeneration Effects 0.000 claims description 8
• 229940113082 thymine Drugs 0.000 claims description 8
• 150000003839 salts Chemical class 0.000 claims description 7
• 102100026882 Alpha-synuclein Human genes 0.000 claims description 6
• 239000003085 diluting agent Substances 0.000 claims description 6
• 201000010099 disease Diseases 0.000 claims description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
• 239000000126 substance Substances 0.000 claims description 6
• 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 5
• 208000009829 Lewy Body Disease Diseases 0.000 claims description 4
• 208000024891 symptom Diseases 0.000 claims description 4
• 208000024827 Alzheimer disease Diseases 0.000 claims description 2
• 206010061666 Autonomic neuropathy Diseases 0.000 claims description 2
• 206010012289 Dementia Diseases 0.000 claims description 2
• 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 2
• 208000015872 Gaucher disease Diseases 0.000 claims description 2
• 201000002832 Lewy body dementia Diseases 0.000 claims description 2
• 206010061296 Motor dysfunction Diseases 0.000 claims description 2
• 208000001089 Multiple system atrophy Diseases 0.000 claims description 2
• 208000018737 Parkinson disease Diseases 0.000 claims description 2
• 102000003802 alpha-Synuclein Human genes 0.000 claims description 2
• 108090000185 alpha-Synuclein Proteins 0.000 claims description 2
• 230000001668 ameliorated effect Effects 0.000 claims description 2
• 230000006999 cognitive decline Effects 0.000 claims description 2
• 208000010877 cognitive disease Diseases 0.000 claims description 2
• 230000000926 neurological effect Effects 0.000 claims description 2
• 159000000000 sodium salts Chemical group 0.000 claims description 2
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims 6
• 239000002953 phosphate buffered saline Substances 0.000 claims 6
• 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 1
• 230000004520 agglutination Effects 0.000 claims 1
• XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
• 150000003833 nucleoside derivatives Chemical class 0.000 description 39
• 150000007523 nucleic acids Chemical group 0.000 description 26
• 125000003835 nucleoside group Chemical group 0.000 description 23
• OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 20
• 108020004707 nucleic acids Proteins 0.000 description 18
• 102000039446 nucleic acids Human genes 0.000 description 18
• YIMATHOGWXZHFX-WCTZXXKLSA-N (2r,3r,4r,5r)-5-(hydroxymethyl)-3-(2-methoxyethoxy)oxolane-2,4-diol Chemical compound COCCO[C@H]1[C@H](O)O[C@H](CO)[C@H]1O YIMATHOGWXZHFX-WCTZXXKLSA-N 0.000 description 17
• 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 description 10
• 108091028043 Nucleic acid sequence Proteins 0.000 description 8
• 229940104302 cytosine Drugs 0.000 description 7
• -1 phosphorothioate nucleoside Chemical class 0.000 description 7
• 239000000203 mixture Substances 0.000 description 6
• 238000012986 modification Methods 0.000 description 6
• 230000004048 modification Effects 0.000 description 6
• 230000000295 complement effect Effects 0.000 description 5
• 238000000034 method Methods 0.000 description 5
• OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 description 4
• MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 4
• 125000002619 bicyclic group Chemical group 0.000 description 4
• 230000000052 comparative effect Effects 0.000 description 4
• 102000045354 human SNCA Human genes 0.000 description 4
• 230000003389 potentiating effect Effects 0.000 description 4
• 235000021092 sugar substitutes Nutrition 0.000 description 3
• 239000003765 sweetening agent Chemical class 0.000 description 3
• 108091093088 Amplicon Proteins 0.000 description 2
• 230000000692 anti-sense effect Effects 0.000 description 2
• 239000003446 ligand Substances 0.000 description 2
• 108020004999 messenger RNA Proteins 0.000 description 2
• 239000002773 nucleotide Substances 0.000 description 2
• 125000003729 nucleotide group Chemical group 0.000 description 2
• 230000001988 toxicity Effects 0.000 description 2
• 231100000419 toxicity Toxicity 0.000 description 2
• 241001465754 Metazoa Species 0.000 description 1
• 230000002776 aggregation Effects 0.000 description 1
• 238000004220 aggregation Methods 0.000 description 1
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
• 239000000523 sample Substances 0.000 description 1
• 150000008163 sugars Chemical class 0.000 description 1
• 238000010998 test method Methods 0.000 description 1