JP2016533717A5 - - Google Patents

Info

Publication number

JP2016533717A5

JP2016533717A5 JP2016521622A JP2016521622A JP2016533717A5 JP 2016533717 A5 JP2016533717 A5 JP 2016533717A5 JP 2016521622 A JP2016521622 A JP 2016521622A JP 2016521622 A JP2016521622 A JP 2016521622A JP 2016533717 A5 JP2016533717 A5 JP 2016533717A5

Authority

JP

Japan

Prior art keywords

compound according

modified

modified oligonucleotide

compound

linked nucleosides

Prior art date

2014-10-11

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

Links

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• 150000001875 compounds Chemical class 0.000 claims description 88
• 108091034117 Oligonucleotide Proteins 0.000 claims description 44
• 239000002777 nucleoside Substances 0.000 claims description 44
• 125000003835 nucleoside group Chemical group 0.000 claims description 30
• 150000003833 nucleoside derivatives Chemical class 0.000 claims description 14
• 230000000295 complement effect Effects 0.000 claims description 13
• 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 12
• 239000000203 mixture Substances 0.000 claims description 7
• 230000000692 anti-sense effect Effects 0.000 claims description 5
• 125000002619 bicyclic group Chemical group 0.000 claims description 5
• 239000000126 substance Substances 0.000 claims description 4
• RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 3
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
• 150000003839 salts Chemical class 0.000 claims description 3
• LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical group CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 2
• 150000004713 phosphodiesters Chemical class 0.000 claims description 2
• 238000010382 chemical cross-linking Methods 0.000 claims 2
• 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 2
• 239000008194 pharmaceutical composition Substances 0.000 claims 2
• 239000002953 phosphate buffered saline Substances 0.000 claims 2
• 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 1
• 125000003545 alkoxy group Chemical group 0.000 claims 1
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
• 239000008177 pharmaceutical agent Substances 0.000 claims 1
• 159000000000 sodium salts Chemical group 0.000 claims 1
• 238000000034 method Methods 0.000 description 10
• ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 7
• 241000764238 Isis Species 0.000 description 7
• 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 7
• 238000012739 integrated shape imaging system Methods 0.000 description 7
• 241001465754 Metazoa Species 0.000 description 6
• 230000001154 acute effect Effects 0.000 description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
• 241000700159 Rattus Species 0.000 description 5
• 241000699670 Mus sp. Species 0.000 description 3
• 201000010099 disease Diseases 0.000 description 3
• 208000035475 disorder Diseases 0.000 description 3
• 201000011240 Frontotemporal dementia Diseases 0.000 description 2
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
• 230000001934 delay Effects 0.000 description 2
• 108020004999 messenger RNA Proteins 0.000 description 2
• 125000006239 protecting group Chemical group 0.000 description 2
• 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
• KZNQNBZMBZJQJO-UHFFFAOYSA-N 1-(2-azaniumylacetyl)pyrrolidine-2-carboxylate Chemical compound NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
• IVNJKQPHHPMONX-WCCKRBBISA-N 2-aminoacetic acid;(2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid Chemical compound NCC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N IVNJKQPHHPMONX-WCCKRBBISA-N 0.000 description 1
• 241000699666 Mus <mouse, genus> Species 0.000 description 1
• 108091028043 Nucleic acid sequence Proteins 0.000 description 1
• 240000007817 Olea europaea Species 0.000 description 1
• 206010034010 Parkinsonism Diseases 0.000 description 1
• 125000000217 alkyl group Chemical group 0.000 description 1
• 210000004227 basal ganglia Anatomy 0.000 description 1
• 208000025434 cerebellar degeneration Diseases 0.000 description 1
• 230000001054 cortical effect Effects 0.000 description 1
• 230000007850 degeneration Effects 0.000 description 1
• 239000003814 drug Substances 0.000 description 1
• 239000003937 drug carrier Substances 0.000 description 1
• 230000002401 inhibitory effect Effects 0.000 description 1
• 238000004519 manufacturing process Methods 0.000 description 1
• 150000007523 nucleic acids Chemical group 0.000 description 1
• 230000007918 pathogenicity Effects 0.000 description 1
• 239000002243 precursor Substances 0.000 description 1
• 208000011580 syndromic disease Diseases 0.000 description 1