JP2019527549A5 - - Google Patents

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Publication number

JP2019527549A5

JP2019527549A5 JP2019501570A JP2019501570A JP2019527549A5 JP 2019527549 A5 JP2019527549 A5 JP 2019527549A5 JP 2019501570 A JP2019501570 A JP 2019501570A JP 2019501570 A JP2019501570 A JP 2019501570A JP 2019527549 A5 JP2019527549 A5 JP 2019527549A5

Authority

JP

Japan

Prior art keywords

modified oligonucleotide

oligomeric compound

compound according

modified

aspects

Prior art date

2017-07-17

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

• Espacenet
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• 150000001875 compounds Chemical class 0.000 claims description 163
• 108091034117 Oligonucleotide Proteins 0.000 claims description 121
• 239000002777 nucleoside Substances 0.000 claims description 88
• 125000003835 nucleoside group Chemical group 0.000 claims description 62
• 239000002243 precursor Substances 0.000 claims description 41
• 108020004999 messenger RNA Proteins 0.000 claims description 37
• 230000000295 complement effect Effects 0.000 claims description 31
• 150000003833 nucleoside derivatives Chemical class 0.000 claims description 24
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• 239000001257 hydrogen Substances 0.000 claims description 17
• 150000002632 lipids Chemical class 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
• LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 8
• OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 8
• RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 8
• 125000002619 bicyclic group Chemical group 0.000 claims description 7
• 201000010099 disease Diseases 0.000 claims description 7
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
• 210000003205 muscle Anatomy 0.000 claims description 7
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
• RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 7
• ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 6
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 6
• 108700024394 Exon Proteins 0.000 claims description 5
• 125000000217 alkyl group Chemical group 0.000 claims description 5
• 229930024421 Adenine Natural products 0.000 claims description 4
• GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 4
• 229960000643 adenine Drugs 0.000 claims description 4
• 229940104302 cytosine Drugs 0.000 claims description 4
• 229940113082 thymine Drugs 0.000 claims description 4
• 101000617738 Homo sapiens Survival motor neuron protein Proteins 0.000 claims description 3
• 102100021947 Survival motor neuron protein Human genes 0.000 claims description 3
• 230000002159 abnormal effect Effects 0.000 claims description 3
• 235000012000 cholesterol Nutrition 0.000 claims description 3
• GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 3
• 229960001295 tocopherol Drugs 0.000 claims description 3
• 229930003799 tocopherol Natural products 0.000 claims description 3
• 235000010384 tocopherol Nutrition 0.000 claims description 3
• 239000011732 tocopherol Substances 0.000 claims description 3
• 229940035893 uracil Drugs 0.000 claims description 3
• GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 3
• BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 2
• 239000004380 Cholic acid Substances 0.000 claims description 2
• OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical group CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 claims description 2
• BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 2
• 229960002471 cholic acid Drugs 0.000 claims description 2
• 235000019416 cholic acid Nutrition 0.000 claims description 2
• KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 2
• 239000008194 pharmaceutical composition Substances 0.000 claims description 2
• 150000004713 phosphodiesters Chemical class 0.000 claims description 2
• 150000004671 saturated fatty acids Chemical class 0.000 claims description 2
• 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 2
• 108091092195 Intron Proteins 0.000 claims 1
• 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
• 150000003869 acetamides Chemical class 0.000 claims 1
• 230000001268 conjugating effect Effects 0.000 claims 1
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
• 125000006239 protecting group Chemical group 0.000 claims 1
• 125000001424 substituent group Chemical group 0.000 claims 1
• UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims 1
• 238000000034 method Methods 0.000 description 28
• 239000000203 mixture Substances 0.000 description 10
• 210000001519 tissue Anatomy 0.000 description 9
• 210000004027 cell Anatomy 0.000 description 7
• 210000003169 central nervous system Anatomy 0.000 description 5
• 108020004705 Codon Proteins 0.000 description 4
• 102100040243 Microtubule-associated protein tau Human genes 0.000 description 4
• 108020004485 Nonsense Codon Proteins 0.000 description 3
• 230000015556 catabolic process Effects 0.000 description 3
• 238000006731 degradation reaction Methods 0.000 description 3
• 230000001419 dependent effect Effects 0.000 description 3
• 230000007717 exclusion Effects 0.000 description 3
• 230000037434 nonsense mutation Effects 0.000 description 3
• 102000001039 Dystrophin Human genes 0.000 description 2
• 108010069091 Dystrophin Proteins 0.000 description 2
• 101000891579 Homo sapiens Microtubule-associated protein tau Proteins 0.000 description 2
• 239000003814 drug Substances 0.000 description 2
• 125000001183 hydrocarbyl group Chemical group 0.000 description 2
• 238000007910 systemic administration Methods 0.000 description 2
• 108010026424 tau Proteins Proteins 0.000 description 2
• PMDCZENCAXMSOU-UHFFFAOYSA-N N-Ethylacetamide Natural products CCNC(C)=O PMDCZENCAXMSOU-UHFFFAOYSA-N 0.000 description 1
• 230000005856 abnormality Effects 0.000 description 1
• 239000003085 diluting agent Substances 0.000 description 1
• 239000003937 drug carrier Substances 0.000 description 1
• 210000003494 hepatocyte Anatomy 0.000 description 1
• 238000007913 intrathecal administration Methods 0.000 description 1
• -1 linker nucleoside Chemical class 0.000 description 1
• 210000000663 muscle cell Anatomy 0.000 description 1
• 230000003387 muscular Effects 0.000 description 1
• 230000035772 mutation Effects 0.000 description 1
• 210000002569 neuron Anatomy 0.000 description 1
• 230000001105 regulatory effect Effects 0.000 description 1
• 229920006395 saturated elastomer Polymers 0.000 description 1
• 229930195734 saturated hydrocarbon Natural products 0.000 description 1
• 238000007920 subcutaneous administration Methods 0.000 description 1
• 238000002560 therapeutic procedure Methods 0.000 description 1
• 150000003626 triacylglycerols Chemical class 0.000 description 1
• 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1