CA2916252A1 - Compositions and methods for modulation of target nucleic acids - Google Patents
Compositions and methods for modulation of target nucleic acids Download PDFInfo
- Publication number
- CA2916252A1 CA2916252A1 CA2916252A CA2916252A CA2916252A1 CA 2916252 A1 CA2916252 A1 CA 2916252A1 CA 2916252 A CA2916252 A CA 2916252A CA 2916252 A CA2916252 A CA 2916252A CA 2916252 A1 CA2916252 A1 CA 2916252A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- substituted
- nucleoside
- alkyl
- oligonucleotide
- Prior art date
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 101
- 108020004707 nucleic acids Proteins 0.000 title claims abstract description 88
- 102000039446 nucleic acids Human genes 0.000 title claims abstract description 88
- 150000007523 nucleic acids Chemical class 0.000 title claims abstract description 87
- 239000000203 mixture Substances 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 555
- 239000003814 drug Substances 0.000 claims abstract description 13
- 239000002777 nucleoside Substances 0.000 claims description 447
- 108091034117 Oligonucleotide Proteins 0.000 claims description 343
- 125000003835 nucleoside group Chemical group 0.000 claims description 238
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 185
- 235000000346 sugar Nutrition 0.000 claims description 136
- 238000012986 modification Methods 0.000 claims description 120
- 230000000692 anti-sense effect Effects 0.000 claims description 115
- 230000004048 modification Effects 0.000 claims description 105
- 125000005647 linker group Chemical group 0.000 claims description 99
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 98
- -1 succinimidyl Chemical group 0.000 claims description 96
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 claims description 95
- 238000012739 integrated shape imaging system Methods 0.000 claims description 95
- 241000764238 Isis Species 0.000 claims description 86
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 claims description 83
- 230000000295 complement effect Effects 0.000 claims description 71
- 108010056301 Apolipoprotein C-III Proteins 0.000 claims description 70
- 102000030169 Apolipoprotein C-III Human genes 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 229910052736 halogen Inorganic materials 0.000 claims description 62
- 150000002367 halogens Chemical class 0.000 claims description 61
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 58
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 58
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical group [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 57
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 52
- 239000003446 ligand Substances 0.000 claims description 51
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 48
- 241001465754 Metazoa Species 0.000 claims description 48
- 230000000694 effects Effects 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 48
- 108020004999 messenger RNA Proteins 0.000 claims description 42
- 150000004713 phosphodiesters Chemical class 0.000 claims description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims description 37
- 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 34
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- 108091081021 Sense strand Proteins 0.000 claims description 31
- 229910019142 PO4 Inorganic materials 0.000 claims description 30
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 29
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 28
- 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 claims description 27
- 239000010452 phosphate Substances 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 239000007787 solid Substances 0.000 claims description 24
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 24
- 125000000304 alkynyl group Chemical group 0.000 claims description 22
- 238000000338 in vitro Methods 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 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 claims description 21
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 21
- 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 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 19
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical class N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 18
- 150000001408 amides Chemical class 0.000 claims description 18
- 229940107161 cholesterol Drugs 0.000 claims description 17
- 125000001033 ether group Chemical group 0.000 claims description 17
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 16
- 235000012000 cholesterol Nutrition 0.000 claims description 16
- 229940035893 uracil Drugs 0.000 claims description 16
- 229930024421 Adenine Natural products 0.000 claims description 15
- 229960000643 adenine Drugs 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 15
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 229940104302 cytosine Drugs 0.000 claims description 12
- 229940113082 thymine Drugs 0.000 claims description 12
- 101000650578 Salmonella phage P22 Regulatory protein C3 Proteins 0.000 claims description 11
- 101001040920 Triticum aestivum Alpha-amylase inhibitor 0.28 Proteins 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 150000003568 thioethers Chemical class 0.000 claims description 11
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 11
- RUVRGYVESPRHSZ-UHFFFAOYSA-N 2-[2-(2-azaniumylethoxy)ethoxy]acetate Chemical compound NCCOCCOCC(O)=O RUVRGYVESPRHSZ-UHFFFAOYSA-N 0.000 claims description 10
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 10
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 10
- 230000003247 decreasing effect Effects 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 9
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 230000001965 increasing effect Effects 0.000 claims description 8
- 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 7
- 150000003626 triacylglycerols Chemical class 0.000 claims description 7
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 6
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 6
- ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 claims description 6
- 150000003573 thiols Chemical class 0.000 claims description 6
- 229960002684 aminocaproic acid Drugs 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000000913 palmityl 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])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 5
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 150000003212 purines Chemical class 0.000 claims description 4
- 150000003230 pyrimidines Chemical class 0.000 claims description 4
- 125000003696 stearoyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 150000003852 triazoles Chemical class 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 3
- 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 3
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 3
- 101150020251 NR13 gene Proteins 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 claims 3
- 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 abstract description 93
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- 125000004429 atom Chemical group 0.000 description 37
- 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 description 31
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2014
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- 2014-06-23 EP EP14813192.3A patent/EP3011028B1/en active Active
- 2014-06-23 CA CA2916252A patent/CA2916252A1/en not_active Abandoned
- 2014-06-23 US US14/898,873 patent/US20160122761A1/en not_active Abandoned
- 2014-06-23 EP EP20173519.8A patent/EP3730619A1/en not_active Withdrawn
- 2014-06-23 EP EP19179457.7A patent/EP3564374A1/en not_active Withdrawn
- 2014-06-23 JP JP2016521893A patent/JP6694382B2/ja active Active
- 2014-06-23 WO PCT/US2014/043731 patent/WO2014205451A2/en not_active Ceased
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2018
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2019
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2020
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| US20200270609A1 (en) | 2020-08-27 |
| US20190127737A1 (en) | 2019-05-02 |
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| EP3011028A4 (en) | 2017-02-22 |
| EP3011028B1 (en) | 2019-06-12 |
| JP2020099335A (ja) | 2020-07-02 |
| WO2014205451A3 (en) | 2015-02-19 |
| JP6694382B2 (ja) | 2020-05-13 |
| WO2014205451A2 (en) | 2014-12-24 |
| EP3564374A1 (en) | 2019-11-06 |
| EP3730619A1 (en) | 2020-10-28 |
| AU2014284152B2 (en) | 2020-01-23 |
| AU2019284048A1 (en) | 2020-01-23 |
| EP3011028A2 (en) | 2016-04-27 |
| JP2016523087A (ja) | 2016-08-08 |
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