JP2018525030A5 - - Google Patents

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Publication number

JP2018525030A5

JP2018525030A5 JP2018521186A JP2018521186A JP2018525030A5 JP 2018525030 A5 JP2018525030 A5 JP 2018525030A5 JP 2018521186 A JP2018521186 A JP 2018521186A JP 2018521186 A JP2018521186 A JP 2018521186A JP 2018525030 A5 JP2018525030 A5 JP 2018525030A5

Authority

JP

Japan

Prior art keywords

compound

wing segment

modified

modified oligonucleotide

compound according

Prior art date

2016-07-08

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 76
• 239000002777 nucleoside Substances 0.000 claims description 56
• 108091034117 Oligonucleotide Proteins 0.000 claims description 48
• 125000003835 nucleoside group Chemical group 0.000 claims description 37
• 239000000203 mixture Substances 0.000 claims description 19
• 230000000295 complement effect Effects 0.000 claims description 13
• 201000010099 disease Diseases 0.000 claims description 13
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
• 102100035762 Diacylglycerol O-acyltransferase 2 Human genes 0.000 claims description 12
• 101000930020 Homo sapiens Diacylglycerol O-acyltransferase 2 Proteins 0.000 claims description 12
• OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 12
• 150000003833 nucleoside derivatives Chemical class 0.000 claims description 12
• 230000015572 biosynthetic process Effects 0.000 claims description 10
• 238000003786 synthesis reaction Methods 0.000 claims description 10
• 206010049287 Lipodystrophy acquired Diseases 0.000 claims description 9
• 208000006132 lipodystrophy Diseases 0.000 claims description 9
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 9
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 9
• 206010053857 partial lipodystrophy Diseases 0.000 claims description 9
• 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 8
• LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical group CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 8
• 150000003839 salts Chemical class 0.000 claims description 7
• 206010022489 Insulin Resistance Diseases 0.000 claims description 6
• 229940104302 cytosine Drugs 0.000 claims description 6
• 230000002401 inhibitory effect Effects 0.000 claims description 6
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 6
• 210000000593 adipose tissue white Anatomy 0.000 claims description 5
• 150000002632 lipids Chemical class 0.000 claims description 5
• UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 5
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
• 125000002619 bicyclic group Chemical group 0.000 claims description 4
• UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 4
• 210000005228 liver tissue Anatomy 0.000 claims description 4
• 239000002773 nucleotide Substances 0.000 claims description 4
• 125000003729 nucleotide group Chemical group 0.000 claims description 4
• RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 4
• 102000004877 Insulin Human genes 0.000 claims description 3
• 108090001061 Insulin Proteins 0.000 claims description 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 claims description 3
• 229940125396 insulin Drugs 0.000 claims description 3
• 108020004707 nucleic acids Proteins 0.000 claims description 3
• 150000007523 nucleic acids Chemical class 0.000 claims description 3
• 102000039446 nucleic acids Human genes 0.000 claims description 3
• 229930024421 Adenine Natural products 0.000 claims description 2
• GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 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
• 108091028664 Ribonucleotide Proteins 0.000 claims description 2
• 229960000643 adenine Drugs 0.000 claims description 2
• 239000005547 deoxyribonucleotide Substances 0.000 claims description 2
• 125000002637 deoxyribonucleotide group Chemical group 0.000 claims description 2
• 239000003814 drug Substances 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 230000002526 effect on cardiovascular system Effects 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
• 238000002360 preparation method Methods 0.000 claims description 2
• 239000002336 ribonucleotide Substances 0.000 claims description 2
• 125000002652 ribonucleotide group Chemical group 0.000 claims description 2
• 230000011664 signaling Effects 0.000 claims description 2
• 210000001550 testis Anatomy 0.000 claims description 2
• 229940113082 thymine Drugs 0.000 claims description 2
• 239000008194 pharmaceutical composition Substances 0.000 claims 4
• 239000003085 diluting agent Substances 0.000 claims 2
• 239000002953 phosphate buffered saline Substances 0.000 claims 2
• 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 1
• 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 1
• 229940079593 drug Drugs 0.000 claims 1
• 210000004185 liver Anatomy 0.000 claims 1
• -1 nucleoside modified oligonucleotides Chemical class 0.000 claims 1
• 230000035945 sensitivity Effects 0.000 claims 1
• 229910052708 sodium Inorganic materials 0.000 claims 1
• 239000011734 sodium Substances 0.000 claims 1
• 230000001225 therapeutic effect Effects 0.000 claims 1
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
• 238000000034 method Methods 0.000 description 11
• RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 6
• ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 2
• 241000764238 Isis Species 0.000 description 2
• 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 2
• 238000012739 integrated shape imaging system Methods 0.000 description 2
• 238000012986 modification Methods 0.000 description 2
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• 230000002411 adverse Effects 0.000 description 1
• 238000004458 analytical method Methods 0.000 description 1
• 239000008280 blood Substances 0.000 description 1
• 210000004369 blood Anatomy 0.000 description 1
• 230000003285 pharmacodynamic effect Effects 0.000 description 1
• 159000000000 sodium salts Chemical group 0.000 description 1
• 238000002560 therapeutic procedure Methods 0.000 description 1
• 210000002700 urine Anatomy 0.000 description 1