JP2021500903A5 - - Google Patents

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Publication number

JP2021500903A5

JP2021500903A5 JP2020523976A JP2020523976A JP2021500903A5 JP 2021500903 A5 JP2021500903 A5 JP 2021500903A5 JP 2020523976 A JP2020523976 A JP 2020523976A JP 2020523976 A JP2020523976 A JP 2020523976A JP 2021500903 A5 JP2021500903 A5 JP 2021500903A5

Authority

JP

Japan

Prior art keywords

modified oligonucleotide

compound

nucleoside

seq

wing segment

Prior art date

2018-10-31

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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• 150000001875 compounds Chemical class 0.000 claims description 111
• 108091034117 Oligonucleotide Proteins 0.000 claims description 80
• 239000002777 nucleoside Substances 0.000 claims description 60
• 238000000034 method Methods 0.000 claims description 31
• 150000003833 nucleoside derivatives Chemical class 0.000 claims description 27
• 102100037242 Amiloride-sensitive sodium channel subunit alpha Human genes 0.000 claims description 21
• 101710194189 Amiloride-sensitive sodium channel subunit alpha Proteins 0.000 claims description 21
• 230000000295 complement effect Effects 0.000 claims description 18
• 125000003835 nucleoside group Chemical group 0.000 claims description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims description 16
• 201000010099 disease Diseases 0.000 claims description 13
• 208000037265 diseases, disorders, signs and symptoms Diseases 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 11
• 239000003795 chemical substances by application Substances 0.000 claims description 11
• 206010006458 Bronchitis chronic Diseases 0.000 claims description 8
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 8
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 8
• 208000006673 asthma Diseases 0.000 claims description 8
• 206010006451 bronchitis Diseases 0.000 claims description 8
• 208000007451 chronic bronchitis Diseases 0.000 claims description 8
• 239000003085 diluting agent Substances 0.000 claims description 8
• 150000003839 salts Chemical class 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 7
• OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 6
• LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 5
• 230000002401 inhibitory effect Effects 0.000 claims description 4
• 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 Polymers 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
• 229940104302 cytosine Drugs 0.000 claims description 3
• 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 description 3
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
• 229940127557 pharmaceutical product Drugs 0.000 claims description 3
• 239000002953 phosphate buffered saline Substances 0.000 claims description 3
• 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
• 159000000000 sodium salts Chemical class 0.000 claims description 2
• 239000000126 substance Substances 0.000 claims 3
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
• 150000001450 anions Chemical class 0.000 claims 1
• 150000001768 cations Chemical class 0.000 claims 1
• 238000010790 dilution Methods 0.000 claims 1
• 239000012895 dilution Substances 0.000 claims 1
• 238000012986 modification Methods 0.000 claims 1
• 230000004048 modification Effects 0.000 claims 1
• 229910052700 potassium Inorganic materials 0.000 claims 1
• 239000011591 potassium Substances 0.000 claims 1
• 229910052708 sodium Inorganic materials 0.000 claims 1
• 239000011734 sodium Substances 0.000 claims 1
• 239000000203 mixture Substances 0.000 description 15
• 108020004707 nucleic acids Proteins 0.000 description 11
• 150000007523 nucleic acids Chemical class 0.000 description 11
• 102000039446 nucleic acids Human genes 0.000 description 11
• 239000006199 nebulizer Substances 0.000 description 9
• -1 phosphorothioate nucleoside Chemical class 0.000 description 8
• 230000002685 pulmonary effect Effects 0.000 description 6
• 239000000843 powder Substances 0.000 description 3
• 239000000243 solution Substances 0.000 description 3
• 239000000443 aerosol Substances 0.000 description 2
• 125000002619 bicyclic group Chemical group 0.000 description 2
• UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
• RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
• MJUVRTYWUMPBTR-MRXNPFEDSA-N 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-n-[1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)indol-5-yl]cyclopropane-1-carboxamide Chemical group FC=1C=C2N(C[C@@H](O)CO)C(C(C)(CO)C)=CC2=CC=1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 MJUVRTYWUMPBTR-MRXNPFEDSA-N 0.000 description 1
• 108020005345 3' Untranslated Regions Proteins 0.000 description 1
• 229930024421 Adenine Natural products 0.000 description 1
• GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
• 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 description 1
• 101710163270 Nuclease Proteins 0.000 description 1
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
• 229960000643 adenine Drugs 0.000 description 1
• 239000003963 antioxidant agent Substances 0.000 description 1
• 230000003078 antioxidant effect Effects 0.000 description 1
• 230000001886 ciliary effect Effects 0.000 description 1
• 230000021615 conjugation Effects 0.000 description 1
• 239000000470 constituent Substances 0.000 description 1
• PURKAOJPTOLRMP-UHFFFAOYSA-N ivacaftor Chemical group C1=C(O)C(C(C)(C)C)=CC(C(C)(C)C)=C1NC(=O)C1=CNC2=CC=CC=C2C1=O PURKAOJPTOLRMP-UHFFFAOYSA-N 0.000 description 1
• 229960004508 ivacaftor Drugs 0.000 description 1
• 239000007788 liquid Substances 0.000 description 1
• 210000004072 lung Anatomy 0.000 description 1
• 238000005259 measurement Methods 0.000 description 1
• 229940071648 metered dose inhaler Drugs 0.000 description 1
• 230000000420 mucociliary effect Effects 0.000 description 1
• 239000002773 nucleotide Substances 0.000 description 1
• 125000003729 nucleotide group Chemical group 0.000 description 1
• 239000002245 particle Substances 0.000 description 1
• 230000037361 pathway Effects 0.000 description 1
• 239000000651 prodrug Substances 0.000 description 1
• 229940002612 prodrug Drugs 0.000 description 1
• 239000011780 sodium chloride Substances 0.000 description 1
• FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 description 1
• 239000007787 solid Substances 0.000 description 1
• 238000007920 subcutaneous administration Methods 0.000 description 1
• 229950005823 tezacaftor Drugs 0.000 description 1
• RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
• 229940113082 thymine Drugs 0.000 description 1