JPWO2021178736A5 - - Google Patents

Info

Publication number

JPWO2021178736A5

JPWO2021178736A5 JP2022553106A JP2022553106A JPWO2021178736A5 JP WO2021178736 A5 JPWO2021178736 A5 JP WO2021178736A5 JP 2022553106 A JP2022553106 A JP 2022553106A JP 2022553106 A JP2022553106 A JP 2022553106A JP WO2021178736 A5 JPWO2021178736 A5 JP WO2021178736A5

Authority

JP

Japan

Prior art keywords

nucleotide

dsrna agent

pharmaceutical composition

modification

dsrna

Prior art date

2024-03-14

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.)

Pending

Links

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• 230000004048 modification Effects 0.000 claims 37
• 238000012986 modification Methods 0.000 claims 37
• 239000003795 chemical substances by application Substances 0.000 claims 34
• 239000002773 nucleotide Substances 0.000 claims 33
• 125000003729 nucleotide group Chemical group 0.000 claims 30
• 239000008194 pharmaceutical composition Substances 0.000 claims 22
• 102100023418 Ketohexokinase Human genes 0.000 claims 13
• 108010062852 Ketohexokinase Proteins 0.000 claims 13
• 230000000692 anti-sense effect Effects 0.000 claims 10
• 108091081021 Sense strand Proteins 0.000 claims 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 7
• 210000004027 cell Anatomy 0.000 claims 5
• 208000035475 disorder Diseases 0.000 claims 5
• 239000003446 ligand Substances 0.000 claims 5
• RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims 5
• 230000002401 inhibitory effect Effects 0.000 claims 4
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims 4
• YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical group CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 claims 3
• 208000024172 Cardiovascular disease Diseases 0.000 claims 2
• 208000032928 Dyslipidaemia Diseases 0.000 claims 2
• 208000017170 Lipid metabolism disease Diseases 0.000 claims 2
• OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical class CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 claims 2
• 108091028043 Nucleic acid sequence Proteins 0.000 claims 2
• 229910019142 PO4 Inorganic materials 0.000 claims 2
• IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical group O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims 2
• 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 2
• 230000000295 complement effect Effects 0.000 claims 2
• 230000008021 deposition Effects 0.000 claims 2
• 201000010099 disease Diseases 0.000 claims 2
• 230000004064 dysfunction Effects 0.000 claims 2
• 230000002641 glycemic effect Effects 0.000 claims 2
• 208000006575 hypertriglyceridemia Diseases 0.000 claims 2
• 238000000338 in vitro Methods 0.000 claims 2
• 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 2
• 208000017169 kidney disease Diseases 0.000 claims 2
• 208000019423 liver disease Diseases 0.000 claims 2
• 238000000034 method Methods 0.000 claims 2
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims 2
• 239000010452 phosphate Substances 0.000 claims 2
• 108090000623 proteins and genes Proteins 0.000 claims 2
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims 2
• MPCAJMNYNOGXPB-UHFFFAOYSA-N 1,5-anhydrohexitol Chemical class OCC1OCC(O)C(O)C1O MPCAJMNYNOGXPB-UHFFFAOYSA-N 0.000 claims 1
• 208000035657 Abasia Diseases 0.000 claims 1
• 208000009304 Acute Kidney Injury Diseases 0.000 claims 1
• 208000002705 Glucose Intolerance Diseases 0.000 claims 1
• 208000031226 Hyperlipidaemia Diseases 0.000 claims 1
• 206010020772 Hypertension Diseases 0.000 claims 1
• 102000004877 Insulin Human genes 0.000 claims 1
• 108090001061 Insulin Proteins 0.000 claims 1
• 206010022489 Insulin Resistance Diseases 0.000 claims 1
• 101150063450 Khk gene Proteins 0.000 claims 1
• 238000008214 LDL Cholesterol Methods 0.000 claims 1
• 208000001145 Metabolic Syndrome Diseases 0.000 claims 1
• OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 claims 1
• 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 1
• 208000008589 Obesity Diseases 0.000 claims 1
• 208000033626 Renal failure acute Diseases 0.000 claims 1
• 208000026980 Renal tubular disease Diseases 0.000 claims 1
• RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical group OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 claims 1
• 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims 1
• 230000002159 abnormal effect Effects 0.000 claims 1
• 201000011040 acute kidney failure Diseases 0.000 claims 1
• 230000010014 adipocyte dysfunction Effects 0.000 claims 1
• 235000012000 cholesterol Nutrition 0.000 claims 1
• 208000020832 chronic kidney disease Diseases 0.000 claims 1
• 238000010586 diagram Methods 0.000 claims 1
• 210000002889 endothelial cell Anatomy 0.000 claims 1
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
• 150000002334 glycols Chemical class 0.000 claims 1
• 230000028993 immune response Effects 0.000 claims 1
• 230000001771 impaired effect Effects 0.000 claims 1
• 229940125396 insulin Drugs 0.000 claims 1
• 210000001596 intra-abdominal fat Anatomy 0.000 claims 1
• 150000002632 lipids Chemical class 0.000 claims 1
• 125000001921 locked nucleotide group Chemical group 0.000 claims 1
• 108020004999 messenger RNA Proteins 0.000 claims 1
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
• 235000020824 obesity Nutrition 0.000 claims 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
• PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 claims 1
• 230000000291 postprandial effect Effects 0.000 claims 1
• 201000009104 prediabetes syndrome Diseases 0.000 claims 1
• 230000000770 proinflammatory effect Effects 0.000 claims 1
• 210000000512 proximal kidney tubule Anatomy 0.000 claims 1
• 229920002477 rna polymer Polymers 0.000 claims 1
• 208000024891 symptom Diseases 0.000 claims 1
• 150000003527 tetrahydropyrans Chemical class 0.000 claims 1