RU2015151203A - Композиции и способы модулирования экспрессии аполипопротеина c-iii - Google Patents
Композиции и способы модулирования экспрессии аполипопротеина c-iii Download PDFInfo
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- RU2015151203A RU2015151203A RU2015151203A RU2015151203A RU2015151203A RU 2015151203 A RU2015151203 A RU 2015151203A RU 2015151203 A RU2015151203 A RU 2015151203A RU 2015151203 A RU2015151203 A RU 2015151203A RU 2015151203 A RU2015151203 A RU 2015151203A
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- Russia
- Prior art keywords
- modified oligonucleotide
- animal
- compound according
- wing segment
- modified
- Prior art date
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- 102000030169 Apolipoprotein C-III Human genes 0.000 title 1
- 108010056301 Apolipoprotein C-III Proteins 0.000 title 1
- 239000000203 mixture Substances 0.000 title 1
- 108091034117 Oligonucleotide Proteins 0.000 claims 23
- 150000001875 compounds Chemical class 0.000 claims 20
- 239000002777 nucleoside Substances 0.000 claims 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 8
- 125000003835 nucleoside group Chemical group 0.000 claims 8
- 108010004103 Chylomicrons Proteins 0.000 claims 6
- 208000032928 Dyslipidaemia Diseases 0.000 claims 6
- 208000017170 Lipid metabolism disease Diseases 0.000 claims 6
- 206010033645 Pancreatitis Diseases 0.000 claims 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 6
- 230000001268 conjugating effect Effects 0.000 claims 5
- 201000010099 disease Diseases 0.000 claims 5
- 201000011110 familial lipoprotein lipase deficiency Diseases 0.000 claims 4
- 229910052757 nitrogen Inorganic materials 0.000 claims 4
- 150000003833 nucleoside derivatives Chemical class 0.000 claims 4
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical group CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims 3
- 102000004877 Insulin Human genes 0.000 claims 3
- 108090001061 Insulin Proteins 0.000 claims 3
- 230000000295 complement effect Effects 0.000 claims 3
- 206010012601 diabetes mellitus Diseases 0.000 claims 3
- 208000016097 disease of metabolism Diseases 0.000 claims 3
- 208000035475 disorder Diseases 0.000 claims 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims 3
- 208000006575 hypertriglyceridemia Diseases 0.000 claims 3
- 208000027866 inflammatory disease Diseases 0.000 claims 3
- 229940125396 insulin Drugs 0.000 claims 3
- 208000030159 metabolic disease Diseases 0.000 claims 3
- 230000002503 metabolic effect Effects 0.000 claims 3
- 230000002265 prevention Effects 0.000 claims 3
- 150000003626 triacylglycerols Chemical class 0.000 claims 3
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims 2
- 150000002829 nitrogen Chemical class 0.000 claims 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims 2
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- -1 hexitol nucleic acid Chemical class 0.000 claims 1
- 108020004707 nucleic acids Proteins 0.000 claims 1
- 102000039446 nucleic acids Human genes 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 150000003839 salts Chemical group 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 150000003385 sodium Chemical class 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
Classifications
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- A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
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Claims (69)
1. Соединение, содержащее модифицированный олигонуклеотид и конъюгирующую группу, при этом модифицированный олигонуклеотид состоит из 20 смежных нуклеозидов, комплементарных равной по длине части азотистых оснований 3533-3552 в SEQ ID NO: 3, причем указанная последовательность азотистых оснований модифицированного олигонуклеотида по меньшей мере на 80% комплементарна SEQ ID NO: 3, и при этом конъюгирующая группа содержит
2. Соединение по п. 1, отличающееся тем, что:
(i) последовательность азотистых оснований модифицированного олигонуклеотида по меньшей мере на 85%, по меньшей мере на 90%, по меньшей мере на 95% или на 100% комплементарна SEQ ID NO: 3;
(ii) модифицированный олигонуклеотид содержит по меньшей мере один модифицированный сахар;
(iii) по меньшей мере один нуклеозид содержит модифицированное азотистое основание; и/или
(iv) модифицированный олигонуклеотид содержит по меньшей мере одну модифицированную межнуклеозидную связь.
3. Соединение по п. 2, отличающееся тем, что:
(i) (а) по меньшей мере один модифицированный сахар представляет собой бициклический сахар, или (b) по меньшей мере один модифицированный сахар содержит 2'-O-метоксиэтил, стерически затрудненный этил, 3'-фтор-ГНК (hexitol nucleic acid (HNA)) или 4'-(CH2)n-O-2' мостик, где n равен 1 или 2;
(ii) модифицированное азотистое основание представляет собой 5-метилцитозин;
(iii) модифицированная межнуклеозидная связь представляет собой тиофосфатную межнуклеозидную связь и/или
(iv) каждая межнуклеозидная связь модифицированного олигонуклеотида представляет собой тиофосфатную межнуклеозидную связь.
4. Соединение по п. 1, отличающееся тем, что
(i) модифицированный олигонуклеотид является одноцепочечным; и/или
(ii) конъюгирующая группа связана с модифицированным олигонуклеотидом (а) на 5'-конце модифицированного олигонуклеотида или (b) на 3'-конце модифицированного олигонуклеотида.
5. Соединение по п. 2, отличающееся тем, что
(i) модифицированный олигонуклеотид является одноцепочечным; и/или
(ii) конъюгирующая группа связана с модифицированным олигонуклеотидом (а) на 5'-конце модифицированного олигонуклеотида или (b) на 3'-конце модифицированного олигонуклеотида.
6. Соединение по п. 3, отличающееся тем, что
(i) модифицированный олигонуклеотид является одноцепочечным; и/или
(ii) конъюгирующая группа связана с модифицированным олигонуклеотидом (а) на 5'-конце модифицированного олигонуклеотида или (b) на 3'-конце модифицированного олигонуклеотида.
7. Соединение по п. 1, отличающееся тем, что модифицированный олигонуклеотид содержит
сегмент гэп, состоящий из связанных дезоксинуклеозидов;
сегмент крыла 5', состоящий из связанных нуклеозидов;
сегмент крыла 3', состоящий из связанных нуклеозидов;
при этом сегмент гэп расположен между сегментом крыла 5' и сегментом крыла 3', и при этом каждый нуклеозид каждого сегмента крыла содержит модифицированный сахар.
8. Соединение по п. 1, отличающееся тем, что модифицированный олигонуклеотид содержит
сегмент гэп, состоящий из десяти связанных дезоксинуклеозидов;
сегмент крыла 5', состоящий из пяти связанных нуклеозидов;
сегмент крыла 3', состоящий из пяти связанных нуклеозидов;
при этом сегмент гэп расположен между сегментом крыла 5' и сегментом крыла 3', и каждый нуклеозид каждого сегмента крыла содержит 2'-O-метоксиэтил сахар, и каждый цитозиновый остаток представляет собой 5-метилцитозин.
9. Соединение по п. 8, отличающееся тем, что каждая межнуклеозидная связь представляет собой тиофосфатную связь.
10. Соединение по п. 1, оличающееся тем, что модифицированный олигонуклеотид состоит из 20 связанных нуклеозидов с последовательностью азотистых оснований SEQ ID NO: 87, при этом модифицированный олигонуклеотид содержит
сегмент гэп, состоящий из десяти связанных дезоксинуклеозидов;
сегмент крыла 5', состоящий из пяти связанных нуклеозидов;
сегмент крыла 3', состоящий из пяти связанных нуклеозидов;
при этом сегмент гэп расположен между сегментом крыла 5' и сегментом крыла 3', и каждый нуклеозид каждого сегмента крыла содержит 2'-O-метоксиэтил сахар, каждая межнуклеозидная связь представляет собой тиофосфатную связь и каждый цитозиновый остаток представляет собой 5-метилцитозин.
11. Соединение по п. 1, имеющее формулу
где либо R1 представляет собой -OCH2CH2OCH3 (МОЕ), и R2 представляет собой Н; либо R1 и R2 вместе образуют мостик, где R1 представляет собой -О-, и R2 представляет собой -СН2-, -СН(СН3)- или -СН2СН2-, и R1 и R2 связаны напрямую, так что образующийся мостик выбран из: -O-СН2-, -O-СН(СН3)- и -O-СН2СН2-;
и для каждой пары R3 и R4 у одного кольца независимо для каждого кольца либо R3 выбран из Н и -ОСН2СН2ОСН3, и R4 представляет собой Н; либо R3 и R4 вместе образуют мостик, где R3 представляет собой -О-, и R4 представляет собой -СН2-, -СН(СН3)- или -СН2СН2-, и R3 и R4 связаны напрямую, так что образующийся мостик выбран из -O-СН2-, -О-СН(СН3)- и -O-СН2СН2-;
и R5 выбран из Н и -СН3;
и Z выбран из S- и О-.
12. Соединение по п. 1, имеющее формулу
13. Соединение по любому из пп. 1-12, отличающееся тем, что соединение представлено в форме соли.
14. Соединение по п. 13, отличающееся тем, что соединение представлено в форме соли натрия и/или калия.
15. Фармацевтическая композиция, содержащая соединение по любому из пп. 1-12 и фармацевтически приемлемый носитель или разбавитель.
16. Применение соединения по любому из пп. 1-12 для лечения, предупреждения или замедления прогрессирования заболевания, связанного с повышенным уровнем ApoCIII у животного.
17. Применение по п. 16 для
a) предупреждения, лечения, улучшения или замедления прогрессирования сердечно-сосудистого, метаболического и/или воспалительного заболевания, расстройства или состояния;
b) снижения уровня триглицеридов у животного;
c) повышения уровня HDL у животного; и/или
d) повышения клиренса хиломикрона у животного, при этом повышение клиренса хиломикрона обусловливает лечение, предупреждение, отсрочку или облегчение панкреатита у животного.
18. Применение по п. 16, отличающееся тем, что животное страдает или имеет риск возникновения любого одного или нескольких заболеваний из гипертриглицеридемии, дислипидемии Фредриксона типа I, синдром наследственной хиломикронемии (FCS), недостаточность ЛПЛ (LPLD), панкреатита, диабета, нечувствительности к инсулину, хиломикронемии и дислипидемии.
19. Применение соединения по п. 13 для лечения, предупреждения или замедления прогрессирования заболевания, связанного с повышенным уровнем ApoCIII у животного.
20. Применение по п. 19 для
a) предупреждения, лечения, улучшения или замедления прогрессирования сердечно-сосудистого, метаболического и/или воспалительного заболевания, расстройства или состояния;
b) снижения уровня триглицеридов у животного;
c) повышения уровня HDL у животного; и/или
d) повышения клиренса хиломикрона у животного, при этом повышение клиренса хиломикрона обусловливает лечение, предупреждение, отсрочку или облегчение панкреатита у животного.
21. Применение по п. 19, отличающееся тем, что животное страдает или имеет риск возникновения любого одного или нескольких заболеваний из гипертриглицеридемии, дислипидемии Фредриксона типа I, FCS, LPLD, панкреатита, диабета, нечувствительности к инсулину, хиломикронемии и дислипидемии.
22. Применение соединения по п. 14 для лечения, предупреждения или замедления прогрессирования заболевания, связанного с повышенным уровнем ApoCIII у животного.
23. Применение по п. 22 для
a) предупреждения, лечения, улучшения или замедления прогрессирования сердечно-сосудистого, метаболического и/или воспалительного заболевания, расстройства или состояния;
b) снижения уровня триглицеридов у животного;
c) повышения уровня HDL у животного; и/или
d) повышения клиренса хиломикрона у животного, при этом повышение клиренса хиломикрона обусловливает лечение, предупреждение, отсрочку или облегчение панкреатита у животного.
24. Применение по п. 22, отличающееся тем, что животное страдает или имеет риск возникновения любого одного или нескольких заболеваний из гипертриглицеридемии, дислипидемии Фредриксона типа I, FCS, LPLD, панкреатита, диабета, нечувствительности к инсулину, хиломикронемии и дислипидемии.
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