JP5475643B2 - アミノ酸脂質およびその使用 - Google Patents
アミノ酸脂質およびその使用 Download PDFInfo
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- JP5475643B2 JP5475643B2 JP2010506690A JP2010506690A JP5475643B2 JP 5475643 B2 JP5475643 B2 JP 5475643B2 JP 2010506690 A JP2010506690 A JP 2010506690A JP 2010506690 A JP2010506690 A JP 2010506690A JP 5475643 B2 JP5475643 B2 JP 5475643B2
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- Prior art keywords
- alkyl
- amino acid
- acyl
- composition
- acid
- 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.)
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- -1 Amino acid lipids Chemical class 0.000 title claims description 233
- 125000000217 alkyl group Chemical group 0.000 claims description 295
- 239000000203 mixture Substances 0.000 claims description 241
- 150000007523 nucleic acids Chemical class 0.000 claims description 157
- 150000001875 compounds Chemical class 0.000 claims description 152
- 102000039446 nucleic acids Human genes 0.000 claims description 144
- 108020004707 nucleic acids Proteins 0.000 claims description 144
- 125000002252 acyl group Chemical group 0.000 claims description 108
- 108090000623 proteins and genes Proteins 0.000 claims description 88
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 81
- 102000040650 (ribonucleotides)n+m Human genes 0.000 claims description 81
- 239000003814 drug Substances 0.000 claims description 79
- 150000002632 lipids Chemical class 0.000 claims description 78
- 150000001413 amino acids Chemical class 0.000 claims description 65
- 230000009368 gene silencing by RNA Effects 0.000 claims description 61
- 229940079593 drug Drugs 0.000 claims description 57
- 125000003342 alkenyl group Chemical group 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 54
- 239000001257 hydrogen Substances 0.000 claims description 54
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
- 239000013543 active substance Substances 0.000 claims description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 46
- 230000014509 gene expression Effects 0.000 claims description 46
- 125000002091 cationic group Chemical group 0.000 claims description 45
- 201000010099 disease Diseases 0.000 claims description 43
- 125000006539 C12 alkyl 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])C([H])([H])C([H])([H])* 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
- 239000002502 liposome Substances 0.000 claims description 35
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 35
- 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 32
- 125000003892 C18 acyl group Chemical group 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 229910052760 oxygen Inorganic materials 0.000 claims description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 28
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- 125000004429 atom Chemical group 0.000 claims description 21
- 125000000539 amino acid group Chemical group 0.000 claims description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
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- 206010022000 influenza Diseases 0.000 claims description 15
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 13
- 150000008574 D-amino acids Chemical group 0.000 claims description 12
- 150000008575 L-amino acids Chemical group 0.000 claims description 12
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- CNMAQBJBWQQZFZ-LURJTMIESA-N (2s)-2-(pyridin-2-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CC=N1 CNMAQBJBWQQZFZ-LURJTMIESA-N 0.000 claims description 10
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- IFPQOXNWLSRZKX-UHFFFAOYSA-N 2-amino-4-(diaminomethylideneamino)butanoic acid Chemical compound OC(=O)C(N)CCN=C(N)N IFPQOXNWLSRZKX-UHFFFAOYSA-N 0.000 claims description 9
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- WLNARFZDISHUGS-MIXBDBMTSA-N cholesteryl hemisuccinate Chemical compound C1C=C2C[C@@H](OC(=O)CCC(O)=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 WLNARFZDISHUGS-MIXBDBMTSA-N 0.000 claims description 8
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- NVLXHKQYGPUERO-UHFFFAOYSA-N n-[4-(diaminomethylideneamino)-1-(dodecylamino)-1-oxobutan-2-yl]dodecanamide Chemical compound CCCCCCCCCCCCNC(=O)C(CCNC(N)=N)NC(=O)CCCCCCCCCCC NVLXHKQYGPUERO-UHFFFAOYSA-N 0.000 claims description 2
- GBGLVOBJIFHZQQ-UHFFFAOYSA-N n-[4-(diaminomethylideneamino)-1-(hexadecylamino)-1-oxobutan-2-yl]octadec-9-enamide Chemical compound CCCCCCCCCCCCCCCCNC(=O)C(CCNC(N)=N)NC(=O)CCCCCCCC=CCCCCCCCC GBGLVOBJIFHZQQ-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000753 cycloalkyl group Chemical group 0.000 description 26
- 230000004048 modification Effects 0.000 description 26
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- 125000000304 alkynyl group Chemical group 0.000 description 24
- 238000009472 formulation Methods 0.000 description 24
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 24
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- 229920000642 polymer Polymers 0.000 description 23
- 229920001223 polyethylene glycol Polymers 0.000 description 22
- 239000002243 precursor Substances 0.000 description 22
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 21
- 108091027967 Small hairpin RNA Proteins 0.000 description 21
- 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 description 21
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- 159000000000 sodium salts Chemical class 0.000 description 20
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- 239000002202 Polyethylene glycol Substances 0.000 description 17
- 108020004459 Small interfering RNA Proteins 0.000 description 17
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 16
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
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- 125000004432 carbon atom Chemical group C* 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000002270 dispersing agent Substances 0.000 description 12
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- 150000003431 steroids Chemical class 0.000 description 12
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 11
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 11
- 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 description 11
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Description
本発明は、種々の分子を細胞に送達するために有用な脂質を含む、新規な薬物送達増強剤に関する。本発明は、ある範囲の化合物、組成物、処方物、最終的には薬物送達に指向されるこのような薬剤の方法および使用、治療、ならびに疾患および状態(被験体における遺伝子発現もしくは遺伝子活性の調節に応答するものを含む)の診断および処置を提供する。より具体的には、本発明は、化合物、リポソーム、ラメラ小胞、エマルジョン、ミセル、懸濁物、粒子、溶液ならびに薬物増強組成物および処方物の他の形態、ならびに治療方法およびこれら送達物質のための使用に関する。
被験体への治療化合物の送達は、上記化合物が標的細胞もしくは標的組織に達する能力が制限されていること、または細胞内への上記化合物の侵入もしくは行き来(trafficking)の制限によって、妨げられ得る。治療物質の送達は、細胞の膜によって一般に制限されている。送達に対するこれらの障壁および制限は、結果を達成するために所望されるより遙かに高濃度の化合物を使用する必要性を生じ得、このことは、毒性効果および副作用の危険性をもたらす。
本開示は、最終的には治療剤として使用するための薬物因子の細胞内送達およびインビボ送達のための、新規な化合物、組成物および処方物を提供する。本開示の化合物および組成物は、疾患状態もしくは表現型を変化させるために、選択された細胞、組織、器官もしくは区画への薬物因子の送達のために有用である。
本発明は、例えば以下の項目を提供する。
(項目1)
式Iに示される構造を含む化合物:
R 3 −(C=O)−Xaa−Z−R 4 式I
およびその塩であって、ここで
Xaaは、式−NR N −CR 1 R 2 −(C=O)−を有する任意のD−アミノ酸残基もしくはL−アミノ酸残基、または式-{NR N −CR 1 R 2 −(C=O)} n −を有する
n=2〜20のアミノ酸残基のペプチドであり、ここで
R 1 は、独立して、各存在について、非水素、アミノ酸の、置換されたかもしくは置換されていない側鎖であり;
R 2 は独立して、各存在について、水素、または炭素、酸素、窒素、硫黄、および水素原子からなりかつ1〜20個の炭素原子を有する有機基、またはC(1−5)アルキル、シクロアルキル、シクロアルキルアルキル、C(3−5)アルケニル、C(3−5)アルキニル、C(1−5)アルカノイル、C(1−5)アルカノイルオキシ、C(1−5)アルコキシ、C(1−5)アルコキシ−C(1−5)アルキル、C(1−5)アルコキシ−C(1−5)アルコキシ、C(1−5)アルキル−アミノ−C(1−5)アルキル−、C(1−5)ジアルキル−アミノ−C(1−5)アルキル−、ニトロ−C(1−5)アルキル、シアノ−C(1−5)アルキル、アリール−C(1−5)アルキル、4−ビフェニル−C(1−5)アルキル、カルボキシル、もしくはヒドロキシルであり、
R N は独立して、各存在について、水素、または炭素、酸素、窒素、硫黄、および水素原子からなりかつ1〜20個の炭素原子を有する有機基、またはC(1−5)アルキル、シクロアルキル、シクロアルキルアルキル、C(3−5)アルケニル、C(3−5)アルキニル、C(1−5)アルカノイル、C(1−5)アルカノイルオキシ、C(1−5)アルコキシ、C(1−5)アルコキシ−C(1−5)アルキル、C(1−5)アルコキシ−C(1−5)アルコキシ、C(1−5)アルキル−アミノ−C(1−5)アルキル−、C(1−5)ジアルキル−アミノ−C(1−5)アルキル−、ニトロ−C(1−5)アルキル、シアノ−C(1−5)アルキル、アリール−C(1−5)アルキル、4−ビフェニル−C(1−5)アルキル、カルボキシル、もしくはヒドロキシルであり、
R 3 は独立して、天然に存在するかもしくは合成の脂質、リン脂質、糖脂質、トリアシルグリセロール、グリセロリン脂質、スフィンゴ脂質、セラミド、スフィンゴミエリン、セレブロシド、もしくはガングリオシドに由来する親油性テイルであり、ここで該テイルは、ステロイド;または置換されているかもしくは置換されていないC(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキルを含み得;
R 4 は独立して、天然に存在するかもしくは合成の脂質、リン脂質、糖脂質、トリアシルグリセロール、グリセロリン脂質、スフィンゴ脂質、セラミド、スフィンゴミエリン、セレブロシド、もしくはガングリオシドに由来する親油性テイルであり、ここで該テイルは、ステロイド;または置換されているかもしくは置換されていないC(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキルを含み得;
ここでR 3 およびR 4 のうちのいずれか一方は、上記のような親油性テイルであり、他方は、アミノ酸末端基であるか、またはR 3 およびR 4 の両方が親油性テイルであり;該アミノ酸末端基は、水素、ヒドロキシル、アミノ、もしくは有機保護基であり;
Zは、NH、O、S、−CH 2 S−、−CH 2 S(O)−、または水素、炭素、酸素、窒素、および硫黄原子から選択される1〜40個の原子からなる有機性リンカーである、化合物。
(項目2)
式Iに示される構造を含む化合物:
R 3 −(C=O)−Xaa−Z−R 4 式I
およびその塩であって、ここで
Xaaは、式−NR N −CR 1 R 2 −(C=O)−を有するD−アミノ酸残基もしくはL−アミノ酸残基であり、ここで
R 1 は、アミノ酸の、置換されているかもしくは置換されていない塩基性側鎖であり;
R 2 は、水素、もしくはC(1−5)アルキルであり、
R N は、水素、もしくはC(1−5)アルキルであり、
R 3 は独立して、置換されているかもしくは置換されていないC(6−22)アルキルもしくはC(6−22)アルケニルであり;
R 4 は独立して、置換されているかもしくは置換されていないC(6−22)アルキルもしくはC(6−22)アルケニルであり;
Zは、NH、O、もしくは水素、炭素、酸素、窒素、および硫黄原子から選択される1〜40個の原子からなる有機性リンカーである、
化合物。
(項目3)
Xaaは、アルギニン、ホモアルギニン、ノルアルギニン、ノル−ノルアルギニン、オルニチン、リジン、ホモリジン、ヒスチジン、1−メチルヒスチジン、ピリジルアラニン、アスパラギン、N−エチルアスパラギン、グルタミン、4−アミノフェニルアラニン、これらのN−メチル化バージョン、およびこれらの側鎖改変誘導体から選択される、項目2に記載の化合物。
(項目4)
Xaaは、アルギニン、そのN−メチル化バージョン、もしくはその側鎖改変誘導体である、項目2に記載の化合物。
(項目5)
Xaaは、ノルアルギニン、そのN−メチル化バージョン、もしくはその側鎖改変誘導体である、項目2に記載の化合物。
(項目6)
Xaaは、リジン、そのN−メチル化バージョン、もしくはその側鎖改変誘導体である、項目2に記載の化合物。
(項目7)
Xaaは、ヒスチジン、そのN−メチル化バージョン、もしくはその側鎖改変誘導体である、項目2に記載の化合物。
(項目8)
Xaaは、ピリジルアラニン、そのN−メチル化バージョン、もしくはその側鎖改変誘導体である、項目2に記載の化合物。
(項目9)
Xaaはシステインもしくはセリンである、項目2に記載の化合物。
(項目10)
R 2 は水素である、項目2に記載の化合物。
(項目11)
R N は水素である、項目2に記載の化合物。
(項目12)
R 3 およびR 4 は、C(6−22)アルキルであり、かつ同じであるかもしくは異なっている、項目2に記載の化合物。
(項目13)
R 3 およびR 4 は、C(6−22)アルケニルであり、かつ同じであるかもしくは異なっている、項目2に記載の化合物。
(項目14)
R 3 はC(6−22)アルキルであり、R 4 はC(6−22)アルケニルである、項目2に記載の化合物。
(項目15)
R 4 は、C(6−22)アルキルであり、R 3 は、C(6−22)アルケニルである、項目2に記載の化合物。
(項目16)
ZはNHである、項目2に記載の化合物。
(項目17)
ZはOである、項目2に記載の化合物。
(項目18)
Xaaは、2〜20個のアミノ酸残基のペプチドである、項目2に記載の化合物。
(項目19)
Xaaは、5〜7.5のpKaを有する官能基を含む側鎖を有する、項目2に記載の化合物。
(項目20)
Xaaは、3,5−ジヨード−チロシン、1−メチルヒスチジン、2−メチル酪酸、2−o−アニシルプロパン酸、meso−酒石酸、4,6−ジメチルピリミジンアミンp−フタル酸、クレアチニン、酪酸、N,N−ジメチル−1−ナフチルアミン、ペンタン酸、4−メチルペンタン酸、N−メチルアニリン、1,10−フェナントロリン、3−ピリジンカルボン酸、ヘキサン酸、プロパン酸、4−アミノ安息香酸、2−メチルプロパン酸、ヘプタン酸、オクタン酸、シクロヘキサンカルボン酸、キノリン、3−キノリンアミン、2−アミノ安息香酸、4−ピリジンカルボン酸、ノナン酸、メラミン、8−キノリノール、トリメチル酢酸、6−メトキシキノリン、4−(メチルアミノ)安息香酸、p−メチルアニリン、3−(メチルアミノ)安息香酸、リンゴ酸、N−エチルアニリン、2−ベンジルピリジン、3,6−ジニトロフェノール、N,N−ジメチルアニリン、2,5−ジメチルピペラジン、p−フェネチジン、5−メチルキノリン、2−フェニルベンゾイミダゾール、ピリジン、ピコリン酸、3,5−ジヨードチロシン、p−アニシジン、2−(メチルアミノ)安息香酸、2−チアゾールアミン、グルタル酸、アジピン酸、イソキノリン、イタコン酸、o−フタル酸、ベンゾイミダゾール、ピペラジン、ヘプタン二酸、アクリジン、フェナントリジン、コハク酸、メチルコハク酸、4−メチルキノリン、3−メチルピリジン、7−イソキノリノール、マロン酸、メチルマロン酸、2−メチルキノリン、2−エチルピリジン、2−メチルピリジン、4−メチルピリジン、ヒスタミン、ヒスチジン、マレイン酸、cis−1,2−シクロヘキサンジアミン、3,5−ジメチルピリジン、2−エチルベンゾイミダゾール、2−メチルベンゾイミダゾール、カコジル酸、ペリミジン、クエン酸、イソクエン酸、2,5−ジメチルピリジン、パパベリン、6−ヒドロキシ−4−メチルプテリジン、L−チロキシン、3,4−ジメチルピリジン、メトキシピリジン、trans−1,2−シクロヘキサンジアミン、2,5−ピリジンジアミン、l−1−メチルヒスチジン、l−3−メチルヒスチジン、2,3−ジメチルピリジン、キサントプテリン、1,2−プロパンジアミン、N,N−ジエチルアニリン、アロキサン酸、2,6−ジメチルピリジン、L−カルノシン、2−ピリジンアミン、N−b−アラニルヒスチジン、ピロカルピン、1−メチルイミダゾール、1H−イミダゾール、2,4−ジメチルピリジン、4−ニトロフェノール、2−ニトロフェノール、チロシンアミド、5−ヒドロキシキナゾリン、1,1−シクロプロパンジカルボン酸、2,4,6−トリメチルピリジン、ベロナール、2,3−ジクロロフェノール、1,2−エタンジアミン、1−イソキノリンアミン、およびこれらの組み合わせから選択される放出官能基を含む側鎖を有する、項目2に記載の化合物。
(項目21)
項目1に記載の化合物のマルチマーを含む化合物であって、ここで2つ以上の項目1に記載の化合物が架橋されている、化合物。
(項目22)
項目1に記載の化合物の結合体を含む化合物であって、ここでペプチドは、前記アミノ酸残基の側鎖に結合体化されている、化合物。
(項目23)
オリゴマーフレームワークもしくはポリマーフレームワークに結合した項目1に記載の化合物を含む、化合物。
(項目24)
薬学的薬物化合物に結合した項目1に記載の化合物を含む、化合物。
(項目25)
(C10アシル)−Arg−NH−(C10アルキル)、(C12アシル)−Arg−NH−(C12アルキル)、(C14アシル)−Arg−NH−(C14アルキル)、(C16アシル)−Arg−NH−(C16アルキル)、(C18アシル)−Arg−NH−(C18アルキル)、(C12アシル)−Arg−NH−(C14アルキル)、(C18オレイック)−Arg−NH−(C16アルキル)、(C10アシル)−ホモArg−NH−(C10アルキル)、(C12アシル)−ホモArg−NH−(C12アルキル)、(C14アシル)−ホモArg−NH−(C14アルキル)、(C16アシル)−ホモArg−NH−(C16アルキル)、(C18アシル)−ホモArg−NH−(C18アルキル)、(C10アシル)−norArg−NH−(C10アルキル)、(C12アシル)−norArg−NH−(C12アルキル)、(C14アシル)−norArg−NH−(C14アルキル)、(C16アシル)−norArg−NH−(C16アルキル)、(C18アシル)−norArg−NH−(C18アルキル)、(C16アシル)−norArg−NH−(C12アルキル)、(C18オレイック)−norArg−NH−(C12アルキル)、(C18オレイック)−norArg−NH−(C16アルキル)、(C18オレイック)−norArg−NH−(C18アルキル)、(C10アシル)−nornorArg−NH−(C10アルキル)、(C12アシル)−nornorArg−NH−(C12アルキル)、(C14アシル)−nornorArg−NH−(C14アルキル)、(C16アシル)−nornorArg−NH−(C16アルキル)、(C18アシル)−nornorArg−NH−(C18アルキル)、(C10アシル)−4−Pal−NH−(C10アルキル)、(C12アシル)−4−Pal−NH−(C12アルキル)、(C14アシル)−4−Pal−NH−(C14アルキル)、(C16アシル)−4−Pal−NH−(C16アルキル)、(C18アシル)−4−Pal−NH−(C18アルキル)、(C18オレイック)−4−Pal−NH−(C16アルキル)、(C10アシル)−4−Pal(Me)−NH−(C10アルキル)、(C12アシル)−4−Pal(Me)−NH−(C12アルキル)、(C14アシル)−4−Pal(Me)−NH−(C14アルキル)、(C16アシル)−4−Pal(Me)−NH−(C16アルキル)、および(C18アシル)−4−Pal(Me)−NH−(C18アルキル)から選択される、項目1に記載の化合物。
(項目26)
C12−norArg−C12である、化合物N−(4−グアニジノ−1−オキソ−1−(ドデシルアミノ)ブタン−2−イル)ドデカンアミド。
(項目27)
C18(オレイック)−norArg−C16である化合物N−(4−グアニジノ−1−オキソ−1−(ヘキサデシルアミノ)ブタン−2−イル)オクタデカ−9−エナミド。
(項目28)
(C18オレイック)−(1−CH 3 −His)−NH−(C16アルキル)である、化合物N−(3−(1−メチル−1H−イミダゾール−4−イル)−1−オキソ−1−(ヘキサデシルアミノ)プロパン−2−イル)オクタデカ−9−エナミド。
(項目29)
式Iに示される構造を含む化合物およびその塩:
R 3 −(C=O)−Xaa−Z−R 4 式I
であって、ここで
Xaaは、式−NR N −CR 1 R 2 −(C=O)−を有するD−アミノ酸もしくはL−アミノ酸残基であり、ここで
R 1 は、置換されているかもしくは置換されていない、アミノ酸の塩基性側鎖であり;
R 2 は、水素、もしくはC(1−5)アルキルであり、
R N は、水素、もしくはC(1−5)アルキルであり、
R 3 は、独立して、置換されているかもしくは置換されていない、C(6−22)アルキルもしくはC(6−22)アルケニルであり;
R 4 は水素であり;
Zは、NH、O、もしくは水素、炭素、酸素、窒素、および硫黄原子から選択される1〜40個の原子からなる有機性リンカーである;
化合物。
(項目30)
Xaa、アルギニン、ホモアルギニン、ノルアルギニン、ノル−ノルアルギニン、オルニチン、リジン、ホモリジン、ヒスチジン、1−メチルヒスチジン、ピリジルアラニン、アスパラギン、N−エチルアスパラギン、グルタミン、4−アミノフェニルアラニン、これらのN−メチル化バージョン、およびこれらの側鎖改変誘導体から選択される、項目29に記載の化合物。
(項目31)
Xaaは、アルギニン、そのN−メチル化バージョン、もしくはその側鎖改変誘導体である、項目29に記載の化合物。
(項目32)
Xaaは、ノルアルギニン、そのN−メチル化バージョン、もしくはその側鎖改変誘導体である、項目29に記載の化合物。
(項目33)
Xaaは、リジン、そのN−メチル化バージョン、もしくはその側鎖改変誘導体である、項目29に記載の化合物。
(項目34)
Xaaは、ヒスチジン、そのN−メチル化バージョン、もしくはその側鎖改変誘導体である、項目29に記載の化合物。
(項目35)
Xaaは、ピリジルアラニン、そのN−メチル化バージョン、もしくはその側鎖改変誘導体である、項目29に記載の化合物。
(項目36)
Xaaは、システインもしくはセリンである、項目29に記載の化合物。
(項目37)
R 2 は水素である、項目29に記載の化合物。
(項目38)
R N は水素である、項目29に記載の化合物。
(項目39)
R 3 は、C(6−22)アルキルである、項目29に記載の化合物。
(項目40)
R 3 は、C(6−22)アルケニルである、項目29に記載の化合物。
(項目41)
ZはNHである、項目29に記載の化合物。
(項目42)
ZはOである、項目29に記載の化合物。
(項目43)
Xaaは、2〜20アミノ酸残基のペプチドである、項目29に記載の化合物。
(項目44)
Xaaは、5〜7.5のpKaを有する官能基を含む側鎖を有する、項目29に記載の化合物。
(項目45)
Xaaは、3,5−ジヨード−チロシン、1−メチルヒスチジン、2−メチル酪酸、2−o−アニシルプロパン酸、meso−酒石酸、4,6−ジメチルピリミジンアミン p−フタル酸、クレアチニン、酪酸、N,N−ジメチル−1−ナフチルアミン、ペンタン酸、4−メチルペンタン酸、N−メチルアニリン、1,10−フェナントロリン、3−ピリジンカルボン酸、ヘキサン酸、プロパン酸、4−アミノ安息香酸、2−メチルプロパン酸、ヘプタン酸、オクタン酸、シクロヘキサンカルボン酸、キノリン、3−キノリンアミン、2−アミノ安息香酸、4−ピリジンカルボン酸、ノナン酸、メラミン、8−キノリノール、トリメチル酢酸、6−メトキシキノリン、4−(メチルアミノ)安息香酸、p−メチルアニリン、3−(メチルアミノ)安息香酸、リンゴ酸、N−エチルアニリン、2−ベンジルピリジン、3,6−ジニトロフェノール、N,N−ジメチルアニリン、2,5−ジメチルピペラジン、p−フェネチジン、5−メチルキノリン、2−フェニルベンゾイミダゾール、ピリジン、ピコリン酸、3,5−ジヨードチロシン、p−アニシジン、2−(メチルアミノ)安息香酸、2−チアゾールアミン、グルタル酸、アジピン酸、イソキノリン、イタコン酸、o−フタル酸、ベンゾイミダゾール、ピペラジン、ヘプタン二酸、アクリジン、フェナントリジン、コハク酸、メチルコハク酸、4−メチルキノリン、3−メチルピリジン、7−イソキノリノール、マロン酸、メチルマロン酸、2−メチルキノリン、2−エチルピリジン、2−メチルピリジン、4−メチルピリジン、ヒスタミン、ヒスチジン、マレイン酸、cis−1,2−シクロヘキサンジアミン、3,5−ジメチルピリジン、2−エチルベンゾイミダゾール、2−メチルベンゾイミダゾール、カコジル酸、ペリミジン、クエン酸、イソクエン酸、2,5−ジメチルピリジン、パパベリン、6−ヒドロキシ−4−メチルプテリジン、L−チロキシン、3,4−ジメチルピリジン、メトキシピリジン、trans−1,2−シクロヘキサンジアミン、2,5−ピリジンジアミン、l−1−メチルヒスチジン、l−3−メチルヒスチジン、2,3−ジメチルピリジン、キサントプテリン、1,2−プロパンジアミン、N,N−ジエチルアニリン、アロキサン酸、2,6−ジメチルピリジン、L−カルノシン、2−ピリジンアミン、N−b−アラニルヒスチジン、ピロカルピン、1−メチルイミダゾール、1H−イミダゾール、2,4−ジメチルピリジン、4−ニトロフェノール、2−ニトロフェノール、チロシンアミド、5−ヒドロキシキナゾリン、1,1−シクロプロパンジカルボン酸、2,4,6−トリメチルピリジン、ベロナール、2,3−ジクロロフェノール、1,2−エタンジアミン、1−イソキノリンアミン、およびこれらの組み合わせから選択される放出官能基を含む塩基性側鎖を有する、項目29に記載の化合物。
(項目46)
項目29に従う2つ以上の化合物が架橋されている、項目29に記載の化合物のマルチマーを含む化合物。
(項目47)
ペプチドは、前記アミノ酸残基の側鎖に結合体化されている、項目29に記載の化合物の結合体を含む化合物。
(項目48)
オリゴマー化合物フレームワークもしくはポリマーフレームワークに結合されている、項目29に記載の化合物を含む化合物。
(項目49)
薬学的薬物化合物に結合された、項目29に記載の化合物を含む化合物。
(項目50)
項目1〜49のいずれか1項に従う1個以上のアミノ酸脂質および1つ以上の治療核酸を含む、組成物。
(項目51)
前記治療核酸は、遺伝子抑制剤である、項目50に記載の組成物。
(項目52)
前記治療核酸は、RNAi誘導剤である、項目50に記載の組成物。
(項目53)
前記治療核酸は、二本鎖RNAである、項目50に記載の組成物。
(項目54)
前記治療核酸はmdRNAである、項目50に記載の組成物。
(項目55)
前記治療核酸は、改変ヌクレオシドを含む、項目50に記載の組成物。
(項目56)
1種以上の非アミノ酸非カチオン性脂質もしくはステロールをさらに含む、項目50に記載の組成物。
(項目57)
コレステリルヘミスクシネートをさらに含む、項目50に記載の組成物。
(項目58)
1種以上の非アミノ酸カチオン性脂質をさらに含む、項目50に記載の組成物。
(項目59)
1種以上のpeg化脂質もしくはpeg化ステロールをさらに含む、項目50に記載の組成物。
(項目60)
前記核酸は、1種以上のアミノ酸脂質と複合体を形成する、項目50に記載の組成物。
(項目61)
前記組成物は、リポソームを含む、項目50に記載の組成物。
(項目62)
前記組成物は、エマルジョンである、項目50に記載の組成物。
(項目63)
前記組成物は、ミセル分散物である、項目50に記載の組成物。
(項目64)
項目1〜49のいずれか1項に記載の1種以上のアミノ酸脂質化合物、および1種以上の薬物因子もしくは生物学的に活性な薬剤を含む、薬学的組成物。
(項目65)
治療核酸を細胞に送達するための方法であって、該方法は、項目50に記載の組成物を調製する工程、および細胞を該組成物で処理する工程を包含する、方法。
(項目66)
細胞における遺伝子の発現を阻害するための方法であって、該方法は、項目50に記載の組成物を調製する工程、および細胞を該組成物で処理する工程を包含する、方法。
(項目67)
哺乳動物における遺伝子の発現を阻害するための方法であって、該方法は、項目50に記載の組成物を調製する工程、および該哺乳動物に該組成物を投与する工程を包含する、方法。
(項目68)
ヒトにおける疾患を処置するための方法であって、該疾患は、関節リウマチ、肝臓疾患、脳炎、骨折、心疾患、肝炎およびインフルエンザを含むウイルス疾患、敗血症、ならびに癌から選択され、該方法は、項目50に記載の組成物を調製する工程、および該組成物を該ヒトに投与する工程を包含する、方法。
(項目69)
関節リウマチ、肝臓疾患、脳炎、骨折、心疾患、肝炎およびインフルエンザを含むウイルス疾患、敗血症、ならびに癌を含む疾患を処置するための医薬の製造における、項目50に記載の組成物の使用。
(項目70)
関節リウマチ、肝臓疾患、脳炎、骨折、心疾患、肝炎およびインフルエンザを含むウイルス疾患、敗血症、ならびに癌から選択される疾患を処置するための、項目50に記載の組成物の使用。
R3−(C=O)−Xaa−Z−R4 式I
ここで
Xaaは、式−NRN−CR1R2−(C=O)−を有する任意のD−アミノ酸もしくはL−アミノ酸残基であるか、または式−{NRN−CR1R2−(C=O)}n−を有するn=2〜20アミノ酸残基のペプチドであり、
ここで
R1は独立して、各存在について、非水素、アミノ酸の、置換されているかもしくは置換されていない側鎖であり;
R2は独立して、各存在について、水素、または炭素、酸素、窒素、硫黄、および水素原子からなり、かつ1〜20個の炭素原子を有する有機基、またはC(1−5)アルキル、シクロアルキル、シクロアルキルアルキル、C(3−5)アルケニル、C(3−5)アルキニル、C(1−5)アルカノイル、C(1−5)アルカノイルオキシ、C(1−5)アルコキシ、C(1−5)アルコキシ−C(1−5)アルキル、C(1−5)アルコキシ−C(1−5)アルコキシ、C(1−5)アルキル−アミノ−C(1−5)アルキル−、C(1−5)ジアルキル−アミノ−C(1−5)アルキル−、ニトロ−C(1−5)アルキル、シアノ−C(1−5)アルキル、アリール−C(1−5)アルキル、4−ビフェニル−C(1−5)アルキル、カルボキシル、もしくはヒドロキシルであり、
RNは独立して、各存在について、水素、または炭素、酸素、窒素、硫黄、および水素原子からなり、かつ1〜20個の炭素原子を有する有機基、またはC(1−5)アルキル、シクロアルキル、シクロアルキルアルキル、C(3−5)アルケニル、C(3−5)アルキニル、C(1−5)アルカノイル、C(1−5)アルカノイルオキシ、C(1−5)アルコキシ、C(1−5)アルコキシ−C(1−5)アルキル、C(1−5)アルコキシ−C(1−5)アルコキシ、C(1−5)アルキル−アミノ−C(1−5)アルキル−、C(1−5)ジアルキル−アミノ−C(1−5)アルキル−、ニトロ−C(1−5)アルキル、シアノ−C(1−5)アルキル、アリール−C(1−5)アルキル、4−ビフェニル−C(1−5)アルキル、カルボキシル、もしくはヒドロキシルであり、
R3は独立して、天然に存在するかもしくは合成の脂質、リン脂質、糖脂質、トリアシルグリセロール、グリセロリン脂質、スフィンゴ脂質、セラミド、スフィンゴミエリン、セレブロシド、もしくはガングリオシドに由来する親油性テイルであり、ここで上記テイルは、ステロイド;または置換されているかもしくは置換されていないC(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキルを含み得;
R4は、独立して、天然に存在するかもしくは合成の脂質、リン脂質、糖脂質、トリアシルグリセロール、グリセロリン脂質、スフィンゴ脂質、セラミド、スフィンゴミエリン、セレブロシド、もしくはガングリオシドから由来する親油性テイルであり、ここで上記テイルは、ステロイド;または置換されているかもしくは置換されていないC(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキルを含み得;
ここでR3およびR4のうちのいずれか一方は、上記で定義される親油性テイルであり、そして他方はアミノ酸末端基であるか、またはR3およびR4の両方が親油性テイルであり;上記アミノ酸末端基は、水素、ヒドロキシル、アミノ、もしくは有機保護基であり;
Zは、NH、O、S、−CH2S−、−CH2S(O)−、または水素、炭素、酸素、窒素、および硫黄原子から選択される1〜40個の原子からなる有機性リンカーである。
R3−(C=O)−Xaa−Z−R4 式I
ここで
Xaaは、式−NRN−CR1R2−(C=O)−を有するD−アミノ酸残基もしくはL−アミノ酸残基であり、
ここで
R1は、アミノ酸の、置換されているかもしくは置換されていない塩基性側鎖であり;
R2は、水素、もしくはC(1−5)アルキルであり、
RNは、水素、もしくはC(1−5)アルキルであり、
R3は独立して、置換されているかもしくは置換されていないC(6−22)アルキルもしくはC(6−22)アルケニルであり;
R4は独立して、置換されているかもしくは置換されていないC(6−22)アルキルもしくはC(6−22)アルケニルであり;
Zは、NH、O、もしくは水素、炭素、酸素、窒素、および硫黄原子から選択される1〜40個の原子からなる有機性リンカーである。
R3−(C=O)−Xaa−Z−R4 式I
ここで
Xaaは、式−NRN−CR1R2−(C=O)−を有するD−アミノ酸もしくはL−アミノ酸残基であり、
R1は、アミノ酸の、置換されているかもしくは置換されていない塩基性側鎖であり;
R2は、水素、もしくはC(1−5)アルキルであり、
RNは、水素、もしくはC(1−5)アルキルであり、
R3は独立して、置換されているかもしくは置換されていないC(6−22)アルキルもしくはC(6−22)アルケニルであり;
R4は水素であり;
Zは、NH、O、もしくは水素、炭素、酸素、窒素、および硫黄原子から選択される1〜40個の原子からなる有機性リンカーである。
本開示は、一般に、薬物因子の送達のための新規な化合物、組成物およびその使用に関する。本開示の化合物および組成物は、選択された細胞、組織、器官もしくは被験体に治療剤を送達するために有用である。
本発明は、薬物因子の送達および投与、ならびに薬物送達系において使用するための親油性化合物である、ある範囲のアミノ酸脂質を提供する。本開示のアミノ酸脂質は、アミノ酸残基および1つ以上の親油性テイルを含む分子である。
R3−(C=O)−Xaa−Z−R4 式I
ここで
Xaaは、式−NRN−CR1R2−(C=O)−を有する任意のD−アミノ酸残基もしくはL−アミノ酸残基、または式−{NRN−CR1R2−(C=O)}n−を有するn=2〜20アミノ酸残基のペプチドであり、
ここで
R1は独立して、各存在について、非水素、アミノ酸の、置換されているかもしくは置換されていない側鎖であり;
R2は独立して、各存在について、水素、または炭素、酸素、窒素、硫黄、および水素原子からなりかつ1〜20個の炭素原子を有する有機基、またはC(1−5)アルキル、シクロアルキル、シクロアルキルアルキル、C(3−5)アルケニル、C(3−5)アルキニル、C(1−5)アルカノイル、C(1−5)アルカノイルオキシ、C(1−5)アルコキシ、C(1−5)アルコキシ−C(1−5)アルキル、C(1−5)アルコキシ−C(1−5)アルコキシ、C(1−5)アルキル−アミノ−C(1−5)アルキル−、C(1−5)ジアルキル−アミノ−C(1−5)アルキル−、ニトロ−C(1−5)アルキル、シアノ−C(1−5)アルキル、アリール−C(1−5)アルキル、4−ビフェニル−C(1−5)アルキル、カルボキシル、もしくはヒドロキシルであり、
RNは独立して、各存在について、水素、または炭素、酸素、窒素、硫黄、および水素原子からなりかつ1〜20個の炭素原子を有する有機基、またはC(1−5)アルキル、シクロアルキル、シクロアルキルアルキル、C(3−5)アルケニル、C(3−5)アルキニル、C(1−5)アルカノイル、C(1−5)アルカノイルオキシ、C(1−5)アルコキシ、C(1−5)アルコキシ−C(1−5)アルキル、C(1−5)アルコキシ−C(1−5)アルコキシ、C(1−5)アルキル−アミノ−C(1−5)アルキル−、C(1−5)ジアルキル−アミノ−C(1−5)アルキル−、ニトロ−C(1−5)アルキル、シアノ−C(1−5)アルキル、アリール−C(1−5)アルキル、4−ビフェニル−C(1−5)アルキル、カルボキシル、もしくはヒドロキシルであり、
R3は、天然に存在するかもしくは合成のリン脂質、糖脂質、トリアシルグリセロール、グリセロリン脂質、スフィンゴ脂質、セラミド、スフィンゴミエリン、セレブロシド、もしくはガングリオシドに由来する親油性テイル;または置換されているかもしくは置換されていない、C(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキル;または任意の他の天然に存在するかもしくは合成の脂質の親油性テイル、または本明細書において以下に記載されるさらなる送達脂質のうちのいずれか1つの親油性テイルであり、ステロイドを含み得;
R4は、天然に存在するかもしくは合成のリン脂質、糖脂質、トリアシルグリセロール、グリセロリン脂質、スフィンゴ脂質、セラミド、スフィンゴミエリン、セレブロシド、もしくはガングリオシドに由来する親油性テイル;または置換されているかもしくは置換されていない、C(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキル;または任意の他の天然に存在するかもしくは合成の脂質の親油性テイル、または本明細書において以下に記載されるさらなる送達脂質の親油性テイルであり、ステロイドを含み得;
Zは、NH、O、S、−CH2S−、−CH2S(O)−、または水素、炭素、酸素、窒素、および硫黄原子から選択される1〜40個の原子からなる有機リンカーである。
Xaaは、一般式−NRN−CR1R2−(C=O)−を有する任意のD−アミノ酸もしくはL−アミノ酸であり、ここで
R1は、非水素、アミノ酸の、置換されているかもしくは置換されていない塩基性側鎖であり;
R2は、水素、もしくはC(1−5)アルキルであり、
RNは、水素、もしくはC(1−5)アルキルであり、
R3は、天然に存在するかもしくは合成のリン脂質、糖脂質、トリアシルグリセロール、グリセロリン脂質、スフィンゴ脂質、セラミド、スフィンゴミエリン、セレブロシド、もしくはガングリオシドに由来する親油性テイル;または置換されているかもしくは置換されていない、C(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキル;または任意の他の天然に存在するかもしくは合成の脂質の親油性テイル、または本明細書において以下に記載されるさらなる送達脂質のうちのいずれか1つの親油性テイルであり、そしてステロイドを含み得;
R4は、天然に存在するかもしくは合成のリン脂質、糖脂質、トリアシルグリセロール、グリセロリン脂質、スフィンゴ脂質、セラミド、スフィンゴミエリン、セレブロシド、もしくはガングリオシドに由来する親油性テイル;または置換されているかもしくは置換されていない、C(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキル;または任意の他の天然に存在するかもしくは合成の脂質の親油性テイル、または本明細書において以下に記載されるさらなる送達脂質のうちのいずれか1つの親油性テイルであり、そしてステロイドを含み得;
Zは、NH、O、S、−CH2S−、−CH2S(O)−、または水素、炭素、酸素、窒素、および硫黄原子から選択される1〜40個の原子からなる有機リンカーである。
Xaaは、一般式−NRN−CR1R2−(C=O)−を有する任意のD−アミノ酸もしくはL−アミノ酸であり、ここで
R1は、非水素、アミノ酸の、置換されているかもしくは置換されていない塩基性側鎖であり;
R2は、水素、もしくはC(1−5)アルキルであり、
RNは、水素、もしくはC(1−5)アルキルであり、
R3は、置換されているかもしくは置換されていない、C(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキルであり;
R4は、置換されているかもしくは置換されていない、C(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキルであり;
Zは、NH、O、S、−CH2S−、−CH2S(O)−、または水素、炭素、酸素、窒素、および硫黄原子から選択される1〜40個の原子からなる有機リンカーである。
Xaaは、一般式−NRN−CR1R2−(C=O)−を有する任意のD−アミノ酸もしくはL−アミノ酸であり、ここで
R1は、非水素、アミノ酸の、置換されているかもしくは置換されていない塩基性側鎖であり;
R2は、水素、もしくはC(1−5)アルキルであり、
RNは、水素、もしくはC(1−5)アルキルであり、
R3は、置換されているかもしくは置換されていない、C(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキルであり;
R4は、置換されているかもしくは置換されていない、C(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキルであり;
ZはNHである。
Xaaは、一般式−NRN−CR1R2−(C=O)−を有する任意のD−アミノ酸もしくはL−アミノ酸であり、ここで
R1は、非水素、アミノ酸の、置換されているかもしくは置換されていない塩基性側鎖であり;
R2は、水素、もしくはC(1−5)アルキルであり、
RNは、水素、もしくはC(1−5)アルキルであり、
R3は、置換されているかもしくは置換されていない、C(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキルであり;
R4は、置換されているかもしくは置換されていない、C(3−22)アルキル、C(6−12)シクロアルキル、C(6−12)シクロアルキル−C(3−22)アルキル、C(3−22)アルケニル、C(3−22)アルキニル、C(3−22)アルコキシ、もしくはC(6−12)アルコキシ−C(3−22)アルキルであり;
ZはOである。
本発明のいくつかの局面において、アミノ酸脂質およびさらなる非アミノ酸脂質は、調節性RNA成分、RNAアンタゴニスト、干渉RNA、もしくは核酸の送達および投与のために使用され得る。より具体的には、本発明の組成物は、非アミノ酸カチオン性脂質および非アミノ酸非カチオン性脂質とともに、1種以上のアミノ酸脂質を含み得る。
いくつかの局面において、本開示は、一般に、調節性RNAおよびRNA干渉、アンチセンス治療、ならびにRNA治療剤の送達の分野に関する。より具体的には、本発明は、リボ核酸のための組成物および処方物、ならびにこれらの医薬のための使用および治療剤としての送達のための使用に関する。本発明は、一般に、細胞における遺伝子発現の遺伝子特異的阻害のためのRNA干渉において、または疾患状態もしくは表現型を変化させるための哺乳動物において、リボ核酸を使用するための方法に関する。
いくつかの実施形態において、本発明は、哺乳動物被験体における疾患もしくは障害を処置するための方法を提供する。干渉RNA、アミノ酸脂質、非アミノ酸非カチオン性脂質、ポリマー脂質、および1種以上の送達増強成分もしくは賦形剤を含む本発明の組成物の治療上有効な量は、上記組成物によって減少され得るか、低下され得るか、ダウンレギュレートされ得るか、または抑制され得る遺伝子の発現もしくは過剰発現と関連する疾患もしくは障害を有する被験体に、投与され得る。
本発明は、調節性RNAを使用して(例えば、RNA干渉によって)、遺伝子発現を変化させるための組成物および方法を提供する。本発明の組成物は、リボ核酸薬剤を、RNAiの応答を生じ得る細胞へと送達し得る。本発明にとって有用な核酸薬剤の例としては、二本鎖核酸、改変もしくは分解耐性核酸、RNA、siRNA、siRNA、shRNA、miRNA、piRNA、RNAアンタゴニスト、一本鎖核酸、DNA−RNAキメラ、アンチセンス核酸、およびリボザイムが挙げられる。本明細書において使用される場合、用語、siRNA、siRNA、およびshRNAは、それぞれ、siRNA、siRNA、およびshRNAの前駆体を含む。例えば、用語siRNAは、ダイサー酵素の基質として適切である、RNAもしくは二本鎖RNAを含む。
いくつかの局面において、本開示は、一般に、敗血症の分野に関する。より具体的には、本発明は、アミノ酸脂質の組成物および処方物、ならびに医薬のためおよび治療剤としてのそれらの使用に関する。本発明は、一般に、敗血症、敗血性ショック、炎症性敗血症、敗血症、もしくは全身性炎症反応症候群を予防、処置、もしくは改善するために、アミノ酸脂質を使用するための方法に関する。
本発明の化合物および組成物は、上記のように、または当該分野で公知のように、任意の生理学的に活性な薬剤、ならびに活性薬剤の任意の組み合わせの送達のために使用され得る。上記活性薬剤は、望ましい生理学的効果もしくは改善効果を提供するに十分な量において、本発明の組成物および使用において存在し得る。
本明細書において使用される場合、用語「投与する」および「投与」とは、化合物もしくは組成物を作用部位に直接的にもしくは間接的に送達するための全ての手段を包含する。本開示の化合物および組成物は単独で投与されてもよいし、本明細書で開示されていない他の化合物、組成物、もしくは治療剤と組み合わせて投与されてもよい。
本明細書に引用される全ての刊行物、参考文献、特許、特許公開および特許出願は、各々その全体が本明細書に具体的に援用される。
Fmoc−Arg(Pbf)−樹脂。30ml 固相合成用反応容器中、3gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、5.06g(11.7mmol,3当量)のFmoc−Arg(Pbf)−OH(Mw=648.8,Novabiochem,04−12−1145)および2.23ml(12.87mmol,3.3当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−D−Arg(Pmc)−樹脂。30ml 固相合成用反応容器中、3gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g 置換(Novabiochem,01−64−0114)に、5.06g(11.7mmol,3当量)のFmoc−D−Arg(Pmc)−OH(Mw=662.8,Novabiochem,04−12−1145)および2.23ml(12.87mmol,3.3当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−Arg(Pbf)−樹脂。200ml 固相合成用反応容器中、5gの2−クロロトリチルクロリド樹脂と、50mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、8.434g(13mmol,2当量)のFmoc−Arg(Pbf)−OH(Mw=648.8,Novabiochem,04−12−1145)および2.26ml(13mmol,2当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−Arg(Pbf)−樹脂。200ml 固相合成用反応容器中、5gの2−クロロトリチルクロリド樹脂と、50mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、8.434g(13mmol,2当量)のFmoc−Arg(Pbf)−OH(Mw=648.8,Novabiochem,04−12−1145)および2.26ml(13mmol,2当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
実施例1〜4と類似の様式において、C14−Arg−C14(収量:1.6g)、C16−Arg−C16、およびC18−Arg−C18を作製した。
Fmoc−Arg(Pbf)−樹脂。60ml 固相合成用反応容器中、5gの2−クロロトリチルクロリド樹脂と、50mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、8.4g(13mmol,2当量)のFmoc−Arg(Pbf)−OH(Mw=648.8,Novabiochem,04−12−1145)および2.26ml(13mmol,2当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−hArg(ジBoc)−樹脂。30ml 固相合成用反応容器中、3gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、3.57g(5.85mmol,1.5当量)のFmoc−hArg(ジBoc)−OH(Mw=610.69,Novabiochem)および2.04ml(11.7mmol,3.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−hArg(ジBoc)−樹脂。30ml 固相合成用反応容器中、3gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、3.57g(5.85mmol,1.5当量)のFmoc−hArg(ジBoc)−OH(Mw=610.69,Novabiochem)および2.04ml(11.7mmol,3.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
実施例8に類似の様式で、C12−ホモArg−C12(収量:1g)を作製した。
Fmoc−Dap(Boc)−樹脂。30ml 固相合成用反応容器中、3gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、2.5g(5.85mmol,1.5当量)のFmoc−Dap(Boc)−OH(Mw=426.5,(Fmoc−(N−β−Boc)−L−α,β−ジアミノプロピオン酸),AnaSpec,22140)および2.03ml(11.7mmol,3.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−Dap(Boc)−樹脂。30ml 固相合成用反応容器中、3gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、2.5g(5.85mmol,1.5当量)のFmoc−Dap(Boc)−OH(Mw=426.5,(Fmoc−(N−β−Boc)−L−α,β−ジアミノプロピオン酸),AnaSpec,22140)および2.03ml(11.7mmol,3.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−Dap(Boc)−樹脂。30ml 固相合成用反応容器中、3gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、2.5g(5.85mmol,1.5当量)のFmoc−Dap(Boc)−OH(Mw=426.5,(Fmoc−(N−β−Boc)−L−α,β−ジアミノプロピオン酸),AnaSpec,22140)および2.03ml(11.7mmol,3.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−Dab(Boc)−樹脂。30ml 固相合成用反応容器中、3gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、2.577g(5.85mmol,1.5当量)のFmoc−Dab(ジBoc)−OH(Mw=440.5,(Fmoc−(N−γ−Boc)−L−α,γ−ジアミノ酪酸,AnaSpec,28246)および2.23ml(12.87mmol,3.3当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
実施例13に類似の様式で、C10−norArg−C10(収量:1.2g)、C12−norArg−C12(収量:2.9g)、C14−norArg−C14(収量:630mg)、およびC16−norArg−C16(収量:1.0g)を作製した。
Fmoc−Dab(Boc)−樹脂。500ml 固相合成用反応容器中、8gの2−クロロトリチルクロリド樹脂と、100mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、5g(11.35mmol,1.2当量)のFmoc−Dab(Boc)−OH(Mw=440.5,(Fmoc−(N−γ−Boc)−L−α,γ−ジアミノ酪酸,AnaSpec,28246)および4ml(22.7mmol,2.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−Dab(Boc)−樹脂。30ml 固相合成用反応容器中、3gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、2.577g(5.85mmol,1.5当量)のFmoc−Dab(Boc)−OH(Mw=440.5,(Fmoc−(N−γ−Boc)−L−α,γ−ジアミノ酪酸,AnaSpec,28246)および2.03ml(11.7mmol,3.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−Dab(Boc)−樹脂。50ml 固相合成用反応容器中、5gの2−クロロトリチルクロリド樹脂と、50mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、5.726g(13mmol,2当量)のFmoc−Dab(Boc)−OH(Mw=440.5,(Fmoc−(N−γ−Boc)−L−α,γ−ジアミノ酪酸,AnaSpec,28246)および2.26ml(13mmol,2.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−Dab(Boc)−樹脂。50ml 固相合成用反応容器中、5gの2−クロロトリチルクロリド樹脂と、50mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、5.726g(13mmol, 2当量)のFmoc−Dab(Boc)−OH(Mw=440.5,(Fmoc−(N−γ−Boc)−L−α,γ−ジアミノ酪酸,AnaSpec,28246)および2.26ml(13mmol,2.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−Dab(Boc)−樹脂。50ml 固相合成用反応容器中、5gの2−クロロトリチルクロリド樹脂と、50mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、5.726g(13mmol,2当量)のFmoc−Dab(Boc)−OH(Mw=440.5,(Fmoc−(N−γ−Boc)−L−α,γ−ジアミノ酪酸,AnaSpec,28246)および2.26ml(13mmol,2.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−Dab(Boc)−樹脂。60ml 固相合成用反応容器中、5gの2−クロロトリチルクロリド樹脂と、50mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、5.726g(13mmol,2当量)のFmoc−Dab(Boc)−OH(Mw=440.5,(Fmoc−(N−γ−Boc)−L−α,γ−ジアミノ酪酸,AnaSpec,28246)および2.26ml(13mmol,2.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−4−Pal−樹脂。30ml 固相合成用反応容器中、3gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、2.27g(5.85mmol,1.5当量)のFmoc−4−Pal−OH(Fmoc−4−ピリジニルアラニン,Mw=388.42,Advanced ChemTech,FX4140)および2.03ml(11.7mmol,3.0当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−4−Pal−樹脂。200ml 固相合成用反応容器中、6.5gの2−クロロトリチルクロリド樹脂と、70mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、3.5g(9.01mmol,1.5当量)のFmoc−4−Pal−OH(Fmoc−4−ピリジニルアラニン,Mw=388.42,Advanced ChemTech,FX4140)および3.132ml(18mmol,2.2当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
Fmoc−4−Pal−樹脂。50ml 固相合成用反応容器中、5gの2−クロロトリチルクロリド樹脂と、50mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、3.787g(9.75mmol,1.5当量)のFmoc−4−Pal−OH(Mw=388.42,Advanced ChemTech)および1.7ml(9.75mmol,1.5当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)に添加した。
Fmoc−His(1−Me)−樹脂。60ml 固相合成用反応容器中、1.7gの2−クロロトリチルクロリド樹脂と、30mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、1g(2.5mmol,1.2当量)のFmoc−His(1−Me)−OH(Mw=391.43,ChemImpex)および0.435ml(2.5mmol,1.2当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加した。
(提唱される調製)
Fmoc−Tyr(3’,5’−ジI)−樹脂。50ml 固相合成用反応容器中、5gの2−クロロトリチルクロリド樹脂と、50mlの乾燥DCM中の1.3mmol/g置換(Novabiochem,01−64−0114)に、6.388g(9.75mmol,1.5当量)のFmoc−Tyr(3’,5’−ジI)−OH(Mw=655.2,AnaSpec)および1.69ml(9.75mmol,1.5当量)のDIPEA(Aldrich,Mw=129.2,d=0.74)を添加する。
9L/LacZは、細菌ガラクトシダーゼをコードするLacZ遺伝子を安定に発現するラット神経膠肉腫細胞株である。LacZ遺伝子ノックダウン測定を、干渉RNA送達処方物のための一次活性(primary activity)ベースのインビトロアッセイとして使用され得る。
サイクロフィリン B(PPIB)遺伝子ノックダウン測定を、干渉RNA送達処方物のための一次活性ベースのインビトロアッセイとして使用し得る。サイクロフィリン B(PPIB)遺伝子発現ノックダウンを、A549ヒト肺胞基底上皮細胞において測定した。PPIB遺伝子ノックダウン測定のために、A549細胞を、干渉RNA処方物でトランスフェクトし、総RNAを、トランスフェクションの24時間後に調製し、PPIB mRNAを、RT−PCRによってアッセイした。36B4(酸性リボソームホスホプロテインPO) mRNA発現のQRT−PCRを、正規化のために行った。
(配列番号1)
5’−GGCTCCCAGTTCTTCATCAC−3’(順方向)および
(配列番号2)
5’−CCTTCCGCACCACCTC−3’(逆方向)と、
(配列番号3)
上記プローブのために、5’−FAM−CTAGATGGCAAGCATGTGGTGTTTGG−TAMRA−3’。
(配列番号4)
5’−TCTATCATCAACGGGTACAAACGA−3’(順方向)および
(配列番号5)
5’−CTTTTCAGCAAGTGGGAAGGTG−3’(逆方向)と
(配列番号6)
上記プローブのための、5’−FAM−CCTGGCCTTGTCTGTGGAGACGGATTA−TAMRA−3’。
マウスにおけるインフルエンザウイルス力価ノックダウン測定を、干渉RNAアミノ酸脂質送達処方物についての効力のインビボ尺度として使用し得る。
処方物中のdsRNAの濃度を、SYBRTM Goldアッセイによって、以下のように決定し得る:10μlのdsRNA処方物を100μl MeOHに添加し、5分間、55℃でインキュベートする。50μlのヘパリン(200mg/ml)を添加し、その溶液を、5分間、55℃でインキュベートする。790μlのPBS(リン酸緩衝化生理食塩水)を添加し、そのサンプルを、遠沈管中で遠沈して、ペレットにする。上記ペレットのうちの90μlのサンプルを、10μlのSYBRTM Gold試薬(Molecular Probes,Eugene,Oregon)とインキュベートする。蛍光を、発光535nmと励起495nmで読み取る。
このハウスキーピング遺伝子プロトコル(肺もしくは全身)のために、1日目に、C57/B6もしくはBalb/C雌性マウス(8〜10週齡)(マウス5匹/群)に、50μlもしくは200μLのdsRNA処方物を、それぞれ、鼻内投与経路もしくは静脈内投与経路によって、投与した。麻酔剤は、ケタミン/キシラジン(IP−0.2ml用量/マウス)であった。2日目に、肺モデルについては投与の1日後または連続3日間の投与の次の日のいずれかのマウスから全肺を単離し、全身モデルについては、肺、肝臓、腎臓、脾臓、心臓および/もしくは全血を単離した。組織を、2mlのRNALATER RNA Stabilization Reagent(Qiagen 76106)を含む24ウェルプレートに配置した。プレートを、ドライアイス上に置いて、すぐに凍結し、ホモジネートを調製するまで−80℃で保存した。
このアッセイの目的は、dsRNAを投与して48時間後のマウス血中の血清コレステロールレベルを確認することであった。Invitrogen Amplex Red Cholesterol Assay Kit(cat# A12216)を使用した。マウス全血を採取し、Serum Separator Tubes(SST−BD cat #365956)に入れ、次いで、遠心分離して、血清と、上記血液の残りとを分離した。上記血清をDI−H2O 1:40中に希釈し、次いで、上記Amplexアッセイキットの1×反応緩衝液中でさらに1:5(合計1:200)希釈した。標準を、20μg/ml、10μg/ml、8μg/ml、6μg/ml、4μg/ml、2μg/mlおよび1μg/mlの濃度で、コレステロール参照標準から作製し、上記キットに補充した。サンプル、標準物質およびブランクを、平底黒色96ウェルプレート(Costar Catalogue #3916)に添加した。上記Amplexアッセイ混合物を作製し、上記アッセイウェルに添加した。37℃でのインキュベーションの少なくとも30分後に、上記プレートを、Molecular Devices SpectraMax M5を使用して読み取った。「エンドポイント」プロトコルを選択し、励起範囲を、530〜560(好ましくは、544nM)に設定し、発光検出は、〜590nmであった。一旦上記プレートが読み取った後、上記データをエクセルへとエクスポートし、ここでそのパーセントコントロール、パーセント低下および総血清コレステロール(μg/ml単位)で計算した。
本開示のいくらかの二本鎖RNA(dsRNA)の構造を、表1に示す。
本開示の活性RNA処方物を、干渉RNAを緩衝液もしくは細胞培養培地に溶解し、ボルテックスし、送達処方物と、緩衝液もしくは細胞培養培地とを別個に混合し、ボルテックスし、最後に、上記干渉RNA混合物と、上記送達処方物混合物とを混合して、活性RNAiトランスフェクション処方物を作製することによって、調製し得る。
本開示の干渉RNA組成物の例示的リポソーム処方を、表8に示す。
リポソームアミノ酸脂質干渉RNA処方物の例を表9に示す。表9の処方は、各々、1.8のN/Pを有し、約0.08〜0.19の分散値で106〜139nmの粒径を示した。
アミノ酸脂質は、LacZ活性ベースのインビトロアッセイによって、表11に示されるような効率的干渉RNA送達組成物を提供した。表11の結果は、アミノ酸脂質組成物中の干渉RNAによる遺伝子ノックダウンが、RNAIMAX(Invitrogen)で得られるものを上回り得ることを示した。
アミノ酸脂質は、LacZ活性ベースのインビトロアッセイによって、表12において示されるように、効率的な干渉RNA送達組成物を提供した。
いくつかの3成分のアミノ酸脂質RNAi組成物についての遺伝子ノックダウン活性を、インビトロで決定した。
いくつかの4成分のアミノ酸脂質RNAi組成物についてのApoB遺伝子ノックダウン活性を、インビトロで決定した。
3つおよび4つの成分のアミノ酸脂質RNAi組成物についてのApoB遺伝子ノックダウン活性を、インビボで、マウスで決定した。インビボでの上記ApoB mRNA低下活性を、表17に示す。
4成分を有するアミノ酸脂質干渉RNA処方物の例を、表19に示す。表19の処方物を使用して、マウスインフルエンザモデルにおいてインビボで抗ウイルス活性を決定した。
Claims (36)
- 式Iに示される構造を含む化合物:
R3−(C=O)−Xaa−Z−R4 式I
およびその塩であって、ここで
Xaaは、式―NR N −CR 1 R 2 −(C=O)−を有するD−アミノ酸残基もしくはL−アミノ酸残基であって、そのアミノ酸はノルアルギニン、ピリジルアラニン又はそれらのN−メチル化バージョンであり、
R 1 は、前記アミノ酸の置換されているかもしくは置換されていない塩基性側鎖であり;
R 2 は、水素であり;
R N は、水素であり;
R3は独立して、置換されているかもしくは置換されていないC(6−22)アルキルもしくはC(6−22)アルケニルであり;
R4は独立して、置換されているかもしくは置換されていないC(6−22)アルキルもしくはC(6−22)アルケニルであり;
Zは、NH、O、もしくは水素、炭素、酸素、窒素、および硫黄原子から選択される1〜40個の原子からなる有機性リンカーである、化合物。 - Xaaは、下記式:
のいずれか1に示される構造を有するアミノ酸残基である、請求項1に記載の化合物。 - Xaaは、下記式:
- R3およびR4は、C(6−22)アルキルであり、かつ同じであるかもしくは異なっている、請求項1に記載の化合物。
- R3およびR4は、C(6−22)アルケニルであり、かつ同じであるかもしくは異なっている、請求項1に記載の化合物。
- R3はC(6−22)アルキルであり、R4はC(6−22)アルケニルである、請求項1に記載の化合物。
- R4は、C(6−22)アルキルであり、R3は、C(6−22)アルケニルである、請求項1に記載の化合物。
- ZはNHである、請求項1に記載の化合物。
- ZはOである、請求項1に記載の化合物。
- Xaaは、5〜7.5のpKaを有する官能基を含む側鎖を有する、請求項1に記載の化合物。
- 請求項1に記載の化合物のマルチマーを含む化合物であって、ここで2つ以上の請求項1に記載の化合物が架橋されている、化合物。
- 請求項1に記載の化合物の結合体を含む化合物であって、ここでペプチドは、前記ノルアルギニンまたはピリジルアラニンの側鎖に結合体化されている、化合物。
- オリゴマーフレームワークもしくはポリマーフレームワークに結合した請求項1に記載の化合物を含む、化合物。
- 薬学的薬物化合物に結合した請求項1に記載の化合物を含む、化合物。
- (C10アシル)−norArg−NH−(C10アルキル)、(C12アシル)−norArg−NH−(C12アルキル)、(C14アシル)−norArg−NH−(C14アルキル)、(C16アシル)−norArg−NH−(C16アルキル)、(C18アシル)−norArg−NH−(C18アルキル)、(C16アシル)−norArg−NH−(C12アルキル)、(C18オレイック)−norArg−NH−(C12アルキル)、(C18オレイック)−norArg−NH−(C16アルキル)、(C18オレイック)−norArg−NH−(C18アルキル)、(C10アシル)−4−Pal−NH−(C10アルキル)、(C12アシル)−4−Pal−NH−(C12アルキル)、(C14アシル)−4−Pal−NH−(C14アルキル)、(C16アシル)−4−Pal−NH−(C16アルキル)、(C18アシル)−4−Pal−NH−(C18アルキル)、(C18オレイック)−4−Pal−NH−(C16アルキル)、(C10アシル)−4−Pal(Me)−NH−(C10アルキル)、(C12アシル)−4−Pal(Me)−NH−(C12アルキル)、(C14アシル)−4−Pal(Me)−NH−(C14アルキル)、(C16アシル)−4−Pal(Me)−NH−(C16アルキル)、および(C18アシル)−4−Pal(Me)−NH−(C18アルキル)から選択される、請求項1に記載の化合物。
- (C12アルキル)−(C=O)−norArg−NH−(C12アルキル)である、化合物N−(4−グアニジノ−1−オキソ−1−(ドデシルアミノ)ブタン−2−イル)ドデカンアミド。
- C18(オレイック)−norArg−NH−(C16アルキル)である化合物N−(4−グアニジノ−1−オキソ−1−(ヘキサデシルアミノ)ブタン−2−イル)オクタデカ−9−エナミド。
- 請求項1〜17のいずれか1項に従う1個以上の化合物および1つ以上の治療核酸を含む、組成物。
- 前記治療核酸は、遺伝子抑制剤である、請求項18に記載の組成物。
- 前記治療核酸は、RNAi誘導剤である、請求項18に記載の組成物。
- 前記治療核酸は、二本鎖RNAである、請求項18に記載の組成物。
- 前記治療核酸はmdRNAである、請求項18に記載の組成物。
- 前記治療核酸は、改変ヌクレオシドを含む、請求項18に記載の組成物。
- 1種以上の非カチオン性脂質もしくはステロールをさらに含む、請求項18に記載の組成物。
- コレステリルヘミスクシネートをさらに含む、請求項18に記載の組成物。
- 1種以上のカチオン性脂質をさらに含む、請求項18に記載の組成物。
- 1種以上のpeg化脂質もしくはpeg化ステロールをさらに含む、請求項18に記載の組成物。
- 前記核酸は、複合体を形成する、請求項18に記載の組成物。
- 前記組成物は、リポソームを含む、請求項18に記載の組成物。
- 前記組成物は、エマルジョンである、請求項18に記載の組成物。
- 前記組成物は、ミセル分散物である、請求項18に記載の組成物。
- 請求項1〜17のいずれか1項に記載の1種以上の化合物、および1種以上の薬物因子もしくは生物学的に活性な薬剤を含む、薬学的組成物。
- 治療核酸を細胞に送達するための組成物であって、該組成物は、請求項1〜17のいずれか1項に記載の化合物を1種以上の治療核酸とともに含む、組成物。
- 細胞における遺伝子の発現を阻害するための組成物であって、該組成物は、請求項1〜17のいずれか1項に記載の化合物を1種以上の核酸とともに含む、組成物。
- 関節リウマチ、肝臓疾患、脳炎、骨折、心疾患、肝炎およびインフルエンザを含むウイルス疾患、敗血症、ならびに癌を含む疾患を処置するための医薬の調製における、組成物の使用であって、該組成物は、請求項1〜17のいずれか1項に記載の化合物を1種以上の治療核酸とともに含む、使用。
- 関節リウマチ、肝臓疾患、脳炎、骨折、心疾患、肝炎およびインフルエンザを含むウイルス疾患、敗血症、ならびに癌から選択される疾患を処置するための組成物であって、該組成物は、請求項1〜17のいずれか1項に記載の化合物を1種以上の治療核酸とともに含む、組成物。
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JP2016121144A (ja) * | 2007-05-04 | 2016-07-07 | マリーナ バイオテック,インコーポレイテッド | アミノ酸脂質およびその使用 |
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