JP2013533223A - オリゴヌクレオチド送達のための新規な低分子量カチオン性脂質 - Google Patents
オリゴヌクレオチド送達のための新規な低分子量カチオン性脂質 Download PDFInfo
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- JP2013533223A JP2013533223A JP2013513262A JP2013513262A JP2013533223A JP 2013533223 A JP2013533223 A JP 2013533223A JP 2013513262 A JP2013513262 A JP 2013513262A JP 2013513262 A JP2013513262 A JP 2013513262A JP 2013533223 A JP2013533223 A JP 2013533223A
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- compound
- yloxy
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- dimethyl
- propan
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- 125000002091 cationic group Chemical group 0.000 title claims abstract description 35
- 108091034117 Oligonucleotide Proteins 0.000 title claims abstract description 16
- 108020004459 Small interfering RNA Proteins 0.000 claims abstract description 50
- 150000002632 lipids Chemical class 0.000 claims abstract description 50
- 239000002105 nanoparticle Substances 0.000 claims abstract description 16
- 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 abstract description 12
- -1 Cationic lipid Chemical class 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
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- 229910052736 halogen Inorganic materials 0.000 claims description 10
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 229920000768 polyamine Polymers 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 5
- 229940125782 compound 2 Drugs 0.000 claims description 5
- 229940126086 compound 21 Drugs 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- HAIDSQUTIAIJPL-DKMWFJCXSA-N (2s)-1-heptoxy-n,n-dimethyl-3-[(9z,12z)-octadeca-9,12-dienoxy]propan-2-amine Chemical compound CCCCCCCOC[C@H](N(C)C)COCCCCCCCC\C=C/C\C=C/CCCCC HAIDSQUTIAIJPL-DKMWFJCXSA-N 0.000 claims description 4
- QNHQHPALHHOYJN-QYZAPVBRSA-N (2s)-1-hexoxy-n,n-dimethyl-3-[(9z,12z)-octadeca-9,12-dienoxy]propan-2-amine Chemical compound CCCCCCOC[C@H](N(C)C)COCCCCCCCC\C=C/C\C=C/CCCCC QNHQHPALHHOYJN-QYZAPVBRSA-N 0.000 claims description 4
- RSZMLBIJWSQOHJ-LXMBQAHYSA-N (2s)-n,n-dimethyl-1-[(9z,12z)-octadeca-9,12-dienoxy]-3-[(z)-oct-5-enoxy]propan-2-amine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCOC[C@H](N(C)C)COCCCC\C=C/CC RSZMLBIJWSQOHJ-LXMBQAHYSA-N 0.000 claims description 4
- QWSJLMWNUFYNRE-AUGURXLVSA-N n,n-dimethyl-1-nonoxy-3-[(9z,12z)-octadeca-9,12-dienoxy]propan-2-amine Chemical compound CCCCCCCCCOCC(N(C)C)COCCCCCCCC\C=C/C\C=C/CCCCC QWSJLMWNUFYNRE-AUGURXLVSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 229940126208 compound 22 Drugs 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- SXIBBHQQGHVDTJ-UHFFFAOYSA-N n,n-dimethyl-1-octoxy-3-[8-(2-octylcyclopropyl)octoxy]propan-2-amine Chemical compound CCCCCCCCOCC(N(C)C)COCCCCCCCCC1CC1CCCCCCCC SXIBBHQQGHVDTJ-UHFFFAOYSA-N 0.000 claims description 3
- PNJNONWMYGRREY-CYYMFWEFSA-N n,n-dimethyl-1-octoxy-3-[8-[(1s,2s)-2-[[(1r,2r)-2-pentylcyclopropyl]methyl]cyclopropyl]octoxy]propan-2-amine Chemical compound CCCCCCCCOCC(N(C)C)COCCCCCCCC[C@H]1C[C@H]1C[C@@H]1[C@H](CCCCC)C1 PNJNONWMYGRREY-CYYMFWEFSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 2
- JDQVUHMYUPHIKQ-OUVOGOSVSA-N (2r)-1-(3,7-dimethyloctoxy)-n,n-dimethyl-3-[(9z,12z)-octadeca-9,12-dienoxy]propan-2-amine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCOC[C@@H](N(C)C)COCCC(C)CCCC(C)C JDQVUHMYUPHIKQ-OUVOGOSVSA-N 0.000 claims description 2
- UTQGWHQCDVIQQN-HDPCKHQOSA-N (2r)-n,n-dimethyl-1-nonan-2-yloxy-3-[(9z,12z)-octadeca-9,12-dienoxy]propan-2-amine Chemical compound CCCCCCCC(C)OC[C@H](N(C)C)COCCCCCCCC\C=C/C\C=C/CCCCC UTQGWHQCDVIQQN-HDPCKHQOSA-N 0.000 claims description 2
- ZXXMJVTUQDZVLT-JJQGGWDMSA-N (2s)-1-[(11z,14z)-icosa-11,14-dienoxy]-n,n-dimethyl-3-pentoxypropan-2-amine Chemical compound CCCCCOC[C@H](N(C)C)COCCCCCCCCCC\C=C/C\C=C/CCCCC ZXXMJVTUQDZVLT-JJQGGWDMSA-N 0.000 claims description 2
- RAUUWSIWMBUIDV-VTMHRMHWSA-N (2s)-1-[(13z,16z)-docosa-13,16-dienoxy]-3-hexoxy-n,n-dimethylpropan-2-amine Chemical compound CCCCCCOC[C@H](N(C)C)COCCCCCCCCCCCC\C=C/C\C=C/CCCCC RAUUWSIWMBUIDV-VTMHRMHWSA-N 0.000 claims description 2
- GFQUOOFKQHZXHF-WZCSSZMCSA-N (2s)-1-[(z)-docos-13-enoxy]-3-hexoxy-n,n-dimethylpropan-2-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCCOC[C@@H](N(C)C)COCCCCCC GFQUOOFKQHZXHF-WZCSSZMCSA-N 0.000 claims description 2
- XUTPKVMBJILQJR-YSLTZPBHSA-N (2s)-1-hexoxy-3-[(11z,14z)-icosa-11,14-dienoxy]-n,n-dimethylpropan-2-amine Chemical compound CCCCCCOC[C@H](N(C)C)COCCCCCCCCCC\C=C/C\C=C/CCCCC XUTPKVMBJILQJR-YSLTZPBHSA-N 0.000 claims description 2
- DRHHGDVXDOGFPJ-GZEYTEAUSA-N (2s)-n,n-dimethyl-1-[(6z,9z,12z)-octadeca-6,9,12-trienoxy]-3-octoxypropan-2-amine Chemical compound CCCCCCCCOC[C@H](N(C)C)COCCCCC\C=C/C\C=C/C\C=C/CCCCC DRHHGDVXDOGFPJ-GZEYTEAUSA-N 0.000 claims description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 2
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- NAOQDUDLOGYDBP-PFONDFGASA-N 1-[(z)-hexadec-9-enoxy]-n,n-dimethyl-3-octoxypropan-2-amine Chemical compound CCCCCCCCOCC(N(C)C)COCCCCCCCC\C=C/CCCCCC NAOQDUDLOGYDBP-PFONDFGASA-N 0.000 claims description 2
- USYGWEGVUBMGKV-HDXUUTQWSA-N 1-[1-[(9z,12z)-octadeca-9,12-dienoxy]-3-octoxypropan-2-yl]azetidine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCOCC(COCCCCCCCC)N1CCC1 USYGWEGVUBMGKV-HDXUUTQWSA-N 0.000 claims description 2
- AVCZOJGYRPKDBU-HDXUUTQWSA-N 1-[1-[(9z,12z)-octadeca-9,12-dienoxy]-3-octoxypropan-2-yl]pyrrolidine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCOCC(COCCCCCCCC)N1CCCC1 AVCZOJGYRPKDBU-HDXUUTQWSA-N 0.000 claims description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 2
- 229940126657 Compound 17 Drugs 0.000 claims description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 2
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- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012465 retentate Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 150000005672 tetraenes Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000000733 zeta-potential measurement Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
Description
R1およびR2は、独立に、H、(C1−C6)アルキル、ヘテロシクリルおよびポリアミンから選択され、前記アルキル、ヘテロシクリルおよびポリアミンは、R’から選択される1〜3個の置換基で置換されていてもよく、または、R1およびR2は、それらが結合している窒素と一緒に、該窒素に加えて、N、OおよびSから選択される1または2個のさらなるヘテロ原子を含有していてもよい、4〜7員の単環式複素環を形成することができ、前記単環式複素環は、R’から選択される1〜3個の置換基で置換されていてもよく;
R’は、独立に、ハロゲン、R”、OR”、SR”、CN、CO2R”またはCON(R”)2から選択され;
R”は、独立に、Hおよび(C1−C6)アルキルから選択され、前記アルキルは、ハロゲンおよびOHで置換されていてもよく;
L1は、C4−C22アルキルおよびC4−C22アルケニルから選択され、前記アルキルおよびアルケニルは、R’から選択される1個以上の置換基で置換されていてもよく;かつ
L2は、C3−C13アルキルおよびC3−C13アルケニルから選択され、前記アルキルおよびアルケニルは、R’から選択される1個以上の置換基で置換されていてもよい〕;
あるいはその任意の製薬上許容される塩または立体異性体によって示される。
R1およびR2が、各々メチルであり;
L1が、C4−C22アルキルおよびC4−C22アルケニルから選択され;かつ
L2が、C3−C13アルキルおよびC3−C13アルケニルから選択される;
式Aを有する化合物、あるいはその任意の製薬上許容される塩または立体異性体を特徴とする。
R−N,N−ジメチル−1−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−3−(オクチルオキシ)プロパン−2−アミン(化合物2);
S−N,N−ジメチル−1−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−3−(オクチルオキシ)プロパン−2−アミン(化合物1);
1−{2−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−1−[(オクチルオキシ)メチル]エチル}ピロリジン(化合物3);
(2S)−N,N−ジメチル−1−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−3−[(5Z)−オクト−5−エン−1−イルオキシ]プロパン−2−アミン(化合物4);
1−{2−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−1−[(オクチルオキシ)メチル]エチル}アゼチジン(化合物5);
(2S)−1−(ヘキシルオキシ)−N,N−ジメチル−3−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]プロパン−2−アミン(化合物6);
(2S)1−(ヘプチルオキシ)−N,N−ジメチル−3−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]プロパン−2−アミン(化合物7);
N,N−ジメチル−1−(ノニルオキシ)−3−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]プロパン−2−アミン(化合物8);
N,N−ジメチル−1−[(9Z)−オクタデセ−9−エン−1−イルオキシ]−3−(オクチルオキシ)プロパン−2−アミン(化合物9);
(2S)−N,N−ジメチル−1−[(6Z,9Z,12Z)−オクタデカ−6,9,12−トリエン−1−イルオキシ]−3−(オクチルオキシ)プロパン−2−アミン(化合物10);
(2S)−1−[(11Z,14Z)−イコサ−11,14−ジエン−1−イルオキシ]−N,N−ジメチル−3−(ペンチルオキシ)プロパン−2−アミン(化合物11);
(2S)−1−(ヘキシルオキシ)−3−[(11Z,14Z)−イコサ−11,14−ジエン−1−イルオキシ]−N,N−ジメチルプロパン−2−アミン(化合物12);
1−[(11Z,14Z)−イコサ−11,14−ジエン−1−イルオキシ]−N,N−ジメチル−3−(オクチルオキシ)プロパン−2−アミン(化合物13);
1−[(13Z,16Z)−ドコサ−13,16−ジエン−1−イルオキシ]−N,N−ジメチル−3−(オクチルオキシ)プロパン−2−アミン(化合物14);
(2S)−1−[(13Z,16Z)−ドコサ−13,16−ジエン−1−イルオキシ]−3−(ヘキシルオキシ)−N,N−ジメチルプロパン−2−アミン(化合物15);
(2S)−1−[(13Z)−ドコス−13−エン−1−イルオキシ]−3−(ヘキシルオキシ)−N,N−ジメチルプロパン−2−アミン(化合物16);
1−[(13Z)−ドコス−13−エン−1−イルオキシ]−N,N−ジメチル−3−(オクチルオキシ)プロパン−2−アミン(化合物17);
1−[(9Z)−ヘキサデカ−9−エン−1−イルオキシ]−N,N−ジメチル−3−(オクチルオキシ)プロパン−2−アミン(化合物18);
(2R)−N,N−ジメチル−1−[(1−メチルオクチル)オキシ]−3−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]プロパン−2−アミン(化合物19);
(2R)−1−[(3,7−ジメチルオクチル)オキシ]−N,N−ジメチル−3−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]プロパン−2−アミン(化合物20);
N,N−ジメチル−1−(オクチルオキシ)−3−({8−[(1S,2S)−2−{[(1R,2R)−2−ペンチルシクロプロピル]メチル}シクロプロピル]オクチル}オキシ)プロパン−2−アミン(化合物21);および
N,N−ジメチル−1−{[8−(2−オクチルシクロプロピル)オクチル]オキシ}−3−(オクチルオキシ)プロパン−2−アミン(化合物22);
あるいはその任意の製薬上許容される塩または立体異性体である。
ベンゾイミダゾリル、ベンゾフラニル、ベンゾフラザニル、ベンゾピラゾリル、ベンゾトリアゾリル、ベンゾチオフェニル、ベンゾキサゾリル、カルバゾリル、カルボリニル、シンノリニル、フラニル、イミダゾリル、インドリニル、インドリル、インドールアジニル、インダゾリル、イソベンゾフラニル、イソインドリル、イソキノリル、イソチアゾリル、イソキサゾリル、ナフトピリジニル、オキサジアゾリル、オキサゾリル、オキサゾリン、イソキサゾリン、オキセタニル、ピラニル、ピラジニル、ピラゾリル、ピリダジニル、ピリドピリジニル、ピリダジニル、ピリジル、ピリミジル、ピロリル、キナゾリニル、キノリル、キノキサリニル、テトラヒドロピラニル、テトラゾリル、テトラゾロピリジル、チアジアゾリル、チアゾリル、チエニル、トリアゾリル、アゼチジニル、1,4−ジオキサニル、ヘキサヒドロアゼピニル、ピペラジニル、ピペリジニル、ピロリジニル、モルホリニル、チオモルホリニル、ジヒドロベンゾイミダゾリル、ジヒドロベンゾフラニル、ジヒドロベンゾチオフェニル、ジヒドロベンゾキサゾリル、ジヒドロフラニル、ジヒドロイミダゾリル、ジヒドロインドリル、ジヒドロイソオキサゾリル、ジヒドロイソチアゾリル、ジヒドロオキサジアゾリル、ジヒドロオキサゾリル、ジヒドロピラジニル、ジヒドロピラゾリル、ジヒドロピリジニル、ジヒドロピリミジニル、ジヒドロピロリル、ジヒドロキノリニル、ジヒドロテトラゾリル、ジヒドロチアジアゾリル、ジヒドロチアゾリル、ジヒドロチエニル、ジヒドロトリアゾリル、ジヒドロアゼチジニル、メチレンジオキシベンゾイル、テトラヒドロフラニル、およびテトラヒドロチエニル、ならびに、そのすべてがR”から選択される1〜3個の置換基で置換されていてもよい、そのN−酸化物が含まれる。
R−N,N−ジメチル−1−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−3−(オクチルオキシ)プロパン−2−アミン(化合物2)
1H NMR(400MHz,CDCl3):δ5.38(m,4H)、3.52(m,4H)、3.40(m,4H)、2.79(m,3H)、2.40(s,6H)、2.05(m,4H)、1.58(m,4H)、1.30(m,26H)、0.89(m,6H)。
N,N−ジメチル−1−(オクチルオキシ)−3−({8−[(1S,2S)−2−{[(1R,2R)−2−ペンチルシクロプロピル]メチル}シクロプロピル]オクチル}オキシ)プロパン−2−アミン(化合物21)
以下の本発明の脂質ナノ粒子組成(LNPs)は、オリゴヌクレオチド、特にsiRNAおよびmiRNAの送達に有用である:
カチオン性脂質/コレステロール/PEG−DMG 56.6/38/5.4;
カチオン性脂質/コレステロール/PEG−DMG 60/38/2;
カチオン性脂質/コレステロール/PEG−DMG 67.3/29/3.7;
カチオン性脂質/コレステロール/PEG−DMG 49.3/47/3.7;
カチオン性脂質/コレステロール/PEG−DMG 50.3/44.3/5.4;
カチオン性脂質/コレステロール/PEG−C−DMA/DSPC 40/48/2/10;
カチオン性脂質/コレステロール/PEG−DMG/DSPC 40/48/2/10;および
カチオン性脂質/コレステロール/PEG−DMG/DSPC 58/30/2/10。
脂質ナノ粒子(LNP)は、衝突噴流法により調製される。この粒子は、アルコールに溶解した脂質とクエン酸塩緩衝液に溶解したsiRNAを混合することにより形成される。脂質のsiRNAに対する混合比は、脂質45〜55%およびsiRNA65〜45%を目標とする。この脂質溶液は、本発明の新規なカチオン性脂質、ヘルパー脂質(コレステロール)、PEG(例、PEG−C−DMA、PEG−DMG)脂質、および5〜15mg/mLの濃度のDSPCを、アルコール(例えばエタノール)中9〜12mg/mLの目標で含有する。これらの脂質の比は、カチオン性脂質について25〜98モルパーセントの範囲(目標は35〜65)であり、ヘルパー脂質は、0〜75モルパーセントの範囲(目標は30〜50)であり、PEG脂質は、1〜15モルパーセントの範囲(目標は1〜6)であり、DSPCは、0〜15モルパーセントの範囲(目標は0〜12)である。siRNA溶液は、1つ以上のsiRNA配列を0.3〜1.0mg/mLの濃度範囲で含有し、目標は、3.5〜5の範囲のpHのクエン酸ナトリウム緩衝塩溶液中0.3〜0.9mg/mLである。これら2つの液体を、30〜40℃を目標とする、15〜40℃の範囲の温度に加熱した後、衝突噴流ミキサーで混合し、直ちにLNPを形成した。ティー内径(teeID)は、0.25〜1.0mmの範囲であり、全流速は10〜600mL/分の範囲である。流速とチューブ内径(tubing ID)の組合せは、LNPsの粒径を30〜200nmの間に制御する効果がある。次に、溶液を、より高いpHの緩衝液と、1:1〜1:3 容積:容積の範囲であるが1:2 容積:容積を目標とする範囲の混合比で混合する。この緩衝液は、30〜40℃を目標とする、15〜40℃の範囲の温度である。混合したLNPsを、アニオン交換濾過段階の前に30分〜2時間保持した。インキュベーション中の温度は、30〜40℃を目標とする、15〜40℃の範囲である。インキュベートした後、溶液を、アニオン交換分離段階を含む0.8umフィルターに通して濾過する。この方法は、1mm ID〜5mm IDまでのチューブ内径および10〜2000mL/分の流速を使用する。LNPsを濃縮し、限外濾過法によって透析濾過し、アルコールを除去し、クエン酸塩緩衝液を最終の緩衝液、例えばリン酸緩衝生理食塩水などに交換する。限外濾過法は、タンジェンシャルフロー濾過方式(TFF)を使用する。この方法は、公称分子量カットオフが30〜500KDの範囲の膜を使用する。膜形式は、中空糸であってもフラットシートカセットであってもよい。適切な分子量カットオフを用いるTFF法は、LNPを保持液中に保持し、濾液または透過液は、アルコール;クエン酸緩衝液;最終の緩衝液廃棄物を含有する。TFF法は、siRNA濃度に対する初期濃度が1〜3mg/mLの多段階法である。濃縮した後、アルコールを除去して緩衝液交換を実施するために、LNPs溶液を、10〜20容積の最終緩衝液に対して透析濾過する。次に、材料をさらに1〜3倍に濃縮する。LNP法の最終段階は、濃縮したLNP溶液を滅菌濾過し、生成物をバイアルに入れることである。
1)siRNA濃度
siRNA二本鎖濃度は、2996 PDA検出器を備えたWaters 2695 Alliance system(Water Corporation,Milford MA)を用いて、強陰イオン交換高速液体クロマトグラフィー(SAX−HPLC)により決定される。LNPs(そうでなければRNAi送達ビヒクル(RDVs)と呼ばれる)を、0.5% Triton X−100で処理して全siRNAを遊離し、254nmでUV検出するDionex BioLC DNAPac PA 200(4×250mm)カラムを用いるSAX分離により分析した。移動相は、A:25mM NaClO4、10mM トリス、20% EtOH、pH7.0およびB;250mM NaClO4、10mM トリス、20% EtOH、pH7.0で構成され、0〜15分の線形勾配および1ml/分の流速を用いる。siRNA量は、siRNA標準曲線と比較することにより決定される。
蛍光試薬SYBR GoldをRNA定量化に用いて、RDVsのカプセル封入率をモニターする。Triton X−100を含むまたは含まないRDVsを使用して、遊離siRNAおよび全siRNA量を決定する。このアッセイは、Molecular Devices(Sunnyvale,CA)製のSpectraMax M5eマイクロプレート分光光度計を用いて実施される。サンプルは485nmで励起し、530nmで蛍光発光を測定した。siRNA量は、siRNA標準曲線と比較することにより決定される。
3)粒径および多分散性
1μgのsiRNAを含有するRDVsを、1×PBSで希釈して最終容積3mlとする。サンプルの粒径および多分散性を、ZetaPALS機器(Brookhaven Instruments Corporation,Holtsviile、NY)を用いる動的光散乱法により測定する。散乱強度を、散乱角90°で25℃のHe−Neレーザーによって測定する。
1μgのsiRNAを含有するRDVsを、1mMトリス緩衝液(pH7.4)で希釈して最終容積2mlとする。サンプルの電気泳動移動度を、電極および光源としてHe−Neレーザーを備えたZetaPALS機器(Brookhaven Instruments Corporation,Holtsviile,NY)を用いて決定する。Smoluchowskiの極限を、ゼータ電位の計算において仮定する。
個々の脂質濃度は、コロナ荷電化粒子検出器(Corona charged aerosol detector:CAD)(ESA Biosciences,Inc,Chelmsford,MA)を備えたWaters 2695 Alliance system(Waters Corporation,Milford MA)を用いる逆相高速液体クロマトグラフィー(RP−HPLC)により決定する。RDVs中の個々の脂質は、CADを備えたAgilent Zorbax SB−C18(50×4.6mm、粒径1.8μm)カラムを60℃で用いて分析する。移動相は、A:H2O中0.1% TFAおよびB:IPA中0.1%TEAで構成される。勾配は、0時の移動相A60%および移動相B40%から、1.00分の移動相A40%および移動相B60%;1.00〜5.00分の移動相A40%および移動相B60%;5.00分の移動相A40%および移動相B60%から、10.00分の移動相A25%および移動相B75%;10.00分の移動相A25%および移動相B75%から、15.00分の移動相A5%および移動相B95%;そして15.00分の移動相A5%および移動相B95%から、20.00分の移動相A60%および移動相B40%に1ml/分の流速で変化する。個々の脂質濃度は、二次曲線の当てはめによって、RDVs中のすべての脂質成分を含む標準曲線と比較することにより決定される。各々の脂質の分子百分率は、その分子量に基づいて計算される。
公称組成:
カチオン性脂質/コレステロール/PEG−DMG 60/38/2
カチオン性脂質/コレステロール/PEG−DMG 67.3/29/3.7。
5’−iB−AUAAGGCUAUGAAGAGAUATT−iB 3’(配列番号:1)
3’−UUUAUUCCGAUACUUCUCUAU−5’(配列番号:2)
AUGC−リボース
iB−逆位デオキシ脱塩基
UC−2’フルオロ
AGT−2’デオキシ
AGU−2’OCH3
公称組成
カチオン性脂質/コレステロール/PEG−DMG 60/38/2
カチオン性脂質/コレステロール/PEG−DMG/DSPC 40/48/2/10
カチオン性脂質/コレステロール/PEG−DMG/DSPC 58/30/2/10
ApoB siRNA
5’−iB−CUUUAACAAUUCCUGAAAUTT−iB(配列番号:3)
3’−UUGAAAUUGUUAAGGACUUUA−5’(配列番号:4)
AUGC−リボース
iB−逆位デオキシ脱塩基
UC−2’フルオロ
AGT−2’デオキシ
AGU−2’OCH3
公称組成
カチオン性脂質/コレステロール/PEG−DMG 60/38/2
カチオン性脂質/コレステロール/PEG−DMG/DSPC 40/48/2/10
カチオン性脂質/コレステロール/PEG−DMG/DSPC 58/30/2/10
ApoB siRNA
5’−iB−CUUUAACAAUUCCUGAAAUTsT−i−3’B(配列番号:5)
3’−UsUGAAAUUGUUAAGGACUsUsUsA−5’(配列番号:6)
AUGC−リボース
iB−逆位デオキシ脱塩基
UC−2’フルオロ
AGT−2’デオキシ
AGU−2’OCH3
UsA−ホスホロチオエート(phophorothioate)結合
オリゴヌクレオチド、特に、siRNAおよびmiRNAの合成および使用は公知である。(米国特許出願:米国特許出願公開第2006/0083780号、同第2006/0240554号、同第2008/0020058号、同第2009/0263407号および同第2009/0285881号ならびにPCT特許出願:国際公開第2009/086558号、同第2009/127060号、同第2009/132131号、同第2010/042877号、同第2010/054384号、同第2010/054401号、同第2010/054405号および同第2010/054406号参照)。また、Semple S.C.et al.,Rational design of cationic lipids for siRNA delivery,Nature Biotechnology,published online 17 January 2010;doi:10.1038/nbt.l602も参照されたい。
直前に記載される公称組成の化合物1〜2を利用するLNPsを、ルシフェラーゼマウスモデルにおけるインビボ有効性および炎症性サイトカインの誘導について評価した。siRNAは、ホタル(フォチナス・ピラリス(Photinus pyralis))ルシフェラーゼ遺伝子(受託番号M15077)のmRNA転写物を標的にする。ルシフェラーゼsiRNAの一次配列および化学修飾パターンを上に表示する。インビボルシフェラーゼモデルは、ホタルルシフェラーゼコード配列がすべての細胞に存在しているトランスジェニックマウスを用いる。ダナ・ファーバー癌研究所(Dana Farber Cancer Institute)から認可されたROSA26−LoxP−Stop−LoxP−Luc(LSL−Luc)トランスジェニックマウスを、最初にLSL配列を組換えAd−Creウイルス(Vector Biolabs)で除去することにより、ルシフェラーゼ遺伝子を発現するように誘導する。ウイルスの臓器親和性に起因して、尾静脈注射により送達される場合には、発現は肝臓に制限される。肝臓におけるルシフェラーゼ発現レベルを、ルシフェリン基質(Caliper Life Sciences)の投与の後に、IVIS撮像装置(Xenogen)を用いて発光を測定することにより定量化する。投薬前(pre−dose)発光レベルをRDVsの投与の前に測定する。PBS中のルシフェリン(15mg/mL)を、150μLの量で腹腔内(IP)注射する。4分のインキュベーション期間の後、マウスをイソフランで麻酔し、IVIS撮像装置に入れる。PBSビヒクル中のRDVs(siRNAを含有)を、0.2mLの量で尾静脈注射した。最終投与量レベルは、0.3〜3mg/kg siRNAの範囲であった。PBSビヒクル単独は、対照として投与した。投薬の3時間後、マウスを後眼窩から出血させてサイトカイン分析のための血漿を得た。マウスを、投薬の48時間後に上記の方法を用いて撮像した。ルシフェリン光出力の変化は、直接にルシフェラーゼmRNAレベルに相関し、ルシフェラーゼsiRNA活性の間接的な尺度を示す。インビボ有効性の結果は、投薬前発光レベルに対する発光の阻害%として表される。血漿中サイトカイン濃度は、SearchLight多重サイトカイン化学発光アレイ(Pierce/Thermo)を用いて決定した。ルシフェラーゼsiRNA RDVsの全身投与は、ルシフェラーゼ発現を用量依存的に低下させた。オクチル−CLinDMA(OCD)カチオン性脂質を含有するRDVを投与したマウスよりも、RDVsを含有する化合物1を投与したマウスにおいて、より高い有効性が観察された(図1)。OCDは公知であり、国際公開第2010/021865号に記載されている。
上記の公称組成において化合物1を利用するLNPsを、スプラーグ・ドーリー(Crl:CD(SD)雌ラット(Charles River Labs)において、インビボ有効性およびアラニンアミノトランスフェラーゼおよびアスパラギン酸アミノトランスフェラーゼの増加について評価した。siRNAは、ApoB遺伝子(受託番号NM 019287)のmRNA転写物を標的にする。ApoB siRNAの一次配列および化学修飾パターンは上に表示されている。PBSビヒクル中のRDVs(siRNAを含有)を、1〜1.5mLの量で尾静脈注射した。注入速度は、約3ml/分である。各々の投薬群に5匹のラットを使用した。LNPの投与後、ラットを標準的な食餌および水のあるケージに入れる。投薬の6時間後、食物をケージから取り出す。動物の解剖をLNP投薬の24時間後に実施する。ラットを5分間のイソフランで麻酔した後、イソフランの送達を継続しながら全採血が終了するまでラットをノーズ・コーンに入れることにより麻酔下で維持する。血液は、23ゲージバタフライ型静脈穿刺セットを用いて大静脈から採取し、血清化学分析のために血清分離器バキュテイナに等分する。切除した肝尾状葉のパンチを採取し、mRNA分析のためにRNALater(Ambion)に入れる。保存肝組織をホモジナイズし、QiagenビーズミルおよびQiagen miRNA−Easy RNA単離キットを製造業者の説明書に従って用いて全RNAを単離した。肝臓ApoB mRNAレベルを、定量的RT−PCRにより測定した。ラットApoBの市販のプローブセット(Applied Biosystemsカタログ番号RN01499054_ml)を利用して精製RNAからメッセージを増幅させた。PCR反応を、96ウェルFast Blockを備えたABI 7500機器で実施した。ApoB mRNAレベルを、ハウスキーピングPPIB(NM011149)mRNAに正規化する。PPIB mRNAレベルは、RT−PCRにより市販のプローブセット(Applied Biosytemsカタログ番号Mm00478295_ml)を用いて測定した。結果を、ApoB mRNA/PPIB mRNAの比として表す。すべてのmRNAデータは、PBS対照投薬量と比較して表される。血清ALTおよびAST分析を、Siemensアラニンアミノトランスフェラーゼ(カタログ番号03039631)およびアスパラギン酸アミノトランスフェラーゼ(カタログ番号03039631)試薬を利用して、Siemens Advia 1800 Clinical Chemistry Analyzerで実施した。オクチル−CLinDMA(OCD)カチオン性脂質を含有するRDVを投与したラットよりも、RDVを含有する化合物1を投与したラットにおいて、より高い有効性が観察された(図2)。その上、オクチル−CLinDMAカチオン性脂質を含有するRDVを投与したラットよりも、化合物1を含有するRDVを投与したラットにおいて、LFT(ALT/AST)のより低い上昇が観察された(図3)。
肝組織を秤量して20mlバイアルに入れ、9v/wの水中でGenoGrinder 2000(OPS Diagnostics、1600ストローク/分、5分)を用いてホモジナイズした。各々の組織ホモジネートの50μLアリコートを、300μLの抽出/タンパク質沈殿溶媒(500nM内部標準を含有する50/50 アセトニトリル/メタノール)と混合し、プレートを遠心して沈殿したタンパク質を沈降させた。次に、各々の上清の200μLの量を96ウェルプレートの個々のウェルに移し、10μlの試料を直接、LC/MS−MSにより分析した。
Claims (7)
- 式Aのカチオン性脂質:
R1およびR2は、独立に、H、(C1−C6)アルキル、ヘテロシクリルおよびポリアミンから選択され、前記アルキル、ヘテロシクリルおよびポリアミンは、R’から選択される1〜3個の置換基で置換されていてもよく、または、R1およびR2は、それらが結合している窒素と一緒に、該窒素に加えて、N、OおよびSから選択される1または2個のさらなるヘテロ原子を含有していてもよい、4〜7員の単環式複素環を形成することができ、前記単環式複素環は、R’から選択される1〜3個の置換基で置換されていてもよく;
R’は、独立に、ハロゲン、R”、OR”、SR”、CN、CO2R”またはCON(R”)2から選択され;
R”は、独立に、Hおよび(C1−C6)アルキルから選択され、前記アルキルは、ハロゲンおよびOHで置換されていてもよく;
L1は、C4−C22アルキルおよびC4−C22アルケニルから選択され、前記アルキルおよびアルケニルは、R’から選択される1個以上の置換基で置換されていてもよく;かつ
L2は、C3−C13アルキルおよびC3−C13アルケニルから選択され、前記アルキルおよびアルケニルは、R’から選択される1個以上の置換基で置換されていてもよい〕;
または、その任意の製薬上許容される塩もしくは立体異性体。 - R1およびR2が、各々メチルであり;
L1が、C4−C22アルキルおよびC4−C22アルケニルから選択され;かつ
L2が、C3−C13アルキルおよびC3−C13アルケニルから選択される、
請求項1に記載の式Aのカチオン性脂質;
または、その任意の製薬上許容される塩もしくは立体異性体。 - 以下から選択されるカチオン性脂質:
R−N,N−ジメチル−1−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−3−(オクチルオキシ)プロパン−2−アミン(化合物2);
S−N,N−ジメチル−1−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−3−(オクチルオキシ)プロパン−2−アミン(化合物1);
1−{2−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−1−[(オクチルオキシ)メチル]エチル}ピロリジン(化合物3);
(2S)−N,N−ジメチル−1−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−3−[(5Z)−オクト−5−エン−1−イルオキシ]プロパン−2−アミン(化合物4);
1−{2−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]−1−[(オクチルオキシ)メチル]エチル}アゼチジン(化合物5);
(2S)−1−(ヘキシルオキシ)−N,N−ジメチル−3−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]プロパン−2−アミン(化合物6);
(2S)1−(ヘプチルオキシ)−N,N−ジメチル−3−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]プロパン−2−アミン(化合物7);
N,N−ジメチル−1−(ノニルオキシ)−3−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]プロパン−2−アミン(化合物8);
N,N−ジメチル−1−[(9Z)−オクタデセ−9−エン−1−イルオキシ]−3−(オクチルオキシ)プロパン−2−アミン(化合物9);
(2S)−N,N−ジメチル−1−[(6Z,9Z,12Z)−オクタデカ−6,9,12−トリエン−1−イルオキシ]−3−(オクチルオキシ)プロパン−2−アミン(化合物10);
(2S)−1−[(11Z,14Z)−イコサ−11,14−ジエン−1−イルオキシ]−N,N−ジメチル−3−(ペンチルオキシ)プロパン−2−アミン(化合物11);
(2S)−1−(ヘキシルオキシ)−3−[(11Z,14Z)−イコサ−11,14−ジエン−1−イルオキシ]−N,N−ジメチルプロパン−2−アミン(化合物12);
1−[(11Z,14Z)−イコサ−11,14−ジエン−1−イルオキシ]−N,N−ジメチル−3−(オクチルオキシ)プロパン−2−アミン(化合物13);
1−[(13Z,16Z)−ドコサ−13,16−ジエン−1−イルオキシ]−N,N−ジメチル−3−(オクチルオキシ)プロパン−2−アミン(化合物14);
(2S)−1−[(13Z,16Z)−ドコサ−13,16−ジエン−1−イルオキシ]−3−(ヘキシルオキシ)−N,N−ジメチルプロパン−2−アミン(化合物15);
(2S)−1−[(13Z)−ドコス−13−エン−1−イルオキシ]−3−(ヘキシルオキシ)−N,N−ジメチルプロパン−2−アミン(化合物16);
1−[(13Z)−ドコス−13−エン−1−イルオキシ]−N,N−ジメチル−3−(オクチルオキシ)プロパン−2−アミン(化合物17);
1−[(9Z)−ヘキサデカ−9−エン−1−イルオキシ]−N,N−ジメチル−3−(オクチルオキシ)プロパン−2−アミン(化合物18);
(2R)−N,N−ジメチル−1−[(1−メチルオクチル)オキシ]−3−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]プロパン−2−アミン(化合物19);
(2R)−1−[(3,7−ジメチルオクチル)オキシ]−N,N−ジメチル−3−[(9Z,12Z)−オクタデカ−9,12−ジエン−1−イルオキシ]プロパン−2−アミン(化合物20);
N,N−ジメチル−1−(オクチルオキシ)−3−({8−[(1S,2S)−2−{[(1R,2R)−2−ペンチルシクロプロピル]メチル}シクロプロピル]オクチル}オキシ)プロパン−2−アミン(化合物21);および
N,N−ジメチル−1−{[8−(2−オクチルシクロプロピル)オクチル]オキシ}−3−(オクチルオキシ)プロパン−2−アミン(化合物22);
またはその任意の製薬上許容される塩もしくは立体異性体。 - 脂質ナノ粒子の調製のための請求項1に記載のカチオン性脂質の使用。
- オリゴヌクレオチドの送達のための脂質ナノ粒子中の成分としての請求項1に記載のカチオン性脂質の使用。
- 該オリゴヌクレオチドがsiRNAまたはmiRNAである、請求項5に記載の使用。
- 該オリゴヌクレオチドがsiRNAである、請求項5に記載の使用。
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US61/382,067 | 2010-09-13 | ||
PCT/US2011/038490 WO2011153120A1 (en) | 2010-06-04 | 2011-05-31 | Novel low molecular weight cationic lipids for oligonucleotide delivery |
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