JP2017502278A5 - - Google Patents

Info

Publication number

JP2017502278A5

JP2017502278A5 JP2016539206A JP2016539206A JP2017502278A5 JP 2017502278 A5 JP2017502278 A5 JP 2017502278A5 JP 2016539206 A JP2016539206 A JP 2016539206A JP 2016539206 A JP2016539206 A JP 2016539206A JP 2017502278 A5 JP2017502278 A5 JP 2017502278A5

Authority

JP

Japan

Prior art keywords

laccer

inhibitor

subject

pharmaceutical composition

spms

Prior art date

2014-12-12

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Granted

Links

• Espacenet
• Global Dossier
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• 239000003112 inhibitor Substances 0.000 claims 35
• WPIHMWBQRSAMDE-YCZTVTEBSA-N beta-D-galactosyl-(1->4)-beta-D-galactosyl-N-(pentacosanoyl)sphingosine Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO[C@@H]1O[C@H](CO)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O)[C@H](O)\C=C\CCCCCCCCCCCCC WPIHMWBQRSAMDE-YCZTVTEBSA-N 0.000 claims 28
• 238000000034 method Methods 0.000 claims 19
• 208000007118 chronic progressive multiple sclerosis Diseases 0.000 claims 18
• 230000015572 biosynthetic process Effects 0.000 claims 15
• 238000003786 synthesis reaction Methods 0.000 claims 15
• 201000008628 secondary progressive multiple sclerosis Diseases 0.000 claims 14
• 239000008194 pharmaceutical composition Substances 0.000 claims 13
• -1 3 ′, 4′-ethylenedioxy Chemical group 0.000 claims 10
• 102100027386 Beta-1,4-galactosyltransferase 6 Human genes 0.000 claims 10
• 101000937502 Homo sapiens Beta-1,4-galactosyltransferase 6 Proteins 0.000 claims 10
• 150000002305 glucosylceramides Chemical class 0.000 claims 10
• LXBIFEVIBLOUGU-UHFFFAOYSA-N Deoxymannojirimycin Natural products OCC1NCC(O)C(O)C1O LXBIFEVIBLOUGU-UHFFFAOYSA-N 0.000 claims 6
• 230000002401 inhibitory effect Effects 0.000 claims 6
• OFBANDBMHLEMFA-XRKRLSELSA-N (1R,2R)-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol Chemical compound C([C@@H](NC(=O)CCCCCCCCCCCCCCC)[C@H](O)C=1C=CC=CC=1)N1CCOCC1 OFBANDBMHLEMFA-XRKRLSELSA-N 0.000 claims 4
• 102000004547 Glucosylceramidase Human genes 0.000 claims 4
• 108010017544 Glucosylceramidase Proteins 0.000 claims 4
• 206010053395 Progressive multiple sclerosis Diseases 0.000 claims 4
• 102000017852 Saposin Human genes 0.000 claims 4
• 108050007079 Saposin Proteins 0.000 claims 4
• 239000012190 activator Substances 0.000 claims 4
• LXBIFEVIBLOUGU-JGWLITMVSA-N duvoglustat Chemical compound OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O LXBIFEVIBLOUGU-JGWLITMVSA-N 0.000 claims 4
• 239000012634 fragment Substances 0.000 claims 4
• 229960001512 miglustat Drugs 0.000 claims 4
• UQRORFVVSGFNRO-UTINFBMNSA-N miglustat Chemical compound CCCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO UQRORFVVSGFNRO-UTINFBMNSA-N 0.000 claims 4
• 108020004707 nucleic acids Proteins 0.000 claims 4
• 150000007523 nucleic acids Chemical class 0.000 claims 4
• 102000039446 nucleic acids Human genes 0.000 claims 4
• 206010063401 primary progressive multiple sclerosis Diseases 0.000 claims 4
• XVYLNHVEAOOEGI-FAIWKWDXSA-N (2r,3r,4r,5s)-1-[5-(1-adamantylmethoxy)pentyl]-2-(hydroxymethyl)piperidine-3,4,5-triol Chemical compound OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1CCCCCOCC1(C2)CC(C3)CC2CC3C1 XVYLNHVEAOOEGI-FAIWKWDXSA-N 0.000 claims 2
• TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims 2
• HCZQIIVHWYFIPW-UHFFFAOYSA-N 2-(hydroxymethyl)-1-pentylpiperidine-3,4,5-triol Chemical compound CCCCCN1CC(O)C(O)C(O)C1CO HCZQIIVHWYFIPW-UHFFFAOYSA-N 0.000 claims 2
• ZVVDDRQFVGFPTI-UHFFFAOYSA-N 5-cyclopropylidene-7-(difluoromethyl)-n-(2-phenylsulfanylphenyl)-1h-pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound FC(F)C1=CC(=C2CC2)N=C2N1NC=C2C(=O)NC1=CC=CC=C1SC1=CC=CC=C1 ZVVDDRQFVGFPTI-UHFFFAOYSA-N 0.000 claims 2
• OWITVSDXHSDEJK-UHFFFAOYSA-N C1(=CC=CC=C1)C(C(CN1CCCC1)NC(CCCCCCCC)=O)O Chemical compound C1(=CC=CC=C1)C(C(CN1CCCC1)NC(CCCCCCCC)=O)O OWITVSDXHSDEJK-UHFFFAOYSA-N 0.000 claims 2
• SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims 2
• ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims 2
• UYNCFCUHRNOSCN-FYYLOGMGSA-N N-[(1R,2R)-1-hydroxy-3-(4-morpholinyl)-1-phenylpropan-2-yl]decanamide Chemical compound C([C@@H](NC(=O)CCCCCCCCC)[C@H](O)C=1C=CC=CC=1)N1CCOCC1 UYNCFCUHRNOSCN-FYYLOGMGSA-N 0.000 claims 2
• 108091027967 Small hairpin RNA Proteins 0.000 claims 2
• 108020004459 Small interfering RNA Proteins 0.000 claims 2
• YFHRCLAKZBDRHN-MRXNPFEDSA-N [(3s)-1-azabicyclo[2.2.2]octan-3-yl] n-[2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]propan-2-yl]carbamate Chemical compound O([C@H]1C2CCN(CC2)C1)C(=O)NC(C)(C)C(N=1)=CSC=1C1=CC=C(F)C=C1 YFHRCLAKZBDRHN-MRXNPFEDSA-N 0.000 claims 2
• HMKBAAOJDHGSEM-UHFFFAOYSA-N [2-(tert-butylamino)-2-oxoethyl] 2-[2-(4-bromoanilino)-2-oxoethoxy]benzoate Chemical compound CC(C)(C)NC(=O)COC(=O)C1=CC=CC=C1OCC(=O)NC1=CC=C(Br)C=C1 HMKBAAOJDHGSEM-UHFFFAOYSA-N 0.000 claims 2
• 125000000217 alkyl group Chemical group 0.000 claims 2
• 230000000692 anti-sense effect Effects 0.000 claims 2
• 125000001204 arachidyl group Chemical group [H]C([*])([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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
• 125000004432 carbon atom Chemical group C* 0.000 claims 2
• 150000001875 compounds Chemical class 0.000 claims 2
• 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 2
• 125000003438 dodecyl 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 2
• 229960002856 eliglustat Drugs 0.000 claims 2
• KUBARPMUNHKBIQ-VTHUDJRQSA-N eliglustat tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C([C@@H](NC(=O)CCCCCCC)[C@H](O)C=1C=C2OCCOC2=CC=1)N1CCCC1.C([C@@H](NC(=O)CCCCCCC)[C@H](O)C=1C=C2OCCOC2=CC=1)N1CCCC1 KUBARPMUNHKBIQ-VTHUDJRQSA-N 0.000 claims 2
• 125000001925 glucosylceramide group Chemical group 0.000 claims 2
• 108091070501 miRNA Proteins 0.000 claims 2
• 239000002679 microRNA Substances 0.000 claims 2
• 125000001421 myristyl group Chemical group [H]C([*])([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])C([H])([H])[H] 0.000 claims 2
• JMNXWOFCUJJYEO-HYBUGGRVSA-N n-[(1r,2r)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]nonanamide Chemical compound C([C@@H](NC(=O)CCCCCCCC)[C@H](O)C=1C=C2OCCOC2=CC=1)N1CCCC1 JMNXWOFCUJJYEO-HYBUGGRVSA-N 0.000 claims 2
• 125000001400 nonyl group Chemical group [H]C([*])([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])[H] 0.000 claims 2
• 125000000913 palmityl group Chemical group [H]C([*])([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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
• 239000002924 silencing RNA Substances 0.000 claims 2
• 239000004055 small Interfering RNA Substances 0.000 claims 2
• 150000003384 small molecules Chemical group 0.000 claims 2
• 125000004079 stearyl group Chemical group [H]C([*])([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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
• 230000008685 targeting Effects 0.000 claims 2
• 125000002948 undecyl group Chemical group [H]C([*])([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])[H] 0.000 claims 2
• 208000007400 Relapsing-Remitting Multiple Sclerosis Diseases 0.000 claims 1
• 238000000338 in vitro Methods 0.000 claims 1
• 239000000203 mixture Substances 0.000 claims 1
• 201000006417 multiple sclerosis Diseases 0.000 claims 1