MXPA03009957A - Inhibidores de la gsk-3 y estructuras cristalinas de la proteina gsk-3¦ y complejos de proteina. - Google Patents
Inhibidores de la gsk-3 y estructuras cristalinas de la proteina gsk-3¦ y complejos de proteina.Info
- Publication number
- MXPA03009957A MXPA03009957A MXPA03009957A MXPA03009957A MXPA03009957A MX PA03009957 A MXPA03009957 A MX PA03009957A MX PA03009957 A MXPA03009957 A MX PA03009957A MX PA03009957 A MXPA03009957 A MX PA03009957A MX PA03009957 A MXPA03009957 A MX PA03009957A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- phenyl
- gsk
- pyrazolo
- amino acid
- Prior art date
Links
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 title claims abstract description 155
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 title claims abstract description 155
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 title claims description 15
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 title claims description 15
- 239000003112 inhibitor Substances 0.000 title abstract description 145
- 102000007474 Multiprotein Complexes Human genes 0.000 title abstract description 11
- 108010085220 Multiprotein Complexes Proteins 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 177
- 238000000034 method Methods 0.000 claims abstract description 132
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 127
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 125
- 239000013078 crystal Substances 0.000 claims abstract description 75
- 239000000203 mixture Substances 0.000 claims abstract description 60
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 27
- 238000013461 design Methods 0.000 claims abstract description 23
- 238000013500 data storage Methods 0.000 claims abstract description 19
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 14
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 10
- 125000000539 amino acid group Chemical group 0.000 claims description 210
- 235000018102 proteins Nutrition 0.000 claims description 133
- 239000000758 substrate Substances 0.000 claims description 114
- -1 2-cyanophenyl Chemical group 0.000 claims description 91
- 125000003118 aryl group Chemical group 0.000 claims description 67
- 125000001072 heteroaryl group Chemical group 0.000 claims description 61
- 125000004429 atom Chemical group 0.000 claims description 60
- 125000001931 aliphatic group Chemical group 0.000 claims description 56
- 125000000623 heterocyclic group Chemical group 0.000 claims description 56
- 150000005829 chemical entities Chemical class 0.000 claims description 52
- 238000006366 phosphorylation reaction Methods 0.000 claims description 52
- 230000026731 phosphorylation Effects 0.000 claims description 51
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 49
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 49
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 46
- 230000000694 effects Effects 0.000 claims description 36
- 102000001253 Protein Kinase Human genes 0.000 claims description 28
- 108060006633 protein kinase Proteins 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 20
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 230000002401 inhibitory effect Effects 0.000 claims description 19
- 238000002425 crystallisation Methods 0.000 claims description 18
- 230000008025 crystallization Effects 0.000 claims description 18
- 229920002527 Glycogen Polymers 0.000 claims description 17
- 229940096919 glycogen Drugs 0.000 claims description 17
- 238000003786 synthesis reaction Methods 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 239000003981 vehicle Substances 0.000 claims description 15
- 238000002441 X-ray diffraction Methods 0.000 claims description 14
- 239000002671 adjuvant Substances 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 108060000903 Beta-catenin Proteins 0.000 claims description 12
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 12
- 210000004369 blood Anatomy 0.000 claims description 12
- 239000008280 blood Substances 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 102000015735 Beta-catenin Human genes 0.000 claims description 11
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 11
- 239000008103 glucose Substances 0.000 claims description 11
- 102000013498 tau Proteins Human genes 0.000 claims description 11
- 108010026424 tau Proteins Proteins 0.000 claims description 11
- 238000012545 processing Methods 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- 239000011232 storage material Substances 0.000 claims description 9
- 239000012472 biological sample Substances 0.000 claims description 8
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002773 nucleotide Substances 0.000 claims description 8
- 125000003729 nucleotide group Chemical group 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
- 239000001226 triphosphate Substances 0.000 claims description 7
- JHXDLIAMKPRADS-UHFFFAOYSA-N 4-(3-fluorophenyl)-5-phenyl-1h-pyrazolo[3,4-c]pyridazin-3-amine Chemical compound C=1C=CC(F)=CC=1C1=C2C(N)=NNC2=NN=C1C1=CC=CC=C1 JHXDLIAMKPRADS-UHFFFAOYSA-N 0.000 claims description 6
- 108010046277 H 179 Proteins 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 230000003247 decreasing effect Effects 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 235000011178 triphosphate Nutrition 0.000 claims description 6
- 239000000556 agonist Substances 0.000 claims description 5
- 239000005557 antagonist Substances 0.000 claims description 5
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 5
- 239000011549 crystallization solution Substances 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- NRHHPDMHIVEBSS-UHFFFAOYSA-N n-(1h-indazol-3-yl)-2-[2-(trifluoromethyl)phenyl]quinazolin-4-amine Chemical compound FC(F)(F)C1=CC=CC=C1C1=NC(NC=2C3=CC=CC=C3NN=2)=C(C=CC=C2)C2=N1 NRHHPDMHIVEBSS-UHFFFAOYSA-N 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 5
- 230000003936 working memory Effects 0.000 claims description 5
- NPHKXSDZIKFIRU-UHFFFAOYSA-N 4,5-diphenyl-2h-pyrazolo[3,4-c]pyridazin-3-amine Chemical compound C=1C=CC=CC=1C=1C2=C(N)NN=C2N=NC=1C1=CC=CC=C1 NPHKXSDZIKFIRU-UHFFFAOYSA-N 0.000 claims description 4
- 230000007423 decrease Effects 0.000 claims description 4
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims description 4
- LGWDGIALCCNBQU-UHFFFAOYSA-N n-(5-methyl-1h-pyrazol-3-yl)-2-pyridin-4-ylquinazolin-4-amine Chemical compound N1N=C(C)C=C1NC1=NC(C=2C=CN=CC=2)=NC2=CC=CC=C12 LGWDGIALCCNBQU-UHFFFAOYSA-N 0.000 claims description 4
- 239000004299 sodium benzoate Substances 0.000 claims description 4
- 241000701447 unidentified baculovirus Species 0.000 claims description 4
- 230000006951 hyperphosphorylation Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-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
- 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
- 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
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- VQISKCBTGNMDTP-UHFFFAOYSA-N 4,5-bis(4-fluorophenyl)-1h-pyrazolo[3,4-c]pyridazin-3-amine Chemical compound C=1C=C(F)C=CC=1C1=C2C(N)=NNC2=NN=C1C1=CC=C(F)C=C1 VQISKCBTGNMDTP-UHFFFAOYSA-N 0.000 claims description 2
- IVRPJGSBYHTNHT-UHFFFAOYSA-N 4-(4-fluorophenyl)-5-phenyl-1h-pyrazolo[3,4-c]pyridazin-3-amine Chemical compound C=1C=C(F)C=CC=1C1=C2C(N)=NNC2=NN=C1C1=CC=CC=C1 IVRPJGSBYHTNHT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- SJHHGUYUTFSVME-UHFFFAOYSA-N 5-(3-methylphenyl)-4-phenyl-1h-pyrazolo[3,4-c]pyridazin-3-amine Chemical compound CC1=CC=CC(C=2C(=C3C(N)=NNC3=NN=2)C=2C=CC=CC=2)=C1 SJHHGUYUTFSVME-UHFFFAOYSA-N 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 claims description 2
- 229940125797 compound 12 Drugs 0.000 claims description 2
- 229940126543 compound 14 Drugs 0.000 claims description 2
- 229940125758 compound 15 Drugs 0.000 claims description 2
- 229940126142 compound 16 Drugs 0.000 claims description 2
- 229940125782 compound 2 Drugs 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- LETVJWLLIMJADE-UHFFFAOYSA-N pyridazin-3-amine Chemical compound NC1=CC=CN=N1 LETVJWLLIMJADE-UHFFFAOYSA-N 0.000 claims 11
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 7
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims 3
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 2
- AKNGRUGMIBUNNX-UHFFFAOYSA-N 3-(3-amino-4-phenyl-2h-pyrazolo[3,4-c]pyridazin-5-yl)benzamide Chemical compound NC(=O)C1=CC=CC(C=2C(=C3C(N)=NNC3=NN=2)C=2C=CC=CC=2)=C1 AKNGRUGMIBUNNX-UHFFFAOYSA-N 0.000 claims 2
- IDFNMLSYDALSTJ-UHFFFAOYSA-N 3-[3-amino-4-(2-methylphenyl)-2h-pyrazolo[3,4-c]pyridazin-5-yl]benzamide Chemical compound CC1=CC=CC=C1C1=C(C=2C=C(C=CC=2)C(N)=O)N=NC2=C1C(N)=NN2 IDFNMLSYDALSTJ-UHFFFAOYSA-N 0.000 claims 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 2
- AVDISOMQMOJXHY-UHFFFAOYSA-N 4-(4-chlorophenyl)-5-(3-phenoxyphenyl)-2h-pyrazolo[3,4-c]pyridazin-3-amine Chemical compound C=1C=C(Cl)C=CC=1C1=C2C(N)=NNC2=NN=C1C(C=1)=CC=CC=1OC1=CC=CC=C1 AVDISOMQMOJXHY-UHFFFAOYSA-N 0.000 claims 2
- FNXMBCWYAGWKSG-UHFFFAOYSA-N 4-[3-amino-4-(2-methylphenyl)-2h-pyrazolo[3,4-c]pyridazin-5-yl]benzamide Chemical compound CC1=CC=CC=C1C1=C(C=2C=CC(=CC=2)C(N)=O)N=NC2=C1C(N)=NN2 FNXMBCWYAGWKSG-UHFFFAOYSA-N 0.000 claims 2
- REFIMIGHWYMMPC-UHFFFAOYSA-N 4-[3-amino-5-(2-chlorophenyl)-1h-pyrazolo[3,4-c]pyridazin-4-yl]benzonitrile Chemical compound C=1C=C(C#N)C=CC=1C1=C2C(N)=NNC2=NN=C1C1=CC=CC=C1Cl REFIMIGHWYMMPC-UHFFFAOYSA-N 0.000 claims 2
- LLWXDAQULUCWDC-UHFFFAOYSA-N 5-(1,3-benzodioxol-5-yl)-4-phenyl-1h-pyrazolo[3,4-c]pyridazin-3-amine Chemical compound C=12C(N)=NNC2=NN=C(C=2C=C3OCOC3=CC=2)C=1C1=CC=CC=C1 LLWXDAQULUCWDC-UHFFFAOYSA-N 0.000 claims 2
- YYGUSAHCDWSGJE-UHFFFAOYSA-N 5-(3-chlorophenyl)-4-phenyl-1h-pyrazolo[3,4-c]pyridazin-3-amine Chemical compound C=1C=CC=CC=1C1=C2C(N)=NNC2=NN=C1C1=CC=CC(Cl)=C1 YYGUSAHCDWSGJE-UHFFFAOYSA-N 0.000 claims 2
- BNMDZRIGIQLJGI-UHFFFAOYSA-N 5-(3-nitrophenyl)-4-phenyl-1h-pyrazolo[3,4-c]pyridazin-3-amine Chemical compound C=1C=CC=CC=1C1=C2C(N)=NNC2=NN=C1C1=CC=CC([N+]([O-])=O)=C1 BNMDZRIGIQLJGI-UHFFFAOYSA-N 0.000 claims 2
- YTBPMMBYXWEXTC-UHFFFAOYSA-N 5-(3-phenoxyphenyl)-4-phenyl-2h-pyrazolo[3,4-c]pyridazin-3-amine Chemical compound C=1C=CC=CC=1C1=C2C(N)=NNC2=NN=C1C(C=1)=CC=CC=1OC1=CC=CC=C1 YTBPMMBYXWEXTC-UHFFFAOYSA-N 0.000 claims 2
- PHHUDUOMJNIKIV-UHFFFAOYSA-N n-(4,5-diphenyl-1h-pyrazolo[3,4-c]pyridazin-3-yl)acetamide Chemical compound C=1C=CC=CC=1C1=C2C(NC(=O)C)=NNC2=NN=C1C1=CC=CC=C1 PHHUDUOMJNIKIV-UHFFFAOYSA-N 0.000 claims 2
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims 1
- 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 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 claims 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims 1
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- G16B15/00—ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
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| JP4122216B2 (ja) * | 2000-09-19 | 2008-07-23 | ノバルティス バクシンズ アンド ダイアグノスティックス，インコーポレーテッド | ＧＳＫ−３βタンパク質の特徴づけおよびその使用方法 |
| JP4656838B2 (ja) * | 2002-02-06 | 2011-03-23 | バーテックス ファーマシューティカルズ インコーポレイテッド | Ｇｓｋ−３の阻害剤として有用なヘテロアリール化合物 |
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| GB0207249D0 (en) * | 2002-03-27 | 2002-05-08 | Glaxo Group Ltd | Novel compounds |
| CA2565308A1 (en) * | 2003-05-06 | 2004-11-25 | New Century Pharmaceuticals | Albumin binding sites for evaluating drug interactions and methods of evaluating or designing drugs based on their albumin binding properties |
| ATE369370T1 (de) * | 2003-10-10 | 2007-08-15 | Pfizer Prod Inc | Substituierte 2h-(1,2,4)triazolo(4,3-a)pyrazine als gsk-3-inhibitoren |
| WO2005041895A2 (en) * | 2003-11-03 | 2005-05-12 | New Century Pharmaceuticals, Inc. | Albumin binding sites for evaluating drug interactions and methods of evaluating or designing drugs based on their albumin binding properties |
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| WO2005114221A2 (en) * | 2004-05-21 | 2005-12-01 | The Institute For Systems Biology | Compositions and methods for quantification of serum glycoproteins |
| CA2585934C (en) | 2004-10-29 | 2013-09-10 | Abbott Laboratories | Novel pyrazolopyridine urea kinase inhibitors |
| WO2009126335A2 (en) * | 2008-04-08 | 2009-10-15 | University Of Florida Research Foundation, Inc. | Ant2 inhibitor compounds and methods of use thereof |
| US20100016247A1 (en) * | 2008-07-21 | 2010-01-21 | Florida State University Research Foundation | Using budding yeast to screen for inhibitors of aurora kinases |
| WO2010014253A2 (en) * | 2008-08-01 | 2010-02-04 | University Of Florida Research Foundation, Inc. | Ant4 inhibitor compounds and methods of use thereof |
| WO2010027458A2 (en) * | 2008-09-02 | 2010-03-11 | University Of Florida Research Foundation, Inc. | Pdk inhibitor compounds and methods of use thereof |
| WO2010075551A1 (en) * | 2008-12-24 | 2010-07-01 | Massachusetts Institute Of Technology | Compositions of modulators of the wnt/beta-catenin pathway and benzamide and/or hydroxamic acid derivatives to treat bipolar disorder |
| WO2011019651A1 (en) | 2009-08-10 | 2011-02-17 | Epitherix, Llc | Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof |
| BR112012002942A2 (pt) * | 2009-08-10 | 2015-10-13 | Epitherix Llc | indazóis como inibidores da trilha de sinalização de wnt/b-catenina e empregos terapêuticos destes. |
| EP2464647B1 (en) | 2009-08-11 | 2016-09-21 | Bristol-Myers Squibb Company | Azaindazoles as btk kinase modulators and use thereof |
| SMT201700581T1 (it) | 2009-12-21 | 2018-01-11 | Samumed Llc | 1h-pirazolo[3,4-b]piridine e loro usi terapeutici |
| PL2605652T3 (pl) | 2010-08-18 | 2018-04-30 | Samumed, Llc | Diketony i hydroksyketony jako aktywatory szlaku sygnalizacji kateninowej |
| CA2834049C (en) | 2011-04-25 | 2018-05-22 | Usher Iii Initiative, Inc. | Pyrazolopyridazines and methods for treating retinal-degenerative diseases and hearing loss associated with usher syndrome |
| US8673269B2 (en) | 2011-07-14 | 2014-03-18 | Keith R. Latham | Halogenated phenols for diagnostics, antioxidant protection and drug delivery |
| EP3473099A1 (en) | 2011-09-14 | 2019-04-24 | Samumed, LLC | Indazole-3-carboxamides and their use as wnt/b-catenin signaling pathway inhibitors |
| EP2825886A4 (en) * | 2012-03-14 | 2015-11-18 | Stephen Marx | MEDIUM AND METHODS OF DIAGNOSIS AND THERAPY OF ILLNESSES |
| PH12017500997A1 (en) | 2012-04-04 | 2018-02-19 | Samumed Llc | Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof |
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| CA2889537C (en) * | 2012-10-25 | 2017-12-12 | Usher Iii Initiative, Inc. | Pyrazolopyridazines and methods for treating retinal-degenerative diseases and hearing loss associated with usher syndrome |
| US9227976B2 (en) | 2012-10-25 | 2016-01-05 | Usher Iii Initiative, Inc. | Pyrazolopyridazines and methods for treating retinal-degenerative diseases and hearing loss associated with usher syndrome |
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| WO2015155738A2 (en) | 2014-04-09 | 2015-10-15 | Christopher Rudd | Use of gsk-3 inhibitors or activators which modulate pd-1 or t-bet expression to modulate t cell immunity |
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| WO2016040188A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
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| WO2016040182A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 2-(1h-indazol-3-yl)-1h-imidazo[4,5-c]pyridine and therapeutic uses thereof |
| WO2016040185A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 2-(1h-indazol-3-yl)-3h-imidazo[4,5-b]pyridine and therapeutic uses thereof |
| WO2016040181A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
| WO2016040193A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof |
| US10383861B2 (en) | 2015-08-03 | 2019-08-20 | Sammumed, LLC | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
| US10188634B2 (en) | 2015-08-03 | 2019-01-29 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
| WO2017023989A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
| WO2017024021A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc | 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
| WO2017024026A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc | 3-(1h-indol-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof |
| WO2017023996A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
| US10604512B2 (en) | 2015-08-03 | 2020-03-31 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-indazoles and therapeutic uses thereof |
| US10285982B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
| WO2017023972A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
| US10329309B2 (en) | 2015-08-03 | 2019-06-25 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
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| US10206909B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
| WO2017024010A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
| WO2017023987A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
| US10206908B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
| WO2017024003A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
| CN109311956A (zh) | 2015-08-25 | 2019-02-05 | 伊斯迪德股份公司 | 诱导组织形成的化合物及其应用 |
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| WO2017032857A2 (en) * | 2015-08-25 | 2017-03-02 | Histide Ag | Compounds for inducing tissue formation and uses thereof |
| JP6982748B2 (ja) | 2015-11-06 | 2021-12-17 | バイオスプライス セラピューティクス インコーポレイテッド | ２−（１Ｈ−インダゾール−３−イル）−３Ｈ−イミダゾ［４，５−ｃ］ピリジンおよびそれらの抗炎症的使用 |
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| KR102593742B1 (ko) | 2016-10-21 | 2023-10-24 | 사뮤메드, 엘엘씨 | 인다졸-3-카복사마이드를 사용하는 방법 및 wnt/b-카테닌 신호전달 경로 억제제로서의 그들의 용도 |
| JP7630905B2 (ja) | 2016-11-07 | 2025-02-18 | バイオスプライス セラピューティクス インコーポレイテッド | 単回用量の調整済み注射用製剤 |
| EP3628044B1 (en) * | 2017-05-15 | 2023-11-22 | The Regents of The University of Michigan | Pyrrolo[2,3-c]pyridines and related analogs as lsd-1 inhibitors |
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| US4009022A (en) | 1975-10-30 | 1977-02-22 | Rohm And Haas Company | Selective antagonists for triazine herbicides |
| US4886646A (en) * | 1988-03-23 | 1989-12-12 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | Hanging drop crystal growth apparatus and method |
| US5096676A (en) | 1989-01-27 | 1992-03-17 | Mcpherson Alexander | Crystal growing apparatus |
| US5130105A (en) * | 1990-10-23 | 1992-07-14 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | Protein crystal growth tray assembly |
| US5200910A (en) | 1991-01-30 | 1993-04-06 | The Board Of Trustees Of The Leland Stanford University | Method for modelling the electron density of a crystal |
| WO1993002209A1 (en) | 1991-07-22 | 1993-02-04 | The Regents Of The University Of California | Methods of designing specific affectors using three-dimensional conformation of enzyme/affector complex |
| US5221410A (en) * | 1991-10-09 | 1993-06-22 | Schering Corporation | Crystal forming device |
| US5353236A (en) * | 1992-04-23 | 1994-10-04 | The Board Of Trustees Of The Leland Stanford University | High-resolution crystallographic modelling of a macromolecule |
| US5453937A (en) | 1993-04-28 | 1995-09-26 | Immunex Corporation | Method and system for protein modeling |
| US5400741A (en) | 1993-05-21 | 1995-03-28 | Medical Foundation Of Buffalo, Inc. | Device for growing crystals |
| JP3784076B2 (ja) | 1997-02-07 | 2006-06-07 | プリンストン ユニヴァーシティ | 変性ヌクレオチド三燐酸基質を利用できる組み換えタンパクキナーゼ |
| GB9721437D0 (en) * | 1997-10-10 | 1997-12-10 | Glaxo Group Ltd | Heteroaromatic compounds and their use in medicine |
| US6162613A (en) * | 1998-02-18 | 2000-12-19 | Vertex Pharmaceuticals, Inc. | Methods for designing inhibitors of serine/threonine-kinases and tyrosine kinases |
| JP4533534B2 (ja) | 1998-06-19 | 2010-09-01 | ノバルティス バクシンズ アンド ダイアグノスティックス，インコーポレーテッド | グリコーゲンシンターゼキナーゼ３のインヒビター |
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| WO2000036096A1 (en) * | 1998-12-16 | 2000-06-22 | Vertex Pharmaceuticals Incorporated | Crystallized p38 complexes |
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| JP4122216B2 (ja) * | 2000-09-19 | 2008-07-23 | ノバルティス バクシンズ アンド ダイアグノスティックス，インコーポレーテッド | ＧＳＫ−３βタンパク質の特徴づけおよびその使用方法 |
| WO2002024694A1 (en) * | 2000-09-22 | 2002-03-28 | Smithkline Beecham, P.L.C. | Pyrazolopyridines and pyrazolopyridazines as antidiabetics |
| AU2002222274A1 (en) * | 2000-12-18 | 2002-07-01 | Smithkline Beecham Plc | Crystal structure of glycogen synthase kinase 3 beta |
| WO2003068932A2 (en) * | 2002-02-11 | 2003-08-21 | Chiron Corporation | Method for crystallizing human gsk3 and novel crystal structure thereof |
| GB0206723D0 (en) * | 2002-03-21 | 2002-05-01 | Glaxo Group Ltd | Novel compounds |
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| US8318467B2 (en) | 2012-11-27 |
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| CA2444882A1 (en) | 2002-11-07 |
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| US7883881B2 (en) | 2011-02-08 |
| EP2295550A2 (en) | 2011-03-16 |
| US20110129896A1 (en) | 2011-06-02 |
| JP2005504731A (ja) | 2005-02-17 |
| US20100227814A1 (en) | 2010-09-09 |
| EP2082743A2 (en) | 2009-07-29 |
| EP2295550A3 (en) | 2011-12-14 |
| EP1435957B1 (en) | 2009-06-17 |
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