JP2014517035A5 - - Google Patents
Download PDFInfo
- Publication number
- JP2014517035A5 JP2014517035A5 JP2014515878A JP2014515878A JP2014517035A5 JP 2014517035 A5 JP2014517035 A5 JP 2014517035A5 JP 2014515878 A JP2014515878 A JP 2014515878A JP 2014515878 A JP2014515878 A JP 2014515878A JP 2014517035 A5 JP2014517035 A5 JP 2014517035A5
- Authority
- JP
- Japan
- Prior art keywords
- hydrogen
- compound
- hexane
- bicyclo
- benzyl
- 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.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 claims description 201
- -1 2,2-dimethyl-propionyloxymethyl Chemical group 0.000 claims description 94
- 239000001257 hydrogen Substances 0.000 claims description 92
- 229910052739 hydrogen Inorganic materials 0.000 claims description 92
- 125000001153 fluoro group Chemical group F* 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 54
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 49
- 150000002431 hydrogen Chemical class 0.000 claims description 43
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 19
- 201000000980 schizophrenia Diseases 0.000 claims description 15
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 claims description 12
- 208000020925 Bipolar disease Diseases 0.000 claims description 11
- JAPMJSVZDUYFKL-UHFFFAOYSA-N bicyclo[3.1.0]hexane Chemical group C1CCC2CC21 JAPMJSVZDUYFKL-UHFFFAOYSA-N 0.000 claims description 11
- 208000020016 psychiatric disease Diseases 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 7
- 208000029364 generalized anxiety disease Diseases 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 235000019000 fluorine Nutrition 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 238000002360 preparation method Methods 0.000 description 37
- 239000000243 solution Substances 0.000 description 36
- 238000000034 method Methods 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 32
- 229940002612 prodrug Drugs 0.000 description 30
- 239000000651 prodrug Substances 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 28
- 101001071429 Homo sapiens Metabotropic glutamate receptor 2 Proteins 0.000 description 26
- 102100036837 Metabotropic glutamate receptor 2 Human genes 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 230000000694 effects Effects 0.000 description 21
- 238000003556 assay Methods 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 20
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 241000700159 Rattus Species 0.000 description 15
- 239000000556 agonist Substances 0.000 description 15
- 238000011534 incubation Methods 0.000 description 15
- 239000003814 drug Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000012141 concentrate Substances 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- ANUFAWHRSIJTHW-UHFFFAOYSA-N 2-methylheptanedioic acid Chemical compound OC(=O)C(C)CCCCC(O)=O ANUFAWHRSIJTHW-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 108010004620 glycylsarcosine Proteins 0.000 description 11
- VYAMLSCELQQRAE-UHFFFAOYSA-N glycylsarcosine zwitterion Chemical compound OC(=O)CN(C)C(=O)CN VYAMLSCELQQRAE-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 108091006594 SLC15A1 Proteins 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 230000036760 body temperature Effects 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 0 CC(C)c1nnc(*)[n]1 Chemical compound CC(C)c1nnc(*)[n]1 0.000 description 7
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 7
- 102000046014 Peptide Transporter 1 Human genes 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 229950010883 phencyclidine Drugs 0.000 description 7
- 239000000018 receptor agonist Substances 0.000 description 7
- 229940044601 receptor agonist Drugs 0.000 description 7
- 239000012047 saturated solution Substances 0.000 description 7
- 238000001890 transfection Methods 0.000 description 7
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- MWECKFISVWUYDM-UHFFFAOYSA-N bicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound C1CC(C(O)=O)C2C(C(=O)O)C21 MWECKFISVWUYDM-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 229930195712 glutamate Natural products 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- 206010013654 Drug abuse Diseases 0.000 description 5
- 101001032848 Homo sapiens Metabotropic glutamate receptor 3 Proteins 0.000 description 5
- 206010020843 Hyperthermia Diseases 0.000 description 5
- 102100038352 Metabotropic glutamate receptor 3 Human genes 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 230000036031 hyperthermia Effects 0.000 description 5
- 230000000968 intestinal effect Effects 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 208000011117 substance-related disease Diseases 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 208000019901 Anxiety disease Diseases 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 4
- 229940106164 cephalexin Drugs 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000006742 locomotor activity Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- FICWTZOQUXUYOK-AHKKVLALSA-N (1r,2s,4r,5r,6r)-2-[[(2s)-2-aminopropanoyl]amino]-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid;azane;hydrate Chemical compound N.O.S([C@@H]1C[C@@]([C@@H]2[C@H]([C@@H]21)C(O)=O)(NC(=O)[C@@H](N)C)C(O)=O)C1=NC=NN1 FICWTZOQUXUYOK-AHKKVLALSA-N 0.000 description 3
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 3
- OKSYUCYFMKATOR-UHFFFAOYSA-N 2-methylheptanedioic acid;hydrochloride Chemical compound Cl.OC(=O)C(C)CCCCC(O)=O OKSYUCYFMKATOR-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000012737 fresh medium Substances 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000037023 motor activity Effects 0.000 description 3
- NRBNGHCYDWUVLC-UHFFFAOYSA-N mtep Chemical compound S1C(C)=NC(C#CC=2C=NC=CC=2)=C1 NRBNGHCYDWUVLC-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000012799 strong cation exchange Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102000002285 Excitatory Amino Acid Transporter 1 Human genes 0.000 description 2
- 108010000722 Excitatory Amino Acid Transporter 1 Proteins 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- 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 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102100021491 Solute carrier family 15 member 1 Human genes 0.000 description 2
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 2
- WXIONIWNXBAHRU-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Chemical compound C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 WXIONIWNXBAHRU-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 235000012501 ammonium carbonate Nutrition 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000000561 anti-psychotic effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- SWFYNWDZNKVCMX-ZHJQLAIOSA-N bis[(4-methoxyphenyl)methyl] (1r,2s,4s,5r,6r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)[C@@H]1[C@@H]2[C@H]1[C@@H](SC1=NNC=N1)C[C@@]2(NC(=O)OC(C)(C)C)C(=O)OCC1=CC=C(OC)C=C1 SWFYNWDZNKVCMX-ZHJQLAIOSA-N 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000005277 cation exchange chromatography Methods 0.000 description 2
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 2
- 229960003009 clopidogrel Drugs 0.000 description 2
- DCASRSISIKYPDD-UHFFFAOYSA-N clopidogrel carboxylic acid Chemical compound C1CC=2SC=CC=2CN1C(C(=O)O)C1=CC=CC=C1Cl DCASRSISIKYPDD-UHFFFAOYSA-N 0.000 description 2
- 230000036757 core body temperature Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000012048 forced swim test Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000008587 neuronal excitability Effects 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- YPJUNDFVDDCYIH-UHFFFAOYSA-N perfluorobutyric acid Chemical compound OC(=O)C(F)(F)C(F)(F)C(F)(F)F YPJUNDFVDDCYIH-UHFFFAOYSA-N 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000009182 swimming Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- ZBBCOPQWFRZNNR-YZKWPGIPSA-N (1r,2s,4r,5r,6r)-2-amino-4-[(5-methyl-1h-1,2,4-triazol-3-yl)sulfanyl]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound N1C(C)=NN=C1S[C@H]1[C@@H]([C@@H]2C(O)=O)[C@@H]2[C@](N)(C(O)=O)C1 ZBBCOPQWFRZNNR-YZKWPGIPSA-N 0.000 description 1
- ZOZLUXKDWMTXCE-XHEPXMHESA-N (1r,2s,4r,5r,6r)-2-amino-4-[[5-(difluoromethyl)-1h-1,2,4-triazol-3-yl]sulfanyl]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid;hydrochloride Chemical compound Cl.S([C@@H]1C[C@@]([C@@H]2[C@H]([C@@H]21)C(O)=O)(N)C(O)=O)C1=NNC(C(F)F)=N1 ZOZLUXKDWMTXCE-XHEPXMHESA-N 0.000 description 1
- KCOXOYTVOWOBEG-KIZHAORRSA-N (1r,2s,4s,5r,6r)-2-[(2-aminoacetyl)amino]-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid;hydrochloride Chemical compound Cl.S([C@H]1C[C@@]([C@@H]2[C@H]([C@@H]21)C(O)=O)(NC(=O)CN)C(O)=O)C1=NN=CN1 KCOXOYTVOWOBEG-KIZHAORRSA-N 0.000 description 1
- KZULESKPDOSALY-IBUWJVEWSA-N (1r,2s,4s,5r,6r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound S([C@H]1C[C@@]([C@@H]2[C@H]([C@@H]21)C(O)=O)(NC(=O)OC(C)(C)C)C(O)=O)C=1N=CNN=1 KZULESKPDOSALY-IBUWJVEWSA-N 0.000 description 1
- YSOWRGMLMZQSBX-LWEFNAMFSA-N (1r,2s,4s,5r,6r)-2-amino-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound S([C@H]1C[C@@]([C@@H]2[C@H]([C@@H]21)C(O)=O)(N)C(O)=O)C=1N=CNN=1 YSOWRGMLMZQSBX-LWEFNAMFSA-N 0.000 description 1
- DENFAQSAXLELGQ-NDPIOBCDSA-N (1s,2s,5r,6r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound CC(C)(C)OC(=O)N[C@@]1(C(O)=O)CC(=O)[C@H]2[C@H](C(O)=O)[C@@H]12 DENFAQSAXLELGQ-NDPIOBCDSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 description 1
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AFBBKYQYNPNMAT-UHFFFAOYSA-N 1h-1,2,4-triazol-1-ium-3-thiolate Chemical compound SC=1N=CNN=1 AFBBKYQYNPNMAT-UHFFFAOYSA-N 0.000 description 1
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BRAVXLLSVBYDIS-GJGKZLBNSA-N CC(C)(C)C(OCOC([C@@H]([C@@H]1[C@H](C2)Sc3n[nH]cn3)[C@H]1[C@@]2(C(OCOC(C(C)(C)C)=O)=O)NC(OC(C)(C)C)=O)=O)=O Chemical compound CC(C)(C)C(OCOC([C@@H]([C@@H]1[C@H](C2)Sc3n[nH]cn3)[C@H]1[C@@]2(C(OCOC(C(C)(C)C)=O)=O)NC(OC(C)(C)C)=O)=O)=O BRAVXLLSVBYDIS-GJGKZLBNSA-N 0.000 description 1
- VZLMXVGSPYFIEO-SWSUZQIZSA-N CC(C)(C)OC(NC/C(/N)=[O]/OC([C@H](C[C@@H]([C@H]12)Sc3nnc[nH]3)[C@@H]1[C@H]2C(O)=O)=O)=O Chemical compound CC(C)(C)OC(NC/C(/N)=[O]/OC([C@H](C[C@@H]([C@H]12)Sc3nnc[nH]3)[C@@H]1[C@H]2C(O)=O)=O)=O VZLMXVGSPYFIEO-SWSUZQIZSA-N 0.000 description 1
- YJFOMMZPBXXHSO-UHFFFAOYSA-N CC1=CC=C(C=C1)S(=O)(=O)OC2CC(C3C2C3C(=O)OCC4=CC=CC=C4)(C(=O)OCC5=CC=CC=C5)NC(=O)OC(C)(C)C Chemical compound CC1=CC=C(C=C1)S(=O)(=O)OC2CC(C3C2C3C(=O)OCC4=CC=CC=C4)(C(=O)OCC5=CC=CC=C5)NC(=O)OC(C)(C)C YJFOMMZPBXXHSO-UHFFFAOYSA-N 0.000 description 1
- MTQFVFGVUHHBJI-HNLJFRNMSA-N CC[C@@H]1[C@@H]2[C@@H]1[C@@](C[C@@H]2N)(CC3=CC=CC=C3)SC4=NC=NN4 Chemical compound CC[C@@H]1[C@@H]2[C@@H]1[C@@](C[C@@H]2N)(CC3=CC=CC=C3)SC4=NC=NN4 MTQFVFGVUHHBJI-HNLJFRNMSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- GVSNQMFKEPBIOY-UHFFFAOYSA-N Cc1n[nH]nc1 Chemical compound Cc1n[nH]nc1 GVSNQMFKEPBIOY-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 102000034575 Glutamate transporters Human genes 0.000 description 1
- 108091006151 Glutamate transporters Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 206010021033 Hypomenorrhoea Diseases 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 229930195714 L-glutamate Natural products 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000699673 Mesocricetus auratus Species 0.000 description 1
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 description 1
- 102100038357 Metabotropic glutamate receptor 5 Human genes 0.000 description 1
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 1
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 description 1
- VSOZHNCXMJXRJU-UESLGPDASA-N N[C@@](C[C@H]([C@H]12)S/C(/NSC(F)F)=N/N)([C@@H]1[C@H]2C(O)=O)C(O)=O Chemical compound N[C@@](C[C@H]([C@H]12)S/C(/NSC(F)F)=N/N)([C@@H]1[C@H]2C(O)=O)C(O)=O VSOZHNCXMJXRJU-UESLGPDASA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- TWQNSHZTQSLJEE-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]methanol Chemical compound OCC1=CC=CC=C1C(F)(F)F TWQNSHZTQSLJEE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- PTPUOMXKXCCSEN-UHFFFAOYSA-N acetyloxymethyl 2-[2-[2-[5-[3-(acetyloxymethoxy)-2,7-dichloro-6-oxoxanthen-9-yl]-2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]-n-[2-(acetyloxymethoxy)-2-oxoethyl]-4-methylanilino]acetate Chemical compound CC(=O)OCOC(=O)CN(CC(=O)OCOC(C)=O)C1=CC=C(C)C=C1OCCOC1=CC(C2=C3C=C(Cl)C(=O)C=C3OC3=CC(OCOC(C)=O)=C(Cl)C=C32)=CC=C1N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O PTPUOMXKXCCSEN-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- SGNCWPSYNGIKPA-UHFFFAOYSA-N bicyclo[3.1.0]hexane-2-carboxylic acid Chemical compound OC(=O)C1CCC2CC12 SGNCWPSYNGIKPA-UHFFFAOYSA-N 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- HMEVVGALVYKHNW-HSDDCCJMSA-N bis(2,2-dimethylpropanoyloxymethyl) (1r,2s,4s,5r,6r)-2-amino-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound S([C@H]1C[C@](N)([C@H]2[C@@H]1[C@@H]2C(=O)OCOC(=O)C(C)(C)C)C(=O)OCOC(=O)C(C)(C)C)C=1N=CNN=1 HMEVVGALVYKHNW-HSDDCCJMSA-N 0.000 description 1
- GJGYYHWAQSBHKY-POLKJLAJSA-N bis[[3-(trifluoromethyl)phenyl]methyl] (1r,2s,4s,5r,6r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound S([C@H]1C[C@@]([C@@H]2[C@H]([C@@H]21)C(=O)OCC=1C=C(C=CC=1)C(F)(F)F)(NC(=O)OC(C)(C)C)C(=O)OCC=1C=C(C=CC=1)C(F)(F)F)C=1N=CNN=1 GJGYYHWAQSBHKY-POLKJLAJSA-N 0.000 description 1
- 229930189065 blasticidin Natural products 0.000 description 1
- 238000009529 body temperature measurement Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- PCFVXEVBQQKRJE-GWQZLTJGSA-N dibenzyl (1r,2s,4r,5r,6r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(2h-triazol-4-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound S([C@@H]1C[C@@]([C@@H]2[C@H]([C@@H]21)C(=O)OCC=1C=CC=CC=1)(NC(=O)OC(C)(C)C)C(=O)OCC=1C=CC=CC=1)C1=CNN=N1 PCFVXEVBQQKRJE-GWQZLTJGSA-N 0.000 description 1
- YJFOMMZPBXXHSO-YADUJKSQSA-N dibenzyl (1s,2s,4s,5r,6r)-4-(4-methylphenyl)sulfonyloxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]bicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)O[C@@H]1[C@@H]([C@@H]2C(=O)OCC=3C=CC=CC=3)[C@@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OCC=2C=CC=CC=2)C1 YJFOMMZPBXXHSO-YADUJKSQSA-N 0.000 description 1
- BHQPJQCJAWUQDE-NOVLSDETSA-N dibenzyl (1s,2s,4s,5r,6r)-4-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]bicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound O=C([C@H]1[C@@H]2[C@@H](O)C[C@@]([C@H]12)(NC(=O)OC(C)(C)C)C(=O)OCC=1C=CC=CC=1)OCC1=CC=CC=C1 BHQPJQCJAWUQDE-NOVLSDETSA-N 0.000 description 1
- CWNFHYFVLDRCQJ-LFYAFONDSA-N dibenzyl (1s,2s,5r,6r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound O=C([C@H]1[C@@H]2C(=O)C[C@@]([C@H]12)(NC(=O)OC(C)(C)C)C(=O)OCC=1C=CC=CC=1)OCC1=CC=CC=C1 CWNFHYFVLDRCQJ-LFYAFONDSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- HOEGWVKPYDFTSX-RVOOSNJASA-N diethyl (1r,2s,4s,5r,6r)-2-[[(2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound S([C@H]1C[C@@]([C@H]2[C@@H]1[C@@H]2C(=O)OCC)(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCC)C1=NN=CN1 HOEGWVKPYDFTSX-RVOOSNJASA-N 0.000 description 1
- HBDRRZRMCKDHOY-NTGSJNNUSA-N diethyl (1r,2s,4s,5r,6r)-2-[[2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]amino]-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound S([C@H]1C[C@@]([C@H]2[C@@H]1[C@@H]2C(=O)OCC)(NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCC)C1=NN=CN1 HBDRRZRMCKDHOY-NTGSJNNUSA-N 0.000 description 1
- GYJPPBLBPDAKFF-NKWANFOFSA-N diethyl (1r,2s,4s,5r,6r)-2-amino-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate;hydrochloride Chemical compound Cl.S([C@H]1C[C@](N)([C@H]2[C@@H]1[C@@H]2C(=O)OCC)C(=O)OCC)C1=NC=NN1 GYJPPBLBPDAKFF-NKWANFOFSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- JCZVQGLZEAGPRJ-XOCIWYINSA-N ditert-butyl (1r,2s,4r,5r,6r)-4-bromo-2-[(2-methylpropan-2-yl)oxycarbonylamino]bicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@@H](Br)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@@H]12 JCZVQGLZEAGPRJ-XOCIWYINSA-N 0.000 description 1
- SPMPPHYTWYNVJE-JHFNDOPCSA-N ditert-butyl (1r,2s,4s,5r,6r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-(1h-1,2,4-triazol-5-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylate Chemical compound S([C@H]1C[C@@]([C@@H]2[C@H]([C@@H]21)C(=O)OC(C)(C)C)(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C=1N=CNN=1 SPMPPHYTWYNVJE-JHFNDOPCSA-N 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000000848 glutamatergic effect Effects 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 239000011539 homogenization buffer Substances 0.000 description 1
- 230000002977 hyperthermial effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ULSIYEODSMZIPX-UHFFFAOYSA-N phenylethanolamine Chemical compound NCC(O)C1=CC=CC=C1 ULSIYEODSMZIPX-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000007015 preclinical effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HHGMADGROXARPN-UHFFFAOYSA-M sodium;2h-triazole-4-thiolate Chemical compound [Na+].[S-]C=1C=NNN=1 HHGMADGROXARPN-UHFFFAOYSA-M 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- JLEXUIVKURIPFI-UHFFFAOYSA-N tris phosphate Chemical compound OP(O)(O)=O.OCC(N)(CO)CO JLEXUIVKURIPFI-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11382208.4 | 2011-06-17 | ||
| EP11382208 | 2011-06-17 | ||
| US201161522791P | 2011-08-12 | 2011-08-12 | |
| US61/522,791 | 2011-08-12 | ||
| PCT/US2012/041229 WO2012173850A1 (en) | 2011-06-17 | 2012-06-07 | Bicyclo (3.1.0) hexane- 2, 6 -dicarboxylic acid derivatives as mglu2 receptor agonist |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2014517035A JP2014517035A (ja) | 2014-07-17 |
| JP2014517035A5 true JP2014517035A5 (OSRAM) | 2016-06-23 |
| JP5945592B2 JP5945592B2 (ja) | 2016-07-05 |
Family
ID=47357416
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2014515878A Active JP5945592B2 (ja) | 2011-06-17 | 2012-06-07 | Ｍｇｌｕ２受容体アゴニストとしてのビシクロ（３．１．０）ヘキサン−２，６−ジカルボン酸誘導体 |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US9296710B2 (OSRAM) |
| EP (1) | EP2721012B1 (OSRAM) |
| JP (1) | JP5945592B2 (OSRAM) |
| KR (1) | KR101598679B1 (OSRAM) |
| CN (1) | CN103596933B (OSRAM) |
| AU (1) | AU2012271024B2 (OSRAM) |
| BR (1) | BR112013031928B1 (OSRAM) |
| CA (1) | CA2836485C (OSRAM) |
| CY (1) | CY1117682T1 (OSRAM) |
| DK (1) | DK2721012T3 (OSRAM) |
| EA (1) | EA023553B1 (OSRAM) |
| ES (1) | ES2587204T3 (OSRAM) |
| HR (1) | HRP20160676T1 (OSRAM) |
| HU (1) | HUE030171T2 (OSRAM) |
| MX (1) | MX2013014802A (OSRAM) |
| PL (1) | PL2721012T3 (OSRAM) |
| PT (1) | PT2721012T (OSRAM) |
| RS (1) | RS54888B1 (OSRAM) |
| SI (1) | SI2721012T1 (OSRAM) |
| WO (1) | WO2012173850A1 (OSRAM) |
Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993006127A1 (en) | 1991-09-17 | 1993-04-01 | Warner-Lambert Company | Novel amino acid prodrug renin inhibitors |
| US5576323A (en) | 1993-12-03 | 1996-11-19 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| US5849525A (en) | 1994-03-09 | 1998-12-15 | Brigham And Women's Hospital, Inc. | Compositions corresponding to a proton-coupled peptide transporter and methods of making and using same |
| GB9605429D0 (en) | 1995-11-16 | 1996-05-15 | Lilly Co Eli | Excitatory amino acid receptor antagonists |
| BR9611511A (pt) | 1995-11-16 | 1999-05-04 | Lilly Co Eli | Derivados de aminoácidos excitatórios |
| US5688826A (en) | 1995-11-16 | 1997-11-18 | Eli Lilly And Company | Excitatory amino acid derivatives |
| US5952294A (en) | 1996-07-31 | 1999-09-14 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Peptidyl prodrugs and methods of making and using the same |
| ZA983930B (en) | 1997-05-14 | 1999-11-08 | Lilly Co Eli | Excitatory amino acid receptor modulators. |
| DK1052246T3 (da) | 1998-01-28 | 2003-06-16 | Taisho Pharmaceutical Co Ltd | Fluorholdige aminosyrederivater |
| CN1247527C (zh) | 1998-08-31 | 2006-03-29 | 大正制药株式会社 | 6－氟双环[3.1.0]己烷衍生物 |
| US6716452B1 (en) | 2000-08-22 | 2004-04-06 | New River Pharmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
| CN1216038C (zh) | 2000-06-28 | 2005-08-24 | 大正制药株式会社 | 新型二羧酸衍生物 |
| EP1351925A1 (en) | 2001-01-11 | 2003-10-15 | Eli Lilly And Company | Prodrugs of excitatory amino acids |
| HUP0400620A3 (en) | 2001-01-11 | 2012-09-28 | Lilly Co Eli | Prodrugs of excitatory amino acids and pharmaceutical compositions containing them and process for preparation the compounds |
| EP1370519A1 (en) * | 2001-02-22 | 2003-12-17 | Eli Lilly And Company | Synthetic excitatory amino acids |
| CA2450167A1 (en) | 2001-06-12 | 2002-12-19 | Elan Pharmaceuticals, Inc. | Macrocycles useful in the treatment of alzheimer's disease |
| RU2315622C2 (ru) | 2001-12-27 | 2008-01-27 | Тайсо Фармасьютикал Ко.,Лтд. | Производные 6-фторбицикло[3.1.0]гексана |
| US20050192273A1 (en) | 2002-04-03 | 2005-09-01 | Johnson Bryan G. | Therapy for psychoses combining an atypical antipsychotic and an mglu2/3 receptor agonist |
| EP1492595A1 (en) | 2002-04-03 | 2005-01-05 | Eli Lilly And Company | Therapy for psychoses combining an atypical antipsychotic and an mglu2/3 receptor agonist |
| HRP20090058A2 (hr) | 2002-06-11 | 2009-04-30 | Eli Lilly And Company | Prekursorski oblici lijekova za aminokiseline s pobuđivačkom aktivnosti |
| CN101362793A (zh) * | 2002-06-11 | 2009-02-11 | 伊莱利利公司 | 兴奋性氨基酸前药 |
| US7381746B2 (en) * | 2003-06-26 | 2008-06-03 | Taisho Pharmaceutical Co., Ltd. | 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative |
| CN100582087C (zh) * | 2003-06-26 | 2010-01-20 | 大正制药株式会社 | 2-氨基-双环[3.1.0]己烷-2,6-二甲酸酯衍生物 |
| HRP20161461T1 (hr) * | 2009-11-18 | 2017-01-27 | Suven Life Sciences Limited | Biciklički spojevi kao ligandi alfa4beta2 nikotinskih acetilakolinskih receptora |
| AR079343A1 (es) | 2009-12-21 | 2012-01-18 | Lilly Co Eli | Compuesto de acido 2-amino-4-(4h-1,2,4-triazol-3-ilsulfanil)biciclo[3.1.0]hexano-2,6-dicarboxilico, composicion farmaceutica que lo comprende y su uso para preparar un medicamento util para tratar un trastorno psiquiatrico |
-
2012
- 2012-06-07 HR HRP20160676TT patent/HRP20160676T1/hr unknown
- 2012-06-07 WO PCT/US2012/041229 patent/WO2012173850A1/en not_active Ceased
- 2012-06-07 PL PL12729769T patent/PL2721012T3/pl unknown
- 2012-06-07 MX MX2013014802A patent/MX2013014802A/es active IP Right Grant
- 2012-06-07 RS RS20160491A patent/RS54888B1/sr unknown
- 2012-06-07 US US14/123,768 patent/US9296710B2/en active Active
- 2012-06-07 BR BR112013031928-3A patent/BR112013031928B1/pt active IP Right Grant
- 2012-06-07 JP JP2014515878A patent/JP5945592B2/ja active Active
- 2012-06-07 CA CA2836485A patent/CA2836485C/en active Active
- 2012-06-07 DK DK12729769.5T patent/DK2721012T3/en active
- 2012-06-07 HU HUE12729769A patent/HUE030171T2/en unknown
- 2012-06-07 KR KR1020137033028A patent/KR101598679B1/ko active Active
- 2012-06-07 SI SI201230569A patent/SI2721012T1/sl unknown
- 2012-06-07 ES ES12729769.5T patent/ES2587204T3/es active Active
- 2012-06-07 EA EA201391700A patent/EA023553B1/ru not_active IP Right Cessation
- 2012-06-07 EP EP12729769.5A patent/EP2721012B1/en active Active
- 2012-06-07 AU AU2012271024A patent/AU2012271024B2/en active Active
- 2012-06-07 PT PT127297695T patent/PT2721012T/pt unknown
- 2012-06-07 CN CN201280029080.2A patent/CN103596933B/zh active Active
-
2016
- 2016-06-24 CY CY20161100570T patent/CY1117682T1/el unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5779190B2 (ja) | Ｍｇｌｕ２アゴニスト | |
| KR20140067048A (ko) | 라이소포스파티드산 수용체 길항제 | |
| JP2018199710A (ja) | ネプリライシン阻害剤 | |
| JP6714009B2 (ja) | （２ｒ，４ｒ）−５−（５’−クロロ−２’−フルオロビフェニル−４−イル）−２−ヒドロキシ−４−［（５−メチルオキサゾール−２−カルボニル）アミノ］ペンタン酸 | |
| JP5945592B2 (ja) | Ｍｇｌｕ２受容体アゴニストとしてのビシクロ（３．１．０）ヘキサン−２，６−ジカルボン酸誘導体 | |
| JP2014517035A5 (OSRAM) | ||
| JP5755821B2 (ja) | Ｍｇｌｕ２／３アゴニスト | |
| JP2885941B2 (ja) | 細胞付着抑制剤としての（−）−（３ｒ）−３−メチル−４−｛４−［４−（４−ピリジル）ピペラジン−１−イル］フェノキシ｝酪酸 | |
| HK1171228B (en) | Mglu2 agonists |