CA2932218C - S1p3 antagonists - Google Patents
S1p3 antagonists Download PDFInfo
- Publication number
- CA2932218C CA2932218C CA2932218A CA2932218A CA2932218C CA 2932218 C CA2932218 C CA 2932218C CA 2932218 A CA2932218 A CA 2932218A CA 2932218 A CA2932218 A CA 2932218A CA 2932218 C CA2932218 C CA 2932218C
- Authority
- CA
- Canada
- Prior art keywords
- bromo
- pyridin
- amide
- pentanoic acid
- compound
- 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.)
- Active
Links
- 239000005557 antagonist Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 242
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 claims abstract description 36
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 claims abstract description 36
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 193
- 229910052739 hydrogen Inorganic materials 0.000 claims description 95
- 239000000203 mixture Substances 0.000 claims description 90
- 239000001257 hydrogen Substances 0.000 claims description 89
- 229910052736 halogen Inorganic materials 0.000 claims description 75
- 150000002367 halogens Chemical class 0.000 claims description 74
- 239000002253 acid Substances 0.000 claims description 59
- 150000002431 hydrogen Chemical class 0.000 claims description 52
- 125000001153 fluoro group Chemical group F* 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
- 230000008878 coupling Effects 0.000 claims description 32
- 238000010168 coupling process Methods 0.000 claims description 32
- 238000005859 coupling reaction Methods 0.000 claims description 32
- 230000029936 alkylation Effects 0.000 claims description 31
- 238000005804 alkylation reaction Methods 0.000 claims description 31
- 108020003175 receptors Proteins 0.000 claims description 31
- -1 trifluoromethyl-furanyl Chemical group 0.000 claims description 31
- 102000005962 receptors Human genes 0.000 claims description 30
- 239000000460 chlorine Substances 0.000 claims description 27
- 150000001408 amides Chemical class 0.000 claims description 25
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 23
- 229910052794 bromium Inorganic materials 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 150000001721 carbon Chemical group 0.000 claims description 11
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 10
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 10
- 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 9
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 9
- 201000006417 multiple sclerosis Diseases 0.000 claims description 9
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- 230000002757 inflammatory effect Effects 0.000 claims description 8
- 230000004770 neurodegeneration Effects 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- KRRTXVSBTPCDOS-UHFFFAOYSA-N 5-bromopyrazin-2-amine Chemical compound NC1=CN=C(Br)C=N1 KRRTXVSBTPCDOS-UHFFFAOYSA-N 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 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 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- 230000036407 pain Effects 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 238000007126 N-alkylation reaction Methods 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 206010069351 acute lung injury Diseases 0.000 claims description 4
- 206010003246 arthritis Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 210000003734 kidney Anatomy 0.000 claims description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 206010016654 Fibrosis Diseases 0.000 claims description 3
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 206010030043 Ocular hypertension Diseases 0.000 claims description 3
- 208000021811 Sandhoff disease Diseases 0.000 claims description 3
- 208000027418 Wounds and injury Diseases 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 208000006218 bradycardia Diseases 0.000 claims description 3
- 230000036471 bradycardia Effects 0.000 claims description 3
- 230000006378 damage Effects 0.000 claims description 3
- 230000004761 fibrosis Effects 0.000 claims description 3
- 208000019622 heart disease Diseases 0.000 claims description 3
- 208000014674 injury Diseases 0.000 claims description 3
- 208000028867 ischemia Diseases 0.000 claims description 3
- SANOUVWGPVYVAV-UHFFFAOYSA-N isovaleramide Chemical compound CC(C)CC(N)=O SANOUVWGPVYVAV-UHFFFAOYSA-N 0.000 claims description 3
- 208000019553 vascular disease Diseases 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 206010035664 Pneumonia Diseases 0.000 claims description 2
- 238000004296 chiral HPLC Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims 3
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- AWGBKZRMLNVLAF-UHFFFAOYSA-N 3,5-dibromo-n,2-dihydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=CC(Br)=C1O AWGBKZRMLNVLAF-UHFFFAOYSA-N 0.000 claims 1
- 230000007071 enzymatic hydrolysis Effects 0.000 claims 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 claims 1
- 239000010200 folin Substances 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 239000000243 solution Substances 0.000 description 98
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- 239000012043 crude product Substances 0.000 description 47
- 238000010898 silica gel chromatography Methods 0.000 description 45
- 210000004027 cell Anatomy 0.000 description 44
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 39
- 238000003786 synthesis reaction Methods 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 230000015572 biosynthetic process Effects 0.000 description 36
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 36
- 230000014759 maintenance of location Effects 0.000 description 32
- 230000002829 reductive effect Effects 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 30
- 229910052938 sodium sulfate Inorganic materials 0.000 description 29
- 235000011152 sodium sulphate Nutrition 0.000 description 29
- 239000007832 Na2SO4 Substances 0.000 description 28
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 24
- 241000700159 Rattus Species 0.000 description 23
- PREAJPIKNPDDON-APAIHEESSA-N dideuterio-[dichloro(deuterio)methyl]-lambda3-chlorane Chemical compound C(Cl([2H])[2H])(Cl)(Cl)[2H] PREAJPIKNPDDON-APAIHEESSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- 239000003643 water by type Substances 0.000 description 20
- ASNFTDCKZKHJSW-REOHCLBHSA-N Quisqualic acid Chemical compound OC(=O)[C@@H](N)CN1OC(=O)NC1=O ASNFTDCKZKHJSW-REOHCLBHSA-N 0.000 description 19
- 235000017557 sodium bicarbonate Nutrition 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- 210000001130 astrocyte Anatomy 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 18
- 239000012047 saturated solution Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 17
- 150000001412 amines Chemical class 0.000 description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 230000011664 signaling Effects 0.000 description 12
- 230000004913 activation Effects 0.000 description 11
- 230000004054 inflammatory process Effects 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 10
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 10
- ASNFTDCKZKHJSW-UHFFFAOYSA-N DL-Quisqualic acid Natural products OC(=O)C(N)CN1OC(=O)NC1=O ASNFTDCKZKHJSW-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 150000007513 acids Chemical class 0.000 description 10
- 230000008485 antagonism Effects 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 230000001404 mediated effect Effects 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 206010061218 Inflammation Diseases 0.000 description 9
- 108091006629 SLC13A2 Proteins 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 230000014509 gene expression Effects 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 238000013459 approach Methods 0.000 description 8
- 230000003959 neuroinflammation Effects 0.000 description 8
- 210000002569 neuron Anatomy 0.000 description 8
- 238000002953 preparative HPLC Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 108010035597 sphingosine kinase Proteins 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 7
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 229960000556 fingolimod Drugs 0.000 description 7
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 7
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
- 150000002825 nitriles Chemical class 0.000 description 7
- 230000037361 pathway Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 210000000274 microglia Anatomy 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 229940080818 propionamide Drugs 0.000 description 6
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 6
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 5
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 5
- 102100039024 Sphingosine kinase 1 Human genes 0.000 description 5
- 238000006069 Suzuki reaction reaction Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000003542 behavioural effect Effects 0.000 description 5
- 230000033228 biological regulation Effects 0.000 description 5
- 230000000903 blocking effect Effects 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000007822 coupling agent Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000002480 mineral oil Substances 0.000 description 5
- 235000010446 mineral oil Nutrition 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- OVBFMEVBMNZIBR-UHFFFAOYSA-N -2-Methylpentanoic acid Natural products CCCC(C)C(O)=O OVBFMEVBMNZIBR-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 4
- 101000693269 Homo sapiens Sphingosine 1-phosphate receptor 3 Proteins 0.000 description 4
- 102100025747 Sphingosine 1-phosphate receptor 3 Human genes 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 210000004443 dendritic cell Anatomy 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000007170 pathology Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 210000001044 sensory neuron Anatomy 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 150000003408 sphingolipids Chemical class 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- 235000011149 sulphuric acid Nutrition 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
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 238000000825 ultraviolet detection Methods 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WMFATTFQNRPXBQ-UHFFFAOYSA-N 2-bromopentanoic acid Chemical compound CCCC(Br)C(O)=O WMFATTFQNRPXBQ-UHFFFAOYSA-N 0.000 description 3
- 206010001497 Agitation Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- 102100025750 Sphingosine 1-phosphate receptor 1 Human genes 0.000 description 3
- 101710155454 Sphingosine 1-phosphate receptor 1 Proteins 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 230000036428 airway hyperreactivity Effects 0.000 description 3
- 238000006136 alcoholysis reaction Methods 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 210000001742 aqueous humor Anatomy 0.000 description 3
- 230000021523 carboxylation Effects 0.000 description 3
- 238000006473 carboxylation reaction Methods 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 210000002932 cholinergic neuron Anatomy 0.000 description 3
- 230000003920 cognitive function Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 238000010931 ester hydrolysis Methods 0.000 description 3
- ORSIRXYHFPHWTN-UHFFFAOYSA-N ethyl 2-bromopentanoate Chemical compound CCCC(Br)C(=O)OCC ORSIRXYHFPHWTN-UHFFFAOYSA-N 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000002055 immunohistochemical effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 230000002025 microglial effect Effects 0.000 description 3
- 230000000324 neuroprotective effect Effects 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 230000009038 pharmacological inhibition Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 3
- 235000019798 tripotassium phosphate Nutrition 0.000 description 3
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 2
- UCNGGGYMLHAMJG-UHFFFAOYSA-N 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(C)C=C1B1OC(C)(C)C(C)(C)O1 UCNGGGYMLHAMJG-UHFFFAOYSA-N 0.000 description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 2
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 2
- BLGUCBUETMYJTB-UHFFFAOYSA-N 2-(6-chloropyridin-3-yl)acetonitrile Chemical compound ClC1=CC=C(CC#N)C=N1 BLGUCBUETMYJTB-UHFFFAOYSA-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
- AAYYJYDNERMSOZ-UHFFFAOYSA-N 2-fluoropentanoic acid Chemical compound CCCC(F)C(O)=O AAYYJYDNERMSOZ-UHFFFAOYSA-N 0.000 description 2
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 description 2
- ZZHFDFIWLDELCX-UHFFFAOYSA-N 3-bromo-1h-pyrrole Chemical compound BrC=1C=CNC=1 ZZHFDFIWLDELCX-UHFFFAOYSA-N 0.000 description 2
- ZDRVLAOYDGQLFI-UHFFFAOYSA-N 4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol;hydrochloride Chemical compound Cl.C1=CC(O)=CC=C1NC1=NC(C=2C=CC(Cl)=CC=2)=CS1 ZDRVLAOYDGQLFI-UHFFFAOYSA-N 0.000 description 2
- MQOHJAYYYVQBSH-UHFFFAOYSA-N 5-bromo-2-chloropyridine-3-carbonitrile Chemical compound ClC1=NC=C(Br)C=C1C#N MQOHJAYYYVQBSH-UHFFFAOYSA-N 0.000 description 2
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 2
- ZAINTDRBUHCDPZ-UHFFFAOYSA-M Alexa Fluor 546 Chemical compound [H+].[Na+].CC1CC(C)(C)NC(C(=C2OC3=C(C4=NC(C)(C)CC(C)C4=CC3=3)S([O-])(=O)=O)S([O-])(=O)=O)=C1C=C2C=3C(C(=C(Cl)C=1Cl)C(O)=O)=C(Cl)C=1SCC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O ZAINTDRBUHCDPZ-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000028006 Corneal injury Diseases 0.000 description 2
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
- 102000036530 EDG receptors Human genes 0.000 description 2
- 108091007263 EDG receptors Proteins 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 102000016994 Lysolipids receptors Human genes 0.000 description 2
- 101100148566 Mus musculus S1pr3 gene Proteins 0.000 description 2
- 238000006411 Negishi coupling reaction Methods 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 101100172613 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) ERG10 gene Proteins 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- QOMNQGZXFYNBNG-UHFFFAOYSA-N acetyloxymethyl 2-[2-[2-[5-[3-(acetyloxymethoxy)-2,7-difluoro-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(F)C(=O)C=C3OC3=CC(OCOC(C)=O)=C(F)C=C32)=CC=C1N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O QOMNQGZXFYNBNG-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001347 alkyl bromides Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000001949 anaesthesia Methods 0.000 description 2
- 230000003215 anti-neuroinflammatory effect Effects 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000004709 cell invasion Effects 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000009134 cell regulation Effects 0.000 description 2
- 230000033077 cellular process Effects 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 230000001073 episodic memory Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- NKTQZLOIRUPOCR-UHFFFAOYSA-N ethyl 2-(5-bromopyridin-3-yl)acetate Chemical compound CCOC(=O)CC1=CN=CC(Br)=C1 NKTQZLOIRUPOCR-UHFFFAOYSA-N 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 210000003976 gap junction Anatomy 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 238000012224 gene deletion Methods 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000010005 growth-factor like effect Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000005462 in vivo assay Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000015788 innate immune response Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000015654 memory Effects 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 2
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 2
- 231100000189 neurotoxic Toxicity 0.000 description 2
- 230000002887 neurotoxic effect Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000001473 noxious effect Effects 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- 150000003233 pyrroles Chemical class 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 102000007268 rho GTP-Binding Proteins Human genes 0.000 description 2
- 108010033674 rho GTP-Binding Proteins Proteins 0.000 description 2
- 239000011435 rock Substances 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 201000011549 stomach cancer Diseases 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
- 239000005720 sucrose Substances 0.000 description 2
- 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 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 230000006453 vascular barrier function Effects 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical group C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- DWCNNQOORRREID-UHFFFAOYSA-N 1,2-dichloroethane;methanol Chemical compound OC.ClCCCl DWCNNQOORRREID-UHFFFAOYSA-N 0.000 description 1
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- AAAXMNYUNVCMCJ-UHFFFAOYSA-N 1,3-diiodopropane Chemical compound ICCCI AAAXMNYUNVCMCJ-UHFFFAOYSA-N 0.000 description 1
- AORHLVDUGUXRKN-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione;triphenylphosphane Chemical compound BrN1C(=O)CCC1=O.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 AORHLVDUGUXRKN-UHFFFAOYSA-N 0.000 description 1
- PGGMEZOUAPIYOY-UHFFFAOYSA-N 2,2-dicyclohexylacetic acid Chemical compound C1CCCCC1C(C(=O)O)C1CCCCC1 PGGMEZOUAPIYOY-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- LSZMVESSGLHDJE-UHFFFAOYSA-N 2-bromo-4-methylpyridine Chemical compound CC1=CC=NC(Br)=C1 LSZMVESSGLHDJE-UHFFFAOYSA-N 0.000 description 1
- SOHDPICLICFSOP-UHFFFAOYSA-N 2-bromo-6-methylpyridine Chemical compound CC1=CC=CC(Br)=N1 SOHDPICLICFSOP-UHFFFAOYSA-N 0.000 description 1
- JXPDNDHCMMOJPC-UHFFFAOYSA-N 2-hydroxybutanedinitrile Chemical compound N#CC(O)CC#N JXPDNDHCMMOJPC-UHFFFAOYSA-N 0.000 description 1
- HGRXBKDKSYDWLD-UHFFFAOYSA-N 2-methoxy-4-methylpyridine Chemical compound COC1=CC(C)=CC=N1 HGRXBKDKSYDWLD-UHFFFAOYSA-N 0.000 description 1
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical class COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- BELDOPUBSLPBCQ-UHFFFAOYSA-N 3-bromo-5-chloropyridine Chemical compound ClC1=CN=CC(Br)=C1 BELDOPUBSLPBCQ-UHFFFAOYSA-N 0.000 description 1
- RBCARPJOEUEZLS-UHFFFAOYSA-N 3-bromopyridin-2-amine Chemical compound NC1=NC=CC=C1Br RBCARPJOEUEZLS-UHFFFAOYSA-N 0.000 description 1
- WWEINXQNCAWBPD-UHFFFAOYSA-N 3-fluoropyridin-2-amine Chemical compound NC1=NC=CC=C1F WWEINXQNCAWBPD-UHFFFAOYSA-N 0.000 description 1
- ARHCLXWELPFVFQ-UHFFFAOYSA-N 5-bromo-1,3-thiazol-2-amine Chemical compound NC1=NC=C(Br)S1 ARHCLXWELPFVFQ-UHFFFAOYSA-N 0.000 description 1
- QEDCHCLHHGGYBT-UHFFFAOYSA-N 5-bromo-2,3-dihydro-1h-indole Chemical compound BrC1=CC=C2NCCC2=C1 QEDCHCLHHGGYBT-UHFFFAOYSA-N 0.000 description 1
- OEKXUEWGXWCENG-UHFFFAOYSA-N 5-bromo-2-chloro-3-fluoropyridine Chemical compound FC1=CC(Br)=CN=C1Cl OEKXUEWGXWCENG-UHFFFAOYSA-N 0.000 description 1
- XADICJHFELMBGX-UHFFFAOYSA-N 5-bromo-2-methoxypyridine Chemical compound COC1=CC=C(Br)C=N1 XADICJHFELMBGX-UHFFFAOYSA-N 0.000 description 1
- QLXASFJHUCKEHU-UHFFFAOYSA-N 5-bromo-3-fluoropyridin-2-amine Chemical compound NC1=NC=C(Br)C=C1F QLXASFJHUCKEHU-UHFFFAOYSA-N 0.000 description 1
- GDQXDVJFMLNXHX-UHFFFAOYSA-N 5-bromo-3-methyl-1h-indole Chemical compound C1=C(Br)C=C2C(C)=CNC2=C1 GDQXDVJFMLNXHX-UHFFFAOYSA-N 0.000 description 1
- SWQWTDAWUSBMGA-UHFFFAOYSA-N 5-chloro-1,3-thiazol-2-amine Chemical compound NC1=NC=C(Cl)S1 SWQWTDAWUSBMGA-UHFFFAOYSA-N 0.000 description 1
- HWCKAMAVEWVBDO-UHFFFAOYSA-N 5-chloropyrazin-2-amine Chemical compound NC1=CN=C(Cl)C=N1 HWCKAMAVEWVBDO-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 102100021257 Beta-secretase 1 Human genes 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- HIVICFNINOMGDM-UHFFFAOYSA-N C1=CC(=NC=C1Br)NF Chemical compound C1=CC(=NC=C1Br)NF HIVICFNINOMGDM-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- OPFTUNCRGUEPRZ-QLFBSQMISA-N Cyclohexane Natural products CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 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
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 1
- 101150050349 FFAR2 gene Proteins 0.000 description 1
- OUVXYXNWSVIOSJ-UHFFFAOYSA-N Fluo-4 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(F)C(=O)C=C3OC3=CC(O)=C(F)C=C32)N(CC(O)=O)CC(O)=O)=C1 OUVXYXNWSVIOSJ-UHFFFAOYSA-N 0.000 description 1
- 102100040133 Free fatty acid receptor 2 Human genes 0.000 description 1
- 102000008338 G protein-coupled adenosine receptor activity proteins Human genes 0.000 description 1
- 108040002766 G protein-coupled adenosine receptor activity proteins Proteins 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 102000034354 Gi proteins Human genes 0.000 description 1
- 108091006101 Gi proteins Proteins 0.000 description 1
- 108010021582 Glucokinase Proteins 0.000 description 1
- 102000030595 Glucokinase Human genes 0.000 description 1
- 102000003658 Group IV Phospholipases A2 Human genes 0.000 description 1
- 108010082107 Group IV Phospholipases A2 Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 108070000013 Lysolipids receptors Proteins 0.000 description 1
- 108010027749 Lysophospholipid Receptors Proteins 0.000 description 1
- 229920004011 Macrolon® Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 208000037273 Pathologic Processes Diseases 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
- 208000016012 Phenotypic abnormality Diseases 0.000 description 1
- 206010065016 Post-traumatic pain Diseases 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 102100025749 Sphingosine 1-phosphate receptor 2 Human genes 0.000 description 1
- 101710155462 Sphingosine 1-phosphate receptor 2 Proteins 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 108010002321 Tight Junction Proteins Proteins 0.000 description 1
- 102000000591 Tight Junction Proteins Human genes 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 235000018936 Vitellaria paradoxa Nutrition 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 210000001642 activated microglia Anatomy 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 210000002867 adherens junction Anatomy 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Substances [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- MXOQNVMDKHLYCZ-UHFFFAOYSA-N benzamidoxime Chemical compound ON=C(N)C1=CC=CC=C1 MXOQNVMDKHLYCZ-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 229930189065 blasticidin Natural products 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 230000009787 cardiac fibrosis Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 210000000782 cerebellar granule cell Anatomy 0.000 description 1
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- DIBHLCJAJIKHGB-UHFFFAOYSA-N dec-5-ene Chemical compound [CH2]CCCC=CCCCC DIBHLCJAJIKHGB-UHFFFAOYSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- GRRSDGHTSMJICM-UHFFFAOYSA-N diethyl 2-propylpropanedioate Chemical compound CCOC(=O)C(CCC)C(=O)OCC GRRSDGHTSMJICM-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000009699 differential effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000001212 effect on astrocytes Effects 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 230000008497 endothelial barrier function Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 230000004887 epithelial permeability Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 231100000318 excitotoxic Toxicity 0.000 description 1
- 230000003492 excitotoxic effect Effects 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 210000001650 focal adhesion Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- SAVROPQJUYSBDD-UHFFFAOYSA-N formyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CO SAVROPQJUYSBDD-UHFFFAOYSA-N 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 230000004914 glial activation Effects 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 108091006093 heterotrimeric G proteins Proteins 0.000 description 1
- 102000034345 heterotrimeric G proteins Human genes 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 description 1
- 229940099552 hyaluronan Drugs 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000037189 immune system physiology Effects 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 210000004968 inflammatory monocyte/macrophage Anatomy 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 206010062198 microangiopathy Diseases 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 230000004784 molecular pathogenesis Effects 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 239000012120 mounting media Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 210000003098 myoblast Anatomy 0.000 description 1
- 210000000651 myofibroblast Anatomy 0.000 description 1
- 210000000478 neocortex Anatomy 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000002314 neuroinflammatory effect Effects 0.000 description 1
- 230000008906 neuronal response Effects 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 210000000929 nociceptor Anatomy 0.000 description 1
- 108091008700 nociceptors Proteins 0.000 description 1
- 210000000948 non-nucleated cell Anatomy 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-BJUDXGSMSA-N oxygen-15 atom Chemical compound [15O] QVGXLLKOCUKJST-BJUDXGSMSA-N 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 208000027232 peripheral nervous system disease Diseases 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 238000012247 phenotypical assay Methods 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000015629 regulation of autophagy Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 102000000568 rho-Associated Kinases Human genes 0.000 description 1
- 108010041788 rho-Associated Kinases Proteins 0.000 description 1
- 102200057448 rs202194596 Human genes 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003410 sphingosines Chemical class 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 238000003153 stable transfection Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/16—Halogen atoms; Nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13195372.1A EP2878339A1 (en) | 2013-12-02 | 2013-12-02 | SIP3 antagonists |
| EP13195372.1 | 2013-12-02 | ||
| PCT/EP2014/075986 WO2015082357A1 (en) | 2013-12-02 | 2014-11-28 | S1p3 antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2932218A1 CA2932218A1 (en) | 2015-06-11 |
| CA2932218C true CA2932218C (en) | 2023-10-03 |
Family
ID=49674243
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2932218A Active CA2932218C (en) | 2013-12-02 | 2014-11-28 | S1p3 antagonists |
Country Status (12)
| Country | Link |
|---|---|
| US (4) | US9951017B2 (enExample) |
| EP (4) | EP2878339A1 (enExample) |
| JP (2) | JP6595475B2 (enExample) |
| KR (1) | KR102386815B1 (enExample) |
| CN (1) | CN106232182B (enExample) |
| AU (1) | AU2014359489B2 (enExample) |
| CA (1) | CA2932218C (enExample) |
| EA (1) | EA034218B1 (enExample) |
| NZ (1) | NZ721802A (enExample) |
| UA (1) | UA117154C2 (enExample) |
| WO (1) | WO2015082357A1 (enExample) |
| ZA (1) | ZA201604490B (enExample) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2878339A1 (en) | 2013-12-02 | 2015-06-03 | Siena Biotech S.p.A. | SIP3 antagonists |
| KR102131677B1 (ko) | 2018-03-20 | 2020-08-05 | 주식회사 아하 | 가이드 모듈 및 하폐수 처리용 산기장치 |
| BR112021004999A2 (pt) | 2018-09-17 | 2021-06-08 | Yungjin Pharm. Co., Ltd. | composto e método de inibição de cdk7 em um sujeito |
| KR102335637B1 (ko) * | 2020-03-13 | 2021-12-06 | 영진약품 주식회사 | 신규한 cdk7 억제 화합물 및 이의 약제학적으로 허용가능한 염 |
| CN116568671A (zh) * | 2020-10-16 | 2023-08-08 | 分子医学研究中心责任有限公司 | 杂环Cullin-RING泛素连接酶化合物及其用途 |
| WO2023275796A1 (en) * | 2021-07-01 | 2023-01-05 | Novartis Ag | Heterocyclic derivatives as sphingosine-1-phosphate 3 inhibitors |
| JP2025526266A (ja) * | 2022-07-05 | 2025-08-13 | オーリジーン オンコロジー リミテッド | Ｃｄｋ１２／１３阻害剤としての置換ｎ－（ピリジン－２－イル）アセトアミド誘導体 |
Family Cites Families (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0081756B1 (en) | 1981-12-14 | 1985-05-15 | MEDEA RESEARCH S.r.l. | New compounds with antiinflammatory and antitussive activity, process for their preparation and relative pharmaceutical compositions |
| WO1998015278A1 (en) | 1996-10-07 | 1998-04-16 | Smithkline Beecham Corporation | Method for stimulating bone formation |
| GB9823871D0 (en) | 1998-10-30 | 1998-12-23 | Pharmacia & Upjohn Spa | 2-Amino-thiazole derivatives, process for their preparation, and their use as antitumour agents |
| US6320050B1 (en) | 1999-03-29 | 2001-11-20 | Hoffmann-La Roche Inc. | Heteroaromatic glucokinase activators |
| US6610846B1 (en) | 1999-03-29 | 2003-08-26 | Hoffman-La Roche Inc. | Heteroaromatic glucokinase activators |
| CN1384832A (zh) | 1999-11-18 | 2002-12-11 | 诺瓦提斯公司 | 作为农药的氨基杂环基酰胺化合物 |
| ES2233660T3 (es) | 2000-05-03 | 2005-06-16 | F. Hoffmann-La Roche Ag | Activadores de glucokinasa alquinil fenil heteroaromaticos. |
| JP4742333B2 (ja) | 2000-11-13 | 2011-08-10 | 日本農薬株式会社 | Ｎ−チアジアゾリルシクロプロパンカルボン酸アミド類およびこれを有効成分とする殺虫、殺ダニ剤 |
| DK1341774T3 (da) | 2000-12-06 | 2006-06-12 | Hoffmann La Roche | Kondenserede heteroaromatiske glucokinase-aktivatorer |
| WO2003020313A1 (en) * | 2001-09-04 | 2003-03-13 | Ono Pharmaceutical Co., Ltd. | Remedies for respiratory diseases comprising sphingosine-1-phosphate receptor controller |
| EP1458382A1 (en) * | 2001-12-21 | 2004-09-22 | Novo Nordisk A/S | Amide derivatives as gk activators |
| TW200307539A (en) | 2002-02-01 | 2003-12-16 | Bristol Myers Squibb Co | Cycloalkyl inhibitors of potassium channel function |
| EA011297B1 (ru) | 2002-04-26 | 2009-02-27 | Ф. Хоффманн-Ля Рош Аг | Замещённые фенилацетамиды и их применение в качестве активаторов глюкокиназы |
| MY141521A (en) | 2002-12-12 | 2010-05-14 | Hoffmann La Roche | 5-substituted-six-membered heteroaromatic glucokinase activators |
| EP1594863A1 (en) * | 2003-02-11 | 2005-11-16 | Prosidion Limited | Tri(cyclo) substituted amide glucokinase activator compounds |
| GB0329498D0 (en) * | 2003-12-19 | 2004-01-28 | Novartis Ag | Organic compounds |
| PL1700856T3 (pl) * | 2003-12-26 | 2016-05-31 | Kyowa Hakko Kirin Co Ltd | Pochodna tiazolu |
| WO2005075435A1 (en) | 2004-01-30 | 2005-08-18 | Vertex Pharmaceuticals Incorporated | Modulators of atp-binding cassette transporters |
| JP2008521864A (ja) | 2004-12-03 | 2008-06-26 | トランステック・ファーマ、インコーポレイテッド | ヘテロ芳香族グルコキナーゼ活性化剤 |
| US7888374B2 (en) * | 2005-01-28 | 2011-02-15 | Abbott Laboratories | Inhibitors of c-jun N-terminal kinases |
| CA2621227A1 (en) | 2005-08-31 | 2007-03-08 | Astellas Pharma Inc. | Thiazole derivative |
| GT200600429A (es) | 2005-09-30 | 2007-04-30 | Compuestos organicos | |
| EP1935874A4 (en) * | 2005-10-12 | 2010-10-13 | Toa Eiyo Ltd | S1P3 RECEPTOR ANTAGONIST |
| US7671221B2 (en) | 2005-12-28 | 2010-03-02 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-Binding Cassette transporters |
| NZ569327A (en) | 2005-12-28 | 2011-09-30 | Vertex Pharma | 1-(benzo [d] [1,3] dioxol-5-yl) -n- (phenyl) cyclopropane- carboxamide derivatives and related compounds as modulators of ATP-binding cassette transporters for the treatment of cystic fibrosis |
| JP5386350B2 (ja) | 2006-05-31 | 2014-01-15 | タケダ カリフォルニア インコーポレイテッド | グルコキナーゼ活性剤としての、インダゾールおよびイソインドール誘導体 |
| US7888504B2 (en) | 2006-07-06 | 2011-02-15 | Bristol-Myers Squibb Company | Glucokinase activators and methods of using same |
| WO2008063625A2 (en) * | 2006-11-20 | 2008-05-29 | Adolor Corporation | Pyridine compounds and methods of their use |
| TW200831081A (en) | 2006-12-25 | 2008-08-01 | Kyorin Seiyaku Kk | Glucokinase activator |
| WO2008119734A2 (en) | 2007-03-29 | 2008-10-09 | Novartis Ag | Process for the manufacture of organic compounds |
| WO2008141013A1 (en) * | 2007-05-08 | 2008-11-20 | Allergan, Inc. | S1p3 receptor inhibitors for treating pain |
| NZ581259A (en) | 2007-05-09 | 2012-07-27 | Vertex Pharma | Modulators of cystic fibrosis transmembrane conductance regulator |
| CA2687764A1 (en) | 2007-05-25 | 2008-12-04 | Vertex Pharmaceuticals Incorporated | Ion channel modulators and methods of use |
| WO2009011850A2 (en) * | 2007-07-16 | 2009-01-22 | Abbott Laboratories | Novel therapeutic compounds |
| KR20100113518A (ko) | 2008-01-18 | 2010-10-21 | 아스텔라스세이야쿠 가부시키가이샤 | 페닐아세트아미드 유도체 |
| CA2716515A1 (en) * | 2008-02-21 | 2009-08-27 | Boehringer Ingelheim International Gmbh | Amine and ether compounds which modulate the cb2 receptor |
| PT2615085E (pt) | 2008-03-31 | 2015-10-09 | Vertex Pharma | Derivados piridilo como moduladores cftr |
| WO2009140624A2 (en) * | 2008-05-16 | 2009-11-19 | Takeda San Diego, Inc. | Glucokinase activators |
| EA201100311A1 (ru) | 2008-09-11 | 2011-10-31 | Пфайзер Инк. | Амидные производные гетероарилов и их применение в качестве активаторов глюкокиназы |
| UA104876C2 (uk) | 2008-11-06 | 2014-03-25 | Вертекс Фармасьютікалз Інкорпорейтед | Модулятори atф-зв'язувальних касетних транспортерів |
| US20120088800A1 (en) * | 2009-06-30 | 2012-04-12 | Allergan, Inc. | 2-(SUBSTITUTED) (ARYLMETHYL, ARYLOXY and ARYLTHIO))-N-(SUBSTITUTED PYRIDIN-2-YL)-2-(SUBSTITUTED ARYL) COMPOUNDS AS SUBTYPE-SELECTIVE MODULATORS OF SPHINGOSINE-1-PHOSPHATE-3 (S1P3) RECEPTORS |
| US8168795B2 (en) * | 2009-08-11 | 2012-05-01 | Allergan, Inc. | Selective sphingosine-1-phosphate receptor antagonists |
| WO2011133734A1 (en) * | 2010-04-23 | 2011-10-27 | Bristol-Myers Squibb Company | 4 - (5 - isoxazolyl or 5 - pyrrazolyl -1,2,4- oxadiazol - 3 - yl) -mandelic acid amides as sphingosin- 1 - phosphate 1 rreceptor agonists |
| WO2012082817A1 (en) * | 2010-12-16 | 2012-06-21 | Boehringer Ingelheim International Gmbh | Biarylamide inhibitors of leukotriene production |
| US9658211B2 (en) * | 2012-04-18 | 2017-05-23 | Hemoshear, Llc | In vitro model for pathological or physiologic conditions |
| EP2878339A1 (en) * | 2013-12-02 | 2015-06-03 | Siena Biotech S.p.A. | SIP3 antagonists |
-
2013
- 2013-12-02 EP EP13195372.1A patent/EP2878339A1/en not_active Withdrawn
-
2014
- 2014-11-28 EP EP19210115.2A patent/EP3689864A1/en not_active Withdrawn
- 2014-11-28 EA EA201691160A patent/EA034218B1/ru not_active IP Right Cessation
- 2014-11-28 CN CN201480074769.6A patent/CN106232182B/zh active Active
- 2014-11-28 JP JP2016536883A patent/JP6595475B2/ja active Active
- 2014-11-28 AU AU2014359489A patent/AU2014359489B2/en active Active
- 2014-11-28 CA CA2932218A patent/CA2932218C/en active Active
- 2014-11-28 US US15/100,326 patent/US9951017B2/en active Active
- 2014-11-28 EP EP14811790.6A patent/EP3086845B1/en active Active
- 2014-11-28 EP EP21155292.2A patent/EP3896068A1/en not_active Withdrawn
- 2014-11-28 UA UAA201607137A patent/UA117154C2/uk unknown
- 2014-11-28 NZ NZ721802A patent/NZ721802A/en unknown
- 2014-11-28 KR KR1020167017929A patent/KR102386815B1/ko active Active
- 2014-11-28 WO PCT/EP2014/075986 patent/WO2015082357A1/en not_active Ceased
-
2016
- 2016-07-01 ZA ZA201604490A patent/ZA201604490B/en unknown
-
2018
- 2018-03-16 US US15/923,837 patent/US20180201582A1/en not_active Abandoned
-
2019
- 2019-09-26 JP JP2019175781A patent/JP2020023512A/ja active Pending
-
2020
- 2020-01-24 US US16/751,472 patent/US11472772B2/en active Active
-
2022
- 2022-08-03 US US17/880,577 patent/US20220402875A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EA034218B1 (ru) | 2020-01-17 |
| EP3086845B1 (en) | 2019-11-20 |
| WO2015082357A1 (en) | 2015-06-11 |
| EP3896068A1 (en) | 2021-10-20 |
| US20220402875A1 (en) | 2022-12-22 |
| JP6595475B2 (ja) | 2019-10-23 |
| EP2878339A1 (en) | 2015-06-03 |
| US11472772B2 (en) | 2022-10-18 |
| HK1226017A1 (en) | 2017-09-22 |
| US9951017B2 (en) | 2018-04-24 |
| EP3689864A1 (en) | 2020-08-05 |
| CA2932218A1 (en) | 2015-06-11 |
| EP3086845A1 (en) | 2016-11-02 |
| CN106232182B (zh) | 2019-11-01 |
| US20200157052A1 (en) | 2020-05-21 |
| JP2016539174A (ja) | 2016-12-15 |
| UA117154C2 (uk) | 2018-06-25 |
| AU2014359489B2 (en) | 2020-01-30 |
| US20180201582A1 (en) | 2018-07-19 |
| US20160297762A1 (en) | 2016-10-13 |
| NZ721802A (en) | 2022-04-29 |
| AU2014359489A1 (en) | 2016-07-21 |
| KR20160093710A (ko) | 2016-08-08 |
| EA201691160A1 (ru) | 2016-11-30 |
| CN106232182A (zh) | 2016-12-14 |
| KR102386815B1 (ko) | 2022-04-14 |
| ZA201604490B (en) | 2019-11-27 |
| JP2020023512A (ja) | 2020-02-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2932218C (en) | S1p3 antagonists | |
| TWI433830B (zh) | 胺基羧酸衍生物及其醫藥用途 | |
| CN110198938B (zh) | 作为蛋白质聚集调节剂的双-杂芳基衍生物 | |
| RS49921B (sr) | Terapeutski biaril derivati | |
| TW200911254A (en) | Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators-842 | |
| EP2716642A1 (en) | Imidazopyridine compound | |
| US20180222899A1 (en) | Bis-heteroaryl derivatives as modulators of protein aggregation | |
| WO2009146112A1 (en) | Compositions and methods for inhibiting sphingosine kinase | |
| Ibrahim et al. | Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists | |
| CN102639533B (zh) | 氮杂环螺衍生物 | |
| CN108239073A (zh) | 化合物、医药组成物及其用途 | |
| JP2020505368A (ja) | タンパク質凝集のモジュレーターとしてのアルコキシビス−ヘテロアリール誘導体 | |
| HK1226017B (en) | S1p3 antagonists | |
| AU2014214325A1 (en) | Substituted carboxylic acid derivatives as aggrecanase inhibitors for the treatment of osteoarthritis | |
| KR20030018053A (ko) | 매트릭스 메탈로프로티나제 억제제 | |
| JP2015522556A (ja) | イミダゾ−オキサジアゾール及びイミダゾ−チアジアゾール誘導体 | |
| EP3263559A1 (en) | Lipase inhibitors | |
| HK1227786B (zh) | S1p3拮抗剂 | |
| HK1227786A1 (zh) | S1p3拮抗剂 | |
| US5145869A (en) | Phenylsulfonylalkanoic acid compounds and pharmaceuticals thereof | |
| WO2024184471A1 (en) | Sortiline modulators | |
| MXPA06009159A (en) | Compounds and compositions as lxr modulators | |
| HK1168597B (zh) | 氮杂环螺衍生物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20191114 |
|
| EEER | Examination request |
Effective date: 20191114 |
|
| EEER | Examination request |
Effective date: 20191114 |
|
| EEER | Examination request |
Effective date: 20191114 |
|
| EEER | Examination request |
Effective date: 20191114 |
|
| EEER | Examination request |
Effective date: 20191114 |
|
| EEER | Examination request |
Effective date: 20191114 |
|
| EEER | Examination request |
Effective date: 20191114 |
|
| EEER | Examination request |
Effective date: 20191114 |
|
| EEER | Examination request |
Effective date: 20191114 |