JP2022525293A - 貧血の処置におけるムスカリン性アセチルコリン受容体サブタイプ4アンタゴニスト - Google Patents
貧血の処置におけるムスカリン性アセチルコリン受容体サブタイプ4アンタゴニスト Download PDFInfo
- Publication number
- JP2022525293A JP2022525293A JP2021553300A JP2021553300A JP2022525293A JP 2022525293 A JP2022525293 A JP 2022525293A JP 2021553300 A JP2021553300 A JP 2021553300A JP 2021553300 A JP2021553300 A JP 2021553300A JP 2022525293 A JP2022525293 A JP 2022525293A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- hydrogen atom
- bfu
- ethyl
- 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.)
- Pending
Links
- 239000005557 antagonist Substances 0.000 title claims abstract description 89
- 208000007502 anemia Diseases 0.000 title claims abstract description 52
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 title claims abstract description 34
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 title claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 196
- 210000002960 bfu-e Anatomy 0.000 claims abstract description 115
- 238000000034 method Methods 0.000 claims abstract description 59
- 210000004027 cell Anatomy 0.000 claims abstract description 54
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 230000000694 effects Effects 0.000 claims abstract description 11
- 210000003924 normoblast Anatomy 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 71
- 125000005843 halogen group Chemical group 0.000 claims description 45
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 23
- 239000012453 solvate Substances 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 150000001450 anions Chemical class 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 230000001737 promoting effect Effects 0.000 claims description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 10
- -1 small molecule compounds Chemical class 0.000 abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 62
- 239000000243 solution Substances 0.000 description 55
- 239000011541 reaction mixture Substances 0.000 description 43
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 29
- 241000699670 Mus sp. Species 0.000 description 26
- UKLQXHUGTKWPSR-UHFFFAOYSA-M oxyphenonium bromide Chemical compound [Br-].C=1C=CC=CC=1C(O)(C(=O)OCC[N+](C)(CC)CC)C1CCCCC1 UKLQXHUGTKWPSR-UHFFFAOYSA-M 0.000 description 25
- 229960001125 oxyphenonium bromide Drugs 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 210000003743 erythrocyte Anatomy 0.000 description 22
- 101150005883 CHRM4 gene Proteins 0.000 description 21
- 239000011734 sodium Substances 0.000 description 21
- 239000012267 brine Substances 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 230000027455 binding Effects 0.000 description 19
- 241000699666 Mus <mouse, genus> Species 0.000 description 18
- 239000013058 crude material Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 239000007858 starting material Substances 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 241000700605 Viruses Species 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 102000005636 Cyclic AMP Response Element-Binding Protein Human genes 0.000 description 14
- 108010045171 Cyclic AMP Response Element-Binding Protein Proteins 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 13
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 13
- 102000003951 Erythropoietin Human genes 0.000 description 12
- 108090000394 Erythropoietin Proteins 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- 210000004556 brain Anatomy 0.000 description 12
- 229940105423 erythropoietin Drugs 0.000 description 12
- 238000010172 mouse model Methods 0.000 description 12
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 12
- 230000035755 proliferation Effects 0.000 description 12
- 102000005962 receptors Human genes 0.000 description 12
- 108020003175 receptors Proteins 0.000 description 12
- 102000017924 CHRM4 Human genes 0.000 description 11
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 11
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 230000014509 gene expression Effects 0.000 description 11
- 238000005534 hematocrit Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 10
- 108091027967 Small hairpin RNA Proteins 0.000 description 10
- 230000004069 differentiation Effects 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 101000720512 Homo sapiens Muscarinic acetylcholine receptor M4 Proteins 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 238000007451 chromatin immunoprecipitation sequencing Methods 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 229910052740 iodine Inorganic materials 0.000 description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 9
- 238000000159 protein binding assay Methods 0.000 description 9
- 239000004055 small Interfering RNA Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000004663 cell proliferation Effects 0.000 description 8
- 239000006185 dispersion Substances 0.000 description 8
- 239000002287 radioligand Substances 0.000 description 8
- 230000008685 targeting Effects 0.000 description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 7
- 108091006027 G proteins Proteins 0.000 description 7
- 102000030782 GTP binding Human genes 0.000 description 7
- 108091000058 GTP-Binding Proteins 0.000 description 7
- 239000011630 iodine Substances 0.000 description 7
- 229920000609 methyl cellulose Polymers 0.000 description 7
- 239000001923 methylcellulose Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- GFRUPHOKLBPHTQ-UHFFFAOYSA-N 2-(2-cyclohexyl-2-hydroxy-1-oxo-2-phenylethoxy)ethyl-diethyl-methylammonium Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC[N+](C)(CC)CC)C1CCCCC1 GFRUPHOKLBPHTQ-UHFFFAOYSA-N 0.000 description 6
- 229940121683 Acetylcholine receptor antagonist Drugs 0.000 description 6
- 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 6
- 206010018910 Haemolysis Diseases 0.000 description 6
- 238000003559 RNA-seq method Methods 0.000 description 6
- 101150116518 Srsf2 gene Proteins 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 6
- 210000004748 cultured cell Anatomy 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000008588 hemolysis Effects 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 229960002740 oxyphenonium Drugs 0.000 description 6
- 230000037361 pathway Effects 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 102000017927 CHRM1 Human genes 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 102000016979 Other receptors Human genes 0.000 description 5
- 238000000692 Student's t-test Methods 0.000 description 5
- 230000032683 aging Effects 0.000 description 5
- 238000007821 culture assay Methods 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 150000002475 indoles Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- ATHZIFFSGSWIAU-UHFFFAOYSA-N n-[2-(1-benzylpiperidin-4-yl)ethyl]-6,7-dihydro-5h-benzo[2,3]cyclohepta[2,4-d]pyridazin-3-amine Chemical compound C=1C=2CCCC3=CC=CC=C3C=2N=NC=1NCCC(CC1)CCN1CC1=CC=CC=C1 ATHZIFFSGSWIAU-UHFFFAOYSA-N 0.000 description 5
- 210000005259 peripheral blood Anatomy 0.000 description 5
- 239000011886 peripheral blood Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000012353 t test Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- YYTAYINRPUJPNH-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroisoquinoline Chemical compound C1NCCC2=CC(OC)=CC=C21 YYTAYINRPUJPNH-UHFFFAOYSA-N 0.000 description 4
- 102000017926 CHRM2 Human genes 0.000 description 4
- 102000017925 CHRM3 Human genes 0.000 description 4
- 102000017923 CHRM5 Human genes 0.000 description 4
- 101100220044 Homo sapiens CD34 gene Proteins 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229960003957 dexamethasone Drugs 0.000 description 4
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 102100034703 mRNA decay activator protein ZFP36L2 Human genes 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 102220240259 rs569172233 Human genes 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 210000000130 stem cell Anatomy 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 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 4
- WWJHRSCUAQPFQO-UHFFFAOYSA-M 4-DAMP methiodide Chemical compound [I-].C1C[N+](C)(C)CCC1OC(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 WWJHRSCUAQPFQO-UHFFFAOYSA-M 0.000 description 3
- LMIQERWZRIFWNZ-UHFFFAOYSA-N 5-hydroxyindole Chemical class OC1=CC=C2NC=CC2=C1 LMIQERWZRIFWNZ-UHFFFAOYSA-N 0.000 description 3
- 101150060249 CHRM3 gene Proteins 0.000 description 3
- 101150064612 CHRM5 gene Proteins 0.000 description 3
- 101150073075 Chrm1 gene Proteins 0.000 description 3
- 101150012960 Chrm2 gene Proteins 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 3
- 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 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 108010054147 Hemoglobins Proteins 0.000 description 3
- 102000001554 Hemoglobins Human genes 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 3
- 101000782981 Homo sapiens Muscarinic acetylcholine receptor M1 Proteins 0.000 description 3
- 101000802101 Homo sapiens mRNA decay activator protein ZFP36L2 Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 101100425546 Mus musculus Zfp36l2 gene Proteins 0.000 description 3
- 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 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 3
- 229960004373 acetylcholine Drugs 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000004820 blood count Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 230000001276 controlling effect Effects 0.000 description 3
- 229940095074 cyclic amp Drugs 0.000 description 3
- 230000005595 deprotonation Effects 0.000 description 3
- 238000010537 deprotonation reaction Methods 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000001605 fetal effect Effects 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 208000007475 hemolytic anemia Diseases 0.000 description 3
- 102000044890 human EPO Human genes 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 238000011272 standard treatment Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical class COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 2
- QIUIKPQXMJJOQT-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroisoquinolin-2-ium;chloride Chemical compound [Cl-].C1[NH2+]CCC2=CC(OC)=CC=C21 QIUIKPQXMJJOQT-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- MMWCIQZXVOZEGG-XJTPDSDZSA-N D-myo-Inositol 1,4,5-trisphosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H](O)[C@@H]1OP(O)(O)=O MMWCIQZXVOZEGG-XJTPDSDZSA-N 0.000 description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 101000928929 Homo sapiens Muscarinic acetylcholine receptor M2 Proteins 0.000 description 2
- 101000928919 Homo sapiens Muscarinic acetylcholine receptor M3 Proteins 0.000 description 2
- 101000720516 Homo sapiens Muscarinic acetylcholine receptor M5 Proteins 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 208000005074 Retroviridae Infections Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 101100107916 Xenopus laevis chrm4 gene Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000012382 advanced drug delivery Methods 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 150000005130 benzoxazines Chemical class 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000002798 bone marrow cell Anatomy 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000003013 erythroid precursor cell Anatomy 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 2
- 229940093471 ethyl oleate Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- 230000003551 muscarinic effect Effects 0.000 description 2
- 230000010807 negative regulation of binding Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 2
- 229940067157 phenylhydrazine Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000030968 tissue homeostasis Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 description 1
- MMWCIQZXVOZEGG-UHFFFAOYSA-N 1,4,5-IP3 Natural products OC1C(O)C(OP(O)(O)=O)C(OP(O)(O)=O)C(O)C1OP(O)(O)=O MMWCIQZXVOZEGG-UHFFFAOYSA-N 0.000 description 1
- 229940005561 1,4-benzoquinone Drugs 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- RMHMFHUVIITRHF-RLXJOQACSA-N 11-[2-[4-(tritritiomethyl)piperazin-1-yl]acetyl]-5h-pyrido[2,3-b][1,4]benzodiazepin-6-one Chemical compound C1CN(C([3H])([3H])[3H])CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-RLXJOQACSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 101710159080 Aconitate hydratase A Proteins 0.000 description 1
- 101710159078 Aconitate hydratase B Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 101150082143 CD24 gene Proteins 0.000 description 1
- 102000009660 Cholinergic Receptors Human genes 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 238000000018 DNA microarray Methods 0.000 description 1
- 101100219402 Danio rerio calcrla gene Proteins 0.000 description 1
- 101100447432 Danio rerio gapdh-2 gene Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 102000034353 G alpha subunit Human genes 0.000 description 1
- 108091006099 G alpha subunit Proteins 0.000 description 1
- 101150005295 GATA2 gene Proteins 0.000 description 1
- 101150112014 Gapdh gene Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101000835093 Homo sapiens Transferrin receptor protein 1 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 238000001276 Kolmogorov–Smirnov test Methods 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 229940117926 Muscarinic M4 receptor antagonist Drugs 0.000 description 1
- MZDYABXXPZNUCT-UHFFFAOYSA-N N-[2-[2-[(dipropylamino)methyl]-1-piperidinyl]ethyl]-6-oxo-5H-pyrido[2,3-b][1,4]benzodiazepine-11-carboxamide Chemical compound CCCN(CCC)CC1CCCCN1CCNC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 MZDYABXXPZNUCT-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 101150045976 P2ry2 gene Proteins 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 102000044126 RNA-Binding Proteins Human genes 0.000 description 1
- 101710105008 RNA-binding protein Proteins 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000567 anti-anemic effect Effects 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 230000003491 cAMP production Effects 0.000 description 1
- 101150114189 calcrl gene Proteins 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- MEXSQFDSPVYJOM-UHFFFAOYSA-J cerium(4+);disulfate;tetrahydrate Chemical compound O.O.O.O.[Ce+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O MEXSQFDSPVYJOM-UHFFFAOYSA-J 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000002487 chromatin immunoprecipitation Methods 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229940126513 cyclase activator Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 150000001982 diacylglycerols Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- YPMPTULBFPFSEQ-PLNGDYQASA-N ethyl (z)-3-aminobut-2-enoate Chemical compound CCOC(=O)\C=C(\C)N YPMPTULBFPFSEQ-PLNGDYQASA-N 0.000 description 1
- YTBNTDMBGXAOCG-UHFFFAOYSA-N ethyl 5-hydroxy-1,2-dimethylindole-3-carboxylate Chemical compound C1=C(O)C=C2C(C(=O)OCC)=C(C)N(C)C2=C1 YTBNTDMBGXAOCG-UHFFFAOYSA-N 0.000 description 1
- BSNHKSUAAMJXBB-UHFFFAOYSA-N ethyl 5-hydroxy-2-methyl-1h-indole-3-carboxylate Chemical compound C1=C(O)C=C2C(C(=O)OCC)=C(C)NC2=C1 BSNHKSUAAMJXBB-UHFFFAOYSA-N 0.000 description 1
- VWUZPMIHHYWEQB-UHFFFAOYSA-N ethyl 5-methoxy-1,2-dimethylindole-3-carboxylate Chemical compound C1=C(OC)C=C2C(C(=O)OCC)=C(C)N(C)C2=C1 VWUZPMIHHYWEQB-UHFFFAOYSA-N 0.000 description 1
- IRBNTIJXCHIBNA-UHFFFAOYSA-N ethyl 5-methoxy-2-methyl-1h-indole-3-carboxylate Chemical compound C1=C(OC)C=C2C(C(=O)OCC)=C(C)NC2=C1 IRBNTIJXCHIBNA-UHFFFAOYSA-N 0.000 description 1
- HIGHOMQQLWDSCL-UHFFFAOYSA-M ethyl 5-methoxy-4-[(6-methoxy-2-methyl-3,4-dihydro-1H-isoquinolin-2-ium-2-yl)methyl]-1,2-dimethylindole-3-carboxylate iodide Chemical compound CCOC(C(C1=C2C[N+](C)(CCC3=C4)CC3=CC=C4OC)=C(C)N(C)C1=CC=C2OC)=O.[I-] HIGHOMQQLWDSCL-UHFFFAOYSA-M 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- RHWSDJZSKWUHTG-UHFFFAOYSA-N ethyl isoquinoline-1-carboxylate Chemical compound C1=CC=C2C(C(=O)OCC)=NC=CC2=C1 RHWSDJZSKWUHTG-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 101150110248 fzd5 gene Proteins 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 230000030648 nucleus localization Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 229960003941 orphenadrine Drugs 0.000 description 1
- QVYRGXJJSLMXQH-UHFFFAOYSA-N orphenadrine Chemical compound C=1C=CC=C(C)C=1C(OCCN(C)C)C1=CC=CC=C1 QVYRGXJJSLMXQH-UHFFFAOYSA-N 0.000 description 1
- 229960001687 orphenadrine citrate Drugs 0.000 description 1
- MMMNTDFSPSQXJP-UHFFFAOYSA-N orphenadrine citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=C(C)C=1C(OCCN(C)C)C1=CC=CC=C1 MMMNTDFSPSQXJP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940043437 protein kinase A inhibitor Drugs 0.000 description 1
- 239000012656 protein kinase A inhibitor Substances 0.000 description 1
- 108010065251 protein kinase modulator Proteins 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
Classifications
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
本出願は、2019年3月25日に出願された米国特許仮出願第62/823,214号の利益を主張し、この内容のすべてを参照により本明細書に組み込む。
本発明は、アメリカ国立衛生研究所により付与されたHL127522の下、政府支援によりなされた。政府は、本発明において特定の権利を有する。
本開示は、ムスカリン性アセチルコリン受容体サブタイプ4(M4)活性から生じる疾患および状態の処置に一般に関する。より詳細には、本開示は、赤芽球バースト形成単位(BFU-E)細胞の自己複製を促進して貧血を処置する、低分子M4アンタゴニスト化合物の使用に関する。
多くの成体系列の幹細胞および前駆細胞は、組織恒常性、維持および再生の重大な側面である自己複製を経る(North T.E. et al., Nature 447:1007-1011 (2007);He S. et al., Annu Rev Cell Dev Biol 25:377-406 (2009);Simons B.D. et al., Cell 145:851-862 (2011);Seita J. et al., Wiley Interdiscip Rev Syst Biol Med 2:640-653 (2010);Xu Y. et al., Nature 453:338-344 (2008);Sun J. et al., Nature 514:322-347 (2014);Sharpless N.E. et al., Nat Rev Mol Cell Biol 8:703-713 (2007);Rossi D.J. et al., Cell 132:681-696 (2008))。造血系では、赤芽球バースト形成単位(BFU-E)は、第1の系列判定赤芽球前駆細胞であり、自己複製を経て数千の赤血球を生成する実質的可能性を有する。BFU-Eは、分化を経て、後期赤芽球前駆細胞であるコロニー形成単位赤芽球(CFU-E)の形成を生じ、このCFU-Eは、3~4個に限られた細胞分裂を経た後に赤血球を形成する(Zhang L. et al., Genes Dev 25:119-124 (2011))。CFU-Eの生存および分化は、エリスロポエチン(EPO)により主に調節されており、BFU-Eの自己複製および分化の制御は、あまり解明されていない。EPOは、慢性腎臓疾患に見られるような、EPO産生の異常により生じる貧血の処置に主に使用される。しかし、多くの貧血患者は、EPO処置に対する応答に十分なBFU-E、および引き続いて十分なCFU-Eを有しない(Flygare J. et al., Blood 117:3435-3444 (2011);Zhang L. et al., Nature 499:92-96 (2013);Sankaran V.G. et al., Nat Med 21:221-230 (2015);Bauer et al., Genes Dev 13:2996-3002 (1999);Komrokji R.S. et al., Curr Hematol Malig Rep 6:145-153 (2011);Kotla V. et al., J Hematol Onco. 2:36 (2009))。このようなEPO抵抗性貧血を処置するために、BFU-E自己複製の根底にある分子機構のより良い理解が必要とされている。これまでの報告では、化合物PD102807が、ムスカリン性アセチルコリン受容体ファミリーの他のメンバーよりもCHRM4を選択的に阻害することが示されている(C. H. Croy et al., Characterization of PCS1055, a novel muscarinic M4 receptor antagonist. Eur. J. Pharmacol 782, 70-76, 2016;T. M. Boehme et al., Synthesis and pharmacology of benzoxazines as highly selective antagonists at M(4) muscarinic receptors. J Med. Chem 45, 3094-3102, 2002)。
一態様では、本開示は、ムスカリン性アセチルコリン受容体サブタイプ4(M4)アンタゴニストとして機能する化合物を対象とする。M4アンタゴニスト化合物は、他のムスカリン性アセチルコリン受容体サブタイプ(例えば、M1、M2、M3および/またはM5)と比較してM4に対して、少なくともある程度、好ましくは、選択的(すなわち、特異的)である。M4特異的アンタゴニストの有効性は、M4のオルソステリックポケットに結合する能力のおかげで生じると考えられている。また、M4アンタゴニスト化合物では、当技術分野の他のM4アンタゴニスト化合物、例えば、PD102807と比較して、血液脳関門への浸透が、好ましくは、低下する。
実施形態の第1のセットでは、M4アンタゴニスト化合物は、次の構造:
ムスカリン性アセチルコリン受容体CHRM4経路がBFU-E自己複製の重要な制御因子であることが、本発明に従って本明細書において見出された。ムスカリン性アセチルコリン受容体サブタイプ4アンタゴニストにより、BFU-Eの自己複製および増殖が促進され、溶血、MDSおよび老化マウスモデルにおいて貧血が改善されることが本明細書において実証された。したがって、貧血の処置のための治療法におけるM4特異的アンタゴニストの使用を本明細書において提供する。
この実施例では、BFU-E自己複製におけるムスカリン性アセチルコリン受容体CHRM4経路の役割、および低分子ムスカリン性アセチルコリン受容体阻害物質である臭化オキシフェノニウムの、マウスモデルにおける貧血に対する作用を検討するために行った実験を記載する。
この実施例では、他の低分子M4アンタゴニスト、例えば、PCS1055およびPD102807により、BFU-E自己複製が促進され、in vivoにおいて貧血が矯正されるかどうかを検討するために行った実験を記載する。
Claims (51)
- 式:
R1が、HまたはCH3であり、
R2が、炭素原子1~3個を有する炭化水素基であり、
R3、R4およびR5が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SH、SCH3および次の構造(1-1):
R6が、HまたはCH3であり、
R7、R8およびR9が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SHおよびSCH3から独立的に選択され、
そして前記式(1)の化合物が、前記式(1)の化合物の薬学的に許容される塩、溶媒和物、エナンチオマーおよび多形体を含む、化合物。 - R1が水素原子である、請求項1から3のいずれか一項に記載の化合物。
- R1がメチルである、請求項1から3のいずれか一項に記載の化合物。
- R2がエチルである、請求項1から5のいずれか一項に記載の化合物。
- R1が水素原子であり、そしてR2がエチルである、請求項1から3のいずれか一項に記載の化合物。
- R1がメチルであり、そしてR2がエチルである、請求項1から3のいずれか一項に記載の化合物。
- 式:
R1が、HまたはCH3であり、
R2が、炭素原子1~3個を有する炭化水素基であり、
R3、R4およびR5が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SH、SCH3および次の構造(1-2):
R6が、HまたはCH3であり、
R7、R8およびR9が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SHおよびSCH3から独立的に選択され、
X-が、前記化合物の正荷電部分を均衡させるアニオンであり、そして
前記式(1c)の化合物が、前記式(1c)の化合物の薬学的に許容される塩、溶媒和物、エナンチオマーおよび多形体を含む、化合物。 - R1が水素原子である、請求項9から11のいずれか一項に記載の化合物。
- R1がメチルである、請求項9から11のいずれか一項に記載の化合物。
- R2がエチルである、請求項9から13のいずれか一項に記載の化合物。
- R1が水素原子であり、そしてR2がエチルである、請求項9から11のいずれか一項に記載の化合物。
- R1がメチルであり、そしてR2がエチルである、請求項9から11のいずれか一項に記載の化合物。
- R2がエチルである、請求項17に記載の化合物。
- 前記式(2b)の化合物が、単一のエナンチオマーである、請求項17および18のいずれか一項に記載の化合物。
- ムスカリン性アセチルコリン受容体サブタイプ4(M4)活性から生じる疾患または状態を被験体において処置する方法であって、前記方法が、薬学的有効量のM4特異的アンタゴニストを前記被験体に投与するステップを含み、前記M4特異的アンタゴニストが、次の式:
R1が、HまたはCH3であり、
R2が、炭素原子1~3個を有する炭化水素基であり、
R3、R4およびR5が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SH、SCH3および次の構造(1-1):
R6が、HまたはCH3であり、
R7、R8およびR9が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SHおよびSCH3から独立的に選択され、
そして前記式(1)の化合物が、前記式(1)の化合物の薬学的に許容される塩、溶媒和物、エナンチオマーおよび多形体を含む、方法。 - R1が水素原子である、請求項21から23のいずれか一項に記載の方法。
- R1がメチルである、請求項21から23のいずれか一項に記載の方法。
- R2がエチルである、請求項21から25のいずれか一項に記載の方法。
- R1が水素原子であり、そしてR2がエチルである、請求項21から23のいずれか一項に記載の方法。
- R1がメチルであり、そしてR2がエチルである、請求項21から23のいずれか一項に記載の方法。
- ムスカリン性アセチルコリン受容体サブタイプ4(M4)活性から生じる疾患または状態を被験体において処置する方法であって、前記方法が、薬学的有効量のM4特異的アンタゴニストを前記被験体に投与するステップを含み、前記M4特異的アンタゴニストが、次の式:
R1が、HまたはCH3であり、
R2が、炭素原子1~3個を有する炭化水素基であり、
R3、R4およびR5が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SH、SCH3および次の構造(1-2):
R6が、HまたはCH3であり、
R7、R8およびR9が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SHおよびSCH3から独立的に選択され、
X-が、前記化合物の正荷電部分を均衡させるアニオンであり、そして
前記式(1c)の化合物が、前記式(1c)の化合物の薬学的に許容される塩、溶媒和物、エナンチオマーおよび多形体を含む、方法。 - R1が水素原子である、請求項29から31のいずれか一項に記載の方法。
- R1がメチルである、請求項29から31のいずれか一項に記載の方法。
- R2がエチルである、請求項29から33のいずれか一項に記載の方法。
- R1が水素原子であり、そしてR2がエチルである、請求項29から31のいずれか一項に記載の方法。
- R1がメチルであり、そしてR2がエチルである、請求項29から31のいずれか一項に記載の方法。
- 前記疾患または状態が、貧血である、請求項21から36のいずれか一項に記載の方法。
- R2がエチルである、請求項38に記載の方法。
- R2がエチルである、請求項40に記載の方法。
- ムスカリン性アセチルコリン受容体サブタイプ4(M4)活性から生じる疾患または状態を被験体において処置する方法であって、前記方法が、薬学的有効量のM4特異的アンタゴニストを前記被験体に投与するステップを含み、前記M4特異的アンタゴニストが、次の式:
R1が、HまたはCH3であり、
R2が、炭素原子1~3個を有する炭化水素基であり、
R4、R5、R7、R8およびR9が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SHおよびSCH3から独立的に選択され、そして
前記式(2b)の化合物が、前記式(2b)の化合物の薬学的に許容される塩、溶媒和物、エナンチオマーおよび多形体を含む、方法。 - R2がエチルである、請求項42に記載の方法。
- 前記式(2b)の化合物が、単一のエナンチオマーである、請求項42および43のいずれか一項に記載の方法。
- 前記疾患または状態が、貧血である、請求項42から45のいずれか一項に記載の方法。
- 赤芽球バースト形成単位(BFU-E)細胞の自己複製を促進するための方法であって、前記BFU-E細胞をM4特異的アンタゴニストと接触させるステップを含む、方法。
- 前記M4特異的アンタゴニストが、次の式:
R1が、HまたはCH3であり、
R2が、炭素原子1~3個を有する炭化水素基であり、
R3、R4およびR5が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SH、SCH3および次の構造(1-1):
R6が、HまたはCH3であり、
R7、R8およびR9が、水素原子、ハロゲン原子、CH3、CF3、OH、OCH3、SHおよびSCH3から独立的に選択され、
前記方法が、BFU-E細胞の自己複製の増加を生じ、そして
前記式(1)の化合物が、前記式(1)の化合物の薬学的に許容される塩、溶媒和物、エナンチオマーおよび多形体を含む、請求項47に記載の方法。 - 前記BFU-E細胞の自己複製の増加を利用して貧血を処置する、請求項47から50のいずれか一項に記載の方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2024081788A JP2024102364A (ja) | 2019-03-25 | 2024-05-20 | 貧血の処置におけるムスカリン性アセチルコリン受容体サブタイプ4アンタゴニスト |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962823214P | 2019-03-25 | 2019-03-25 | |
US62/823,214 | 2019-03-25 | ||
PCT/US2020/023989 WO2020198054A1 (en) | 2019-03-25 | 2020-03-20 | Muscarinic acetylcholine receptor subtype 4 antagonists in the treatment of anemia |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024081788A Division JP2024102364A (ja) | 2019-03-25 | 2024-05-20 | 貧血の処置におけるムスカリン性アセチルコリン受容体サブタイプ4アンタゴニスト |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2022525293A true JP2022525293A (ja) | 2022-05-12 |
JPWO2020198054A5 JPWO2020198054A5 (ja) | 2023-03-28 |
Family
ID=72608578
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021553300A Pending JP2022525293A (ja) | 2019-03-25 | 2020-03-20 | 貧血の処置におけるムスカリン性アセチルコリン受容体サブタイプ4アンタゴニスト |
JP2024081788A Pending JP2024102364A (ja) | 2019-03-25 | 2024-05-20 | 貧血の処置におけるムスカリン性アセチルコリン受容体サブタイプ4アンタゴニスト |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2024081788A Pending JP2024102364A (ja) | 2019-03-25 | 2024-05-20 | 貧血の処置におけるムスカリン性アセチルコリン受容体サブタイプ4アンタゴニスト |
Country Status (12)
Country | Link |
---|---|
US (1) | US20220185821A1 (ja) |
EP (1) | EP3946321A4 (ja) |
JP (2) | JP2022525293A (ja) |
KR (1) | KR20210144697A (ja) |
CN (1) | CN113613650A (ja) |
AU (1) | AU2020247812A1 (ja) |
BR (1) | BR112021019189A2 (ja) |
CA (1) | CA3132381A1 (ja) |
IL (1) | IL286617A (ja) |
MX (1) | MX2021011588A (ja) |
SG (1) | SG11202109857UA (ja) |
WO (1) | WO2020198054A1 (ja) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6500837B2 (en) * | 2000-09-22 | 2002-12-31 | Warner-Lambert Company | Fused ring system containing indole as M4 selective aza-anthracene muscarinic receptor antagonists |
EA016633B1 (ru) * | 2006-05-23 | 2012-06-29 | Общество С Ограниченной Ответственностью "Инновационная Фармацевтика" | Замещенные индолы, способ их получения и применения |
WO2011113036A2 (en) * | 2010-03-12 | 2011-09-15 | Whitehead Institute For Biomedical Research | Compositions and methods for expanding bfu-e cells |
US11253594B2 (en) * | 2017-07-07 | 2022-02-22 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Drug combinations for protecting against neuronal cell death |
-
2020
- 2020-03-20 KR KR1020217029823A patent/KR20210144697A/ko unknown
- 2020-03-20 WO PCT/US2020/023989 patent/WO2020198054A1/en unknown
- 2020-03-20 CN CN202080024089.9A patent/CN113613650A/zh active Pending
- 2020-03-20 SG SG11202109857U patent/SG11202109857UA/en unknown
- 2020-03-20 CA CA3132381A patent/CA3132381A1/en active Pending
- 2020-03-20 JP JP2021553300A patent/JP2022525293A/ja active Pending
- 2020-03-20 US US17/442,926 patent/US20220185821A1/en active Pending
- 2020-03-20 AU AU2020247812A patent/AU2020247812A1/en active Pending
- 2020-03-20 BR BR112021019189A patent/BR112021019189A2/pt unknown
- 2020-03-20 MX MX2021011588A patent/MX2021011588A/es unknown
- 2020-03-20 EP EP20776829.2A patent/EP3946321A4/en active Pending
-
2021
- 2021-09-23 IL IL286617A patent/IL286617A/en unknown
-
2024
- 2024-05-20 JP JP2024081788A patent/JP2024102364A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
CN113613650A (zh) | 2021-11-05 |
BR112021019189A2 (pt) | 2021-11-30 |
CA3132381A1 (en) | 2020-10-01 |
SG11202109857UA (en) | 2021-10-28 |
WO2020198054A1 (en) | 2020-10-01 |
JP2024102364A (ja) | 2024-07-30 |
KR20210144697A (ko) | 2021-11-30 |
US20220185821A1 (en) | 2022-06-16 |
MX2021011588A (es) | 2021-12-15 |
IL286617A (en) | 2021-10-31 |
EP3946321A1 (en) | 2022-02-09 |
AU2020247812A1 (en) | 2021-09-30 |
EP3946321A4 (en) | 2023-03-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA3039760C (en) | Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors | |
CA3041563C (en) | Pyrimidin-2-amine derivatives and pharmaceutical compositions thereof useful as inhibitors of cyclin-dependent kinase 12 (cdk12) | |
US20210363139A1 (en) | Cxcr4 inhibitors and uses thereof | |
KR102241258B1 (ko) | 암을 치료하기 위한 1-테트라히드로피라닐카르보닐-2,3-디히드로-1h-인돌 화합물 | |
TW202110446A (zh) | 用於治療nash/nafld及相關疾病之組合 | |
JP6592197B2 (ja) | アクリル酸誘導体、製造方法、および医薬としてのその使用 | |
KR101749953B1 (ko) | α7 양성 알로스테릭 조절제로서의 모르폴리노티아졸 | |
EP2621902B1 (en) | 3-azabicyclo[3.1.0]hexane compounds useful for the treatment of cns disorders | |
EA025322B1 (ru) | Производные дигидробензооксазина и дигидропиридооксазина | |
JP2021518367A (ja) | Idoおよびtdo調節のための化合物および方法、ならびにそれらのための兆候 | |
CA3104674A1 (en) | Natural killer cells | |
US20070179172A1 (en) | Positive modulators of nicotinic acetylcholine receptors | |
TW201103944A (en) | 2-carboxamide cycloamino ureas | |
JP2022522942A (ja) | 有機化合物 | |
CN113301963A (zh) | 用于治疗癌症的作为nlrp3调节剂的取代的喹唑啉类 | |
EP3108883A1 (en) | Therapeutic uses of non-peptide inhibitors of the calcineurin - nfat signalling pathway | |
JP2022525293A (ja) | 貧血の処置におけるムスカリン性アセチルコリン受容体サブタイプ4アンタゴニスト | |
KR20140022840A (ko) | 당뇨병을 치료하기 위한 호르몬 감수성 리파제 저해제로서의 2급-하이드록시사이클로헥실 유도체 | |
CA3230542A1 (en) | Novel ras inhibitors | |
WO2023030335A1 (zh) | 作为tyk2/jak1假激酶结构域抑制剂的化合物及合成和使用方法 | |
WO2021003339A1 (en) | Amp-activated protein kinase inhibitors and methods of making and using the same | |
US11801243B2 (en) | Bromodomain inhibitors for androgen receptor-driven cancers | |
WO2023131677A1 (en) | Compounds containing a hydroxyphenyl moiety and their use | |
WO2022243365A1 (fr) | Composés bifonctionnels de type protac ciblant pxr, leur procédé de préparation et leur utilisation en thérapeutique | |
WO2023044315A2 (en) | Kca3.1 inhibitors for podocyte protection |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230317 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20230317 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20240215 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20240220 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240520 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20240820 |