JP6923917B2 - 白内障の予防剤および治療剤、ならびに、これらを製造するためのhif経路阻害剤の使用 - Google Patents
白内障の予防剤および治療剤、ならびに、これらを製造するためのhif経路阻害剤の使用 Download PDFInfo
- Publication number
- JP6923917B2 JP6923917B2 JP2017181717A JP2017181717A JP6923917B2 JP 6923917 B2 JP6923917 B2 JP 6923917B2 JP 2017181717 A JP2017181717 A JP 2017181717A JP 2017181717 A JP2017181717 A JP 2017181717A JP 6923917 B2 JP6923917 B2 JP 6923917B2
- Authority
- JP
- Japan
- Prior art keywords
- hif
- cataract
- therapeutic agent
- preventive
- cataracts
- 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
- 208000002177 Cataract Diseases 0.000 title claims description 80
- 239000003814 drug Substances 0.000 title claims description 63
- 229940124597 therapeutic agent Drugs 0.000 title claims description 57
- 230000000069 prophylactic effect Effects 0.000 title claims description 16
- 230000037361 pathway Effects 0.000 title description 49
- 239000003112 inhibitor Substances 0.000 title description 43
- 230000003449 preventive effect Effects 0.000 claims description 46
- -1 1-benzylindazol-3-yl Chemical group 0.000 claims description 20
- 239000004480 active ingredient Substances 0.000 claims description 17
- 206010007749 Cataract diabetic Diseases 0.000 claims description 13
- 201000007025 diabetic cataract Diseases 0.000 claims description 13
- 239000002552 dosage form Substances 0.000 claims description 9
- 239000003889 eye drop Substances 0.000 claims description 9
- OQQVFCKUDYMWGV-UHFFFAOYSA-N [5-[1-(phenylmethyl)-3-indazolyl]-2-furanyl]methanol Chemical compound O1C(CO)=CC=C1C(C1=CC=CC=C11)=NN1CC1=CC=CC=C1 OQQVFCKUDYMWGV-UHFFFAOYSA-N 0.000 claims description 8
- CQOQDQWUFQDJMK-SSTWWWIQSA-N 2-methoxy-17beta-estradiol Chemical compound C([C@@H]12)C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CCC1=C2C=C(OC)C(O)=C1 CQOQDQWUFQDJMK-SSTWWWIQSA-N 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 101001046870 Homo sapiens Hypoxia-inducible factor 1-alpha Proteins 0.000 description 30
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 30
- 239000003795 chemical substances by application Substances 0.000 description 25
- 210000000695 crystalline len Anatomy 0.000 description 23
- 239000000126 substance Substances 0.000 description 22
- 201000010099 disease Diseases 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- OJYIBEYSBXIQOP-UHFFFAOYSA-N 1-methoxy-4-[2-(4-methoxyphenyl)propan-2-yl]benzene Chemical group C1=CC(OC)=CC=C1C(C)(C)C1=CC=C(OC)C=C1 OJYIBEYSBXIQOP-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 10
- 230000010534 mechanism of action Effects 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000002779 inactivation Effects 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- BPBPYQWMFCTCNG-UHFFFAOYSA-N 2-(butan-2-yldisulfanyl)-1H-imidazole Chemical compound CCC(C)SSC1=NC=CN1 BPBPYQWMFCTCNG-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- RTIXKCRFFJGDFG-UHFFFAOYSA-N chrysin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 RTIXKCRFFJGDFG-UHFFFAOYSA-N 0.000 description 4
- 210000001508 eye Anatomy 0.000 description 4
- 229940012356 eye drops Drugs 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- BJRPPNOJYFZSLY-UHFFFAOYSA-N methyl 3-[[2-[4-(1-adamantyl)phenoxy]acetyl]amino]-4-hydroxybenzoate Chemical compound COC(=O)C1=CC=C(O)C(NC(=O)COC=2C=CC(=CC=2)C23CC4CC(CC(C4)C2)C3)=C1 BJRPPNOJYFZSLY-UHFFFAOYSA-N 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 4
- IJMBOKOTALXLKS-UHFFFAOYSA-N 2-(6-morpholin-4-ylpyrimidin-4-yl)-4-(triazol-1-yl)-1h-pyrazol-3-one Chemical compound O=C1C(N2N=NC=C2)=CNN1C(N=CN=1)=CC=1N1CCOCC1 IJMBOKOTALXLKS-UHFFFAOYSA-N 0.000 description 3
- GIGCDIVNDFQKRA-LTCKWSDVSA-N 4-[(2s)-2-amino-2-carboxyethyl]-n,n-bis(2-chloroethyl)benzeneamine oxide;dihydrochloride Chemical compound Cl.Cl.OC(=O)[C@@H](N)CC1=CC=C([N+]([O-])(CCCl)CCCl)C=C1 GIGCDIVNDFQKRA-LTCKWSDVSA-N 0.000 description 3
- CDJNNOJINJAXPV-UHFFFAOYSA-N 5-[1-[[2-(4-cyclopropylpiperazin-1-yl)pyridin-4-yl]methyl]-5-methylpyrazol-3-yl]-3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole Chemical compound CC1=CC(C=2ON=C(N=2)C=2C=CC(OC(F)(F)F)=CC=2)=NN1CC(C=1)=CC=NC=1N(CC1)CCN1C1CC1 CDJNNOJINJAXPV-UHFFFAOYSA-N 0.000 description 3
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- OUQVKRKGTAUJQA-UHFFFAOYSA-N n-[(1-chloro-4-hydroxyisoquinolin-3-yl)carbonyl]glycine Chemical compound C1=CC=CC2=C(O)C(C(=O)NCC(=O)O)=NC(Cl)=C21 OUQVKRKGTAUJQA-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- YOZBGTLTNGAVFU-UHFFFAOYSA-N roxadustat Chemical compound C1=C2C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=CC=C1OC1=CC=CC=C1 YOZBGTLTNGAVFU-UHFFFAOYSA-N 0.000 description 3
- DLROLUIVVKTFPW-LVEBQJTPSA-N (5s,5as,8ar,9r)-9-(4-hydroxy-3,5-dimethoxyphenyl)-5-(4-nitroanilino)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](NC=3C=CC(=CC=3)[N+]([O-])=O)[C@@H]3[C@@H]2C(OC3)=O)=C1 DLROLUIVVKTFPW-LVEBQJTPSA-N 0.000 description 2
- 102100035905 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 Human genes 0.000 description 2
- DGHHQBMTXTWTJV-BQAIUKQQSA-N 119413-54-6 Chemical compound Cl.C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 DGHHQBMTXTWTJV-BQAIUKQQSA-N 0.000 description 2
- QFWCYNPOPKQOKV-UHFFFAOYSA-N 2-(2-amino-3-methoxyphenyl)chromen-4-one Chemical compound COC1=CC=CC(C=2OC3=CC=CC=C3C(=O)C=2)=C1N QFWCYNPOPKQOKV-UHFFFAOYSA-N 0.000 description 2
- RUEYEZADQJCKGV-UHFFFAOYSA-N 2-[(1,3-dicyclohexyl-2,4,6-trioxo-1,3-diazinane-5-carbonyl)amino]acetic acid Chemical compound O=C1N(C2CCCCC2)C(=O)C(C(=O)NCC(=O)O)C(=O)N1C1CCCCC1 RUEYEZADQJCKGV-UHFFFAOYSA-N 0.000 description 2
- CAOSCCRYLYQBES-UHFFFAOYSA-N 2-[[[4-hydroxy-2-oxo-1-(phenylmethyl)-3-quinolinyl]-oxomethyl]amino]acetic acid Chemical compound O=C1C(C(=O)NCC(=O)O)=C(O)C2=CC=CC=C2N1CC1=CC=CC=C1 CAOSCCRYLYQBES-UHFFFAOYSA-N 0.000 description 2
- YCKKCNHGMXZJDR-RFVFDIJPSA-N 3-(carboxymethyl)-3-hydroxypentanedioic acid;(7r,8s,9s,13s,14s,17e)-17-[2-[2-(dimethylamino)ethoxy]ethylidene]-7,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-3-ol Chemical compound OC(=O)CC(O)(CC(O)=O)CC(O)=O.C1C[C@]2(C)C(=C/COCCN(C)C)/CC[C@H]2[C@@H]2[C@H](C)CC3=CC(O)=CC=C3[C@H]21 YCKKCNHGMXZJDR-RFVFDIJPSA-N 0.000 description 2
- XVUOIWIIQVGWAJ-UHFFFAOYSA-N 3-[[(2,4-dinitrophenyl)-oxomethyl]amino]benzoic acid [2-(4-methylphenyl)-2-oxoethyl] ester Chemical compound C1=CC(C)=CC=C1C(=O)COC(=O)C1=CC=CC(NC(=O)C=2C(=CC(=CC=2)[N+]([O-])=O)[N+]([O-])=O)=C1 XVUOIWIIQVGWAJ-UHFFFAOYSA-N 0.000 description 2
- PTBDIHRZYDMNKB-UHFFFAOYSA-M 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate Chemical compound OCC(C)(CO)C([O-])=O PTBDIHRZYDMNKB-UHFFFAOYSA-M 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- RTUZVPPGTJRELI-UHFFFAOYSA-N 5-amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methylchromen-4-one Chemical compound FC=1C(C)=C(F)C(N)=C(C(C=2)=O)C=1OC=2C1=CC=C(N)C(F)=C1 RTUZVPPGTJRELI-UHFFFAOYSA-N 0.000 description 2
- VJNZMSLGVUSPCF-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-n-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C1CC1CONC(=O)C=1C=C(Br)C(F)=C(F)C=1NC1=CC=C(I)C=C1Cl VJNZMSLGVUSPCF-UHFFFAOYSA-N 0.000 description 2
- YGWHMSNGVVTUIT-XZTJDVGNSA-N 64t9qz8n2y Chemical compound CN1[C@H]2C[C@@H](C(O)=O)[C@@H]1[C@@H]1CC(C=CC=C3OC)=C3[C@H](CO)N1[C@H]2C#N YGWHMSNGVVTUIT-XZTJDVGNSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- 101150052909 CCL2 gene Proteins 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 101150074775 Csf1 gene Proteins 0.000 description 2
- 101150030419 Cx3cl1 gene Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 101150054336 EFEMP1 gene Proteins 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[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 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101150061822 HBEGF gene Proteins 0.000 description 2
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 2
- 101000929840 Homo sapiens 1-acylglycerol-3-phosphate O-acyltransferase ABHD5 Proteins 0.000 description 2
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- CZQHHVNHHHRRDU-UHFFFAOYSA-N LY294002 Chemical compound C1=CC=C2C(=O)C=C(N3CCOCC3)OC2=C1C1=CC=CC=C1 CZQHHVNHHHRRDU-UHFFFAOYSA-N 0.000 description 2
- 206010024214 Lenticular opacities Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 101100046559 Mus musculus Tnfrsf12a gene Proteins 0.000 description 2
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 2
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 101150062285 PGF gene Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- MYEJFUXQJGHEQK-ALRJYLEOSA-N Proscillaridin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C=C2CC[C@H]3[C@@]4(O)CC[C@H](C5=COC(=O)C=C5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1 MYEJFUXQJGHEQK-ALRJYLEOSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102000000344 Sirtuin 1 Human genes 0.000 description 2
- 108010041191 Sirtuin 1 Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[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 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 2
- 101150095461 Tfrc gene Proteins 0.000 description 2
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- PEJLNXHANOHNSU-UHFFFAOYSA-N acridine-3,6-diamine;10-methylacridin-10-ium-3,6-diamine;chloride Chemical compound [Cl-].C1=CC(N)=CC2=NC3=CC(N)=CC=C3C=C21.C1=C(N)C=C2[N+](C)=C(C=C(N)C=C3)C3=CC2=C1 PEJLNXHANOHNSU-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- KUFRQPKVAWMTJO-LMZWQJSESA-N alvespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCCN(C)C)C(=O)C=C1C2=O KUFRQPKVAWMTJO-LMZWQJSESA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- KZNIFHPLKGYRTM-UHFFFAOYSA-N apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 description 2
- 108010045569 atelocollagen Proteins 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 229950010337 daprodustat Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- QTQAWLPCGQOSGP-KSRBKZBZSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-KSRBKZBZSA-N 0.000 description 2
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 229920006158 high molecular weight polymer Polymers 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 2
- 229950001364 molidustat Drugs 0.000 description 2
- CDQUJZKBRAFWNG-UHFFFAOYSA-N n-(3-chloro-5-fluorophenyl)-4-nitro-2,1,3-benzoxadiazol-5-amine Chemical compound C1=CC2=NON=C2C([N+](=O)[O-])=C1NC1=CC(F)=CC(Cl)=C1 CDQUJZKBRAFWNG-UHFFFAOYSA-N 0.000 description 2
- XUIFJAMZXWXRLO-UHFFFAOYSA-N n-[2-(dimethylamino)ethyl]-9-nitrodibenzo-p-dioxin-1-carboxamide;hydrochloride Chemical compound Cl.O1C2=CC=CC([N+]([O-])=O)=C2OC2=C1C=CC=C2C(=O)NCCN(C)C XUIFJAMZXWXRLO-UHFFFAOYSA-N 0.000 description 2
- WXLPERVDMILVIF-UHFFFAOYSA-N n-[bis(4-methoxyphenyl)methyl]-6-oxo-2-pyridazin-3-yl-1h-pyrimidine-5-carboxamide Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)NC(=O)C1=CN=C(C=2N=NC=CC=2)N=C1O WXLPERVDMILVIF-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 229960003452 romidepsin Drugs 0.000 description 2
- 108010091666 romidepsin Proteins 0.000 description 2
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 2
- 229950008113 roxadustat Drugs 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 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
- 239000001509 sodium citrate Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 229960000235 temsirolimus Drugs 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- SGEWCQFRYRRZDC-VPRICQMDSA-N vitexin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C=CC(O)=CC=1)=CC2=O SGEWCQFRYRRZDC-VPRICQMDSA-N 0.000 description 2
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 2
- QCPDBEXGCHOIDE-UHFFFAOYSA-N (-)-6xi-Methyl-(2ar,4axi,8at,12bt,12ct)-2a,3,4,4a,5,6,7,8a,12b,12c-decahydro-5xi,12dxi-aethano-furo[4',3',2';4,10]anthra[9,1-bc]oxepin-2,9,12-trion Natural products CC1COC2C(C(C=CC3=O)=O)=C3C3C4C22CCC1C2CCC4C(=O)O3 QCPDBEXGCHOIDE-UHFFFAOYSA-N 0.000 description 1
- HDIJLRXRAJUXQB-JWQCQUIFSA-N (11br)-3-ethyl-9,10-dimethoxy-2-[[(1r)-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl]-4,6,7,11b-tetrahydro-1h-benzo[a]quinolizine Chemical compound COC1=C(OC)C=C2[C@H]3CC(C[C@@H]4C5=CC=CC=C5CCN4)=C(CC)CN3CCC2=C1 HDIJLRXRAJUXQB-JWQCQUIFSA-N 0.000 description 1
- JTUWBMRONSWGPE-ICSQUKMHSA-N (1s)-3-methyl-6-[4-[(1s,2r,3r,4r)-1,2,4-trimethyl-7-oxabicyclo[2.2.1]heptan-3-yl]butan-2-yl]cyclohex-2-en-1-ol Chemical compound C([C@H]1[C@@]2(C)CC[C@@](O2)(C)[C@@H]1C)CC(C)C1CCC(C)=C[C@H]1O JTUWBMRONSWGPE-ICSQUKMHSA-N 0.000 description 1
- HBUBKKRHXORPQB-FJFJXFQQSA-N (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O HBUBKKRHXORPQB-FJFJXFQQSA-N 0.000 description 1
- AWUUHEHYNQGEFC-XLZVTALKSA-N (2S)-5-amino-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[2-[[(2R)-2-amino-3-[[(2R,5S,8S,11S,14S,17S)-11-benzyl-17-[(4-hydroxyphenyl)methyl]-5,8-bis(2-methylpropyl)-3,6,9,12,15,18-hexaoxo-14-propan-2-yl-1,4,7,10,13,16-hexazacyclooctadec-2-yl]methyldisulfanyl]propanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoic acid Chemical compound O=C([C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)CNC(=O)[C@@H](N)CSSC[C@H]1C(=O)N[C@H](C(N[C@@H](CC(C)C)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(C)C)=O)CC(C)C)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O AWUUHEHYNQGEFC-XLZVTALKSA-N 0.000 description 1
- IXQKXEUSCPEQRD-NRNCYQGDSA-N (2S,4R,23E)-2,16beta,20-trihydroxy-9beta,10,14-trimethyl-1,11,22-trioxo-4,9-cyclo-9,10-secocholesta-5,23-dien-25-yl acetate Chemical compound C([C@H]1[C@]2(C)C[C@@H](O)[C@@H]([C@]2(CC(=O)[C@]11C)C)[C@@](C)(O)C(=O)C=CC(C)(C)OC(=O)C)C=C2[C@H]1C[C@H](O)C(=O)C2(C)C IXQKXEUSCPEQRD-NRNCYQGDSA-N 0.000 description 1
- HYJVYOWKYPNSTK-UONOGXRCSA-N (2r,3s)-3-benzamido-2-hydroxy-3-phenylpropanoic acid Chemical compound N([C@H]([C@@H](O)C(O)=O)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 HYJVYOWKYPNSTK-UONOGXRCSA-N 0.000 description 1
- YQJWOUQGXATDAE-ACNBBOPNSA-N (8s,9s,13r,14s)-2-methoxy-13-methyl-6,7,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthrene-3-carboxamide Chemical compound C([C@@H]12)C[C@]3(C)C=CC[C@H]3[C@@H]1CCC1=C2C=C(OC)C(C(N)=O)=C1 YQJWOUQGXATDAE-ACNBBOPNSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- UMHSKUILJUFIEK-UHFFFAOYSA-N 2,5-dichlorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC(Cl)=CC=C1Cl UMHSKUILJUFIEK-UHFFFAOYSA-N 0.000 description 1
- MHYCOGDEWYAFLM-UHFFFAOYSA-N 2-(4-bromophenyl)-3-ethylsulfonyl-7-methyl-4-oxidoquinoxalin-1-ium 1-oxide Chemical compound [O-][N+]1=C2C=C(C)C=CC2=[N+]([O-])C(S(=O)(=O)CC)=C1C1=CC=C(Br)C=C1 MHYCOGDEWYAFLM-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- KWBPKUMWVXUSCA-AXQDKOMKSA-N 3-[(3s,5s,8r,9s,10r,13r,14s,17r)-5,14-dihydroxy-3-[(2r,4s,5r,6r)-4-methoxy-6-methyl-5-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-10,13-dimethyl-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl] Chemical compound C1([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C)CC[C@@H](C[C@@]5(O)CC[C@H]4[C@@]3(O)CC2)O[C@H]2C[C@@H]([C@@H]([C@@H](C)O2)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)OC)=CC(=O)OC1 KWBPKUMWVXUSCA-AXQDKOMKSA-N 0.000 description 1
- LYAPWXJZNZBLBH-UHFFFAOYSA-N 3-ethyl-9,10-dimethoxy-2-(1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)-4,6,7,11b-tetrahydro-1h-benzo[a]quinolizine;hydrobromide Chemical compound [Br-].COC1=C(OC)C=C2C3CC(CC4C5=CC=CC=C5CCN4)=C(CC)C[NH+]3CCC2=C1 LYAPWXJZNZBLBH-UHFFFAOYSA-N 0.000 description 1
- RPJFWRZEEKJTGN-UHFFFAOYSA-N 4-[2-(4-hydroxyphenyl)propan-2-yl]-2,6-dimethylphenol Chemical compound CC1=C(O)C(C)=CC(C(C)(C)C=2C=CC(O)=CC=2)=C1 RPJFWRZEEKJTGN-UHFFFAOYSA-N 0.000 description 1
- NYCXYKOXLNBYID-UHFFFAOYSA-N 5,7-Dihydroxychromone Natural products O1C=CC(=O)C=2C1=CC(O)=CC=2O NYCXYKOXLNBYID-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- QOMCOKJKSCUOBB-UHFFFAOYSA-N 9h-carbazole-4-carboxylic acid Chemical compound N1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O QOMCOKJKSCUOBB-UHFFFAOYSA-N 0.000 description 1
- LPMXVESGRSUGHW-UHFFFAOYSA-N Acolongiflorosid K Natural products OC1C(O)C(O)C(C)OC1OC1CC2(O)CCC3C4(O)CCC(C=5COC(=O)C=5)C4(C)CC(O)C3C2(CO)C(O)C1 LPMXVESGRSUGHW-UHFFFAOYSA-N 0.000 description 1
- 102100030907 Aryl hydrocarbon receptor nuclear translocator Human genes 0.000 description 1
- 206010069649 Atopic cataract Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- JTUWBMRONSWGPE-MODAFTMZSA-N CC(CC[C@@H]1[C@@H](C)C2(C)CC[C@]1(C)O2)C1CCC(C)=C[C@H]1O Chemical compound CC(CC[C@@H]1[C@@H](C)C2(C)CC[C@]1(C)O2)C1CCC(C)=C[C@H]1O JTUWBMRONSWGPE-MODAFTMZSA-N 0.000 description 1
- AUJXLBOHYWTPFV-BLWRDSOESA-N CS[C@H]1SC[C@H]2N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C(=O)[C@@H]1N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C2=O)NC(=O)c1cnc2ccccc2n1)NC(=O)c1cnc2ccccc2n1 Chemical compound CS[C@H]1SC[C@H]2N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C(=O)[C@@H]1N(C)C(=O)[C@@H](C)NC(=O)[C@H](COC(=O)[C@@H](C(C)C)N(C)C2=O)NC(=O)c1cnc2ccccc2n1)NC(=O)c1cnc2ccccc2n1 AUJXLBOHYWTPFV-BLWRDSOESA-N 0.000 description 1
- 101100369802 Caenorhabditis elegans tim-1 gene Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007747 Cataract congenital Diseases 0.000 description 1
- 206010007766 Cataract traumatic Diseases 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
- IHTCCHVMPGDDSL-ZJNDIJRCSA-N Cucurbitacin A Natural products O=C([C@@](O)(C)[C@H]1[C@@H](O)C[C@]2(C)[C@]1(C)CC(=O)[C@]1(CO)[C@H]2CC=C2C(C)(C)C(=O)[C@H](O)C[C@@H]12)/C=C/C(OC(=O)C)(C)C IHTCCHVMPGDDSL-ZJNDIJRCSA-N 0.000 description 1
- CVKKIVYBGGDJCR-SXDZHWHFSA-N Cucurbitacin B Natural products CC(=O)OC(C)(C)C=CC(=O)[C@@](C)(O)[C@@H]1[C@@H](O)C[C@]2(C)C3=CC[C@@H]4C(C)(C)C(=O)[C@H](O)C[C@@]4(C)[C@@H]3CC(=O)[C@@]12C CVKKIVYBGGDJCR-SXDZHWHFSA-N 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 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
- 108010092160 Dactinomycin Proteins 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- QZJJDOYZVRUEDY-UHFFFAOYSA-N Dihydrocucurbitacin B Natural products CC12C(=O)CC3(C)C(C(C)(O)C(=O)CCC(C)(C)OC(=O)C)C(O)CC3(C)C1CC=C1C2CC(O)C(=O)C1(C)C QZJJDOYZVRUEDY-UHFFFAOYSA-N 0.000 description 1
- 108010009858 Echinomycin Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 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
- 241000282326 Felis catus Species 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 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
- 108010024636 Glutathione Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 101000793115 Homo sapiens Aryl hydrocarbon receptor nuclear translocator Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 102000002177 Hypoxia-inducible factor-1 alpha Human genes 0.000 description 1
- 108050009527 Hypoxia-inducible factor-1 alpha Proteins 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- KJQFBVYMGADDTQ-CVSPRKDYSA-N L-buthionine-(S,R)-sulfoximine Chemical compound CCCCS(=N)(=O)CC[C@H](N)C(O)=O KJQFBVYMGADDTQ-CVSPRKDYSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- FJHBVJOVLFPMQE-UHFFFAOYSA-N LSM-6189 Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C(C(C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- BIMZLRFONYSTPT-UHFFFAOYSA-N N-oxalylglycine Chemical compound OC(=O)CNC(=O)C(O)=O BIMZLRFONYSTPT-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- LPMXVESGRSUGHW-GHYGWZAOSA-N Ouabain Natural products O([C@@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1)[C@H]1C[C@@H](O)[C@@]2(CO)[C@@](O)(C1)CC[C@H]1[C@]3(O)[C@@](C)([C@H](C4=CC(=O)OC4)CC3)C[C@@H](O)[C@H]21 LPMXVESGRSUGHW-GHYGWZAOSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- OKPNYGAWTYOBFZ-UHFFFAOYSA-N Pirenoxine Chemical compound C12=NC3=CC=CC=C3OC2=CC(=O)C2=C1C(=O)C=C(C(=O)O)N2 OKPNYGAWTYOBFZ-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 206010037756 Radiation cataract Diseases 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- QTQDDTSVRVWHMO-BQBZGAKWSA-N S-methylglutathione Chemical compound OC(=O)CNC(=O)[C@H](CSC)NC(=O)CC[C@H](N)C(O)=O QTQDDTSVRVWHMO-BQBZGAKWSA-N 0.000 description 1
- JMFSHKGXVSAJFY-UHFFFAOYSA-N Saponaretin Natural products OCC(O)C1OC(Oc2c(O)cc(O)c3C(=O)C=C(Oc23)c4ccc(O)cc4)C(O)C1O JMFSHKGXVSAJFY-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 244000166550 Strophanthus gratus Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 101150077804 TIMP1 gene Proteins 0.000 description 1
- 102000005353 Tissue Inhibitor of Metalloproteinase-1 Human genes 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- MOZJVOCOKZLBQB-UHFFFAOYSA-N Vitexin Natural products OCC1OC(Oc2c(O)c(O)cc3C(=O)C=C(Oc23)c4ccc(O)cc4)C(O)C(O)C1O MOZJVOCOKZLBQB-UHFFFAOYSA-N 0.000 description 1
- XYFFWTYOFPSZRM-IPQLZRNVSA-N [(3r,5r,6r,7s,8e,10s,11r,12z,14e)-21-amino-6-hydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-17-azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate Chemical compound N1C(=O)\C(C)=C\C=C/[C@@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@H](OC)C[C@H](C)CC2=C(N)C(=O)C=C1C2=O XYFFWTYOFPSZRM-IPQLZRNVSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 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
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 229940023020 acriflavine Drugs 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 235000008714 apigenin Nutrition 0.000 description 1
- 229940117893 apigenin Drugs 0.000 description 1
- XADJWCRESPGUTB-UHFFFAOYSA-N apigenin Natural products C1=CC(O)=CC=C1C1=CC(=O)C2=CC(O)=C(O)C=C2O1 XADJWCRESPGUTB-UHFFFAOYSA-N 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000005018 aryl alkenyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000005015 aryl alkynyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960002233 benzalkonium bromide Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- DFELABABMXOKTD-IYFIADHGSA-N beta-D-glucosyl-N-eicosanoylsphingosine Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)N[C@H]([C@H](O)\C=C\CCCCCCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O DFELABABMXOKTD-IYFIADHGSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000015838 chrysin Nutrition 0.000 description 1
- 229940043370 chrysin Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- IXQKXEUSCPEQRD-DKRGWESNSA-N cucurbitacin B Chemical compound C([C@H]1[C@]2(C)C[C@@H](O)[C@@H]([C@]2(CC(=O)[C@]11C)C)[C@@](C)(O)C(=O)/C=C/C(C)(C)OC(=O)C)C=C2[C@H]1C[C@H](O)C(=O)C2(C)C IXQKXEUSCPEQRD-DKRGWESNSA-N 0.000 description 1
- 108010054990 cyclo(cysteinyl-leucyl-leucyl-phenylalanyl-valyl-tyrosyl) Proteins 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- BNJOZDZCRHCODO-UHFFFAOYSA-N dimethyloxalylglycine Chemical compound COC(=O)CNC(=O)C(=O)OC BNJOZDZCRHCODO-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 239000002526 disodium citrate Substances 0.000 description 1
- 235000019262 disodium citrate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940045109 genistein Drugs 0.000 description 1
- 235000006539 genistein Nutrition 0.000 description 1
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002305 glucosylceramides Chemical class 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000005734 heterodimerization reaction Methods 0.000 description 1
- AKWHREAVLKZDDE-UHFFFAOYSA-N hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone Chemical compound CCCCCCCC=CC=CC=CCCCC(=O)CCC=CCC(=O)CCCC(=O)CCCCCCC(=O)C(C)=O AKWHREAVLKZDDE-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 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 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- JTUWBMRONSWGPE-AIFSHUDHSA-N laurenditerpenol Natural products C([C@@H]1[C@@H](CC[C@H]2[C@@]3(C)CC[C@@](O3)(C)[C@@H]2C)C)CC(C)=C[C@H]1O JTUWBMRONSWGPE-AIFSHUDHSA-N 0.000 description 1
- 210000001542 lens epithelial cell Anatomy 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- DHMTURDWPRKSOA-RUZDIDTESA-N lonafarnib Chemical compound C1CN(C(=O)N)CCC1CC(=O)N1CCC([C@@H]2C3=C(Br)C=C(Cl)C=C3CCC3=CC(Br)=CN=C32)CC1 DHMTURDWPRKSOA-RUZDIDTESA-N 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- CGZKSZVSWAAUHE-UHFFFAOYSA-N n-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,4-dihydroindeno[1,2-c]pyrazol-3-amine Chemical compound O1CCOC2=CC(NC3=NNC=4C5=CC=CC=C5CC3=4)=CC=C21 CGZKSZVSWAAUHE-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229960002950 novobiocin Drugs 0.000 description 1
- YJQPYGGHQPGBLI-KGSXXDOSSA-N novobiocin Chemical compound O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 1
- 229960003343 ouabain Drugs 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229950010632 perifosine Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- VJLPGQYJETUIQE-UHFFFAOYSA-N phenanthrene-3-carboxamide Chemical compound C1=CC=C2C3=CC(C(=O)N)=CC=C3C=CC2=C1 VJLPGQYJETUIQE-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical compound NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 description 1
- 229960005071 pirenoxine Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 210000000184 posterior capsule of the len Anatomy 0.000 description 1
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229940111695 potassium tartrate Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229930190098 proscillaridin Natural products 0.000 description 1
- 229960003584 proscillaridin Drugs 0.000 description 1
- MYEJFUXQJGHEQK-UHFFFAOYSA-N proscillaridin A Natural products OC1C(O)C(O)C(C)OC1OC1C=C2CCC3C4(O)CCC(C5=COC(=O)C=C5)C4(C)CCC3C2(C)CC1 MYEJFUXQJGHEQK-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- GOHMRMDXUXWCDQ-UHFFFAOYSA-N pseudolaric acid B Natural products CC(=O)OC12CCC(C)=CCC11C(=O)OC(C)(C=CC=C(C)C(O)=O)C2CC1 GOHMRMDXUXWCDQ-UHFFFAOYSA-N 0.000 description 1
- VDGOFNMYZYBUDT-YDRCMHEVSA-N pseudolaric acid b Chemical compound C([C@@]12OC(C)=O)CC(C(=O)OC)=CC[C@@]11C(=O)O[C@](C)(\C=C\C=C(/C)C(O)=O)[C@@H]2CC1 VDGOFNMYZYBUDT-YDRCMHEVSA-N 0.000 description 1
- VDGOFNMYZYBUDT-UHFFFAOYSA-N pseudolarix acid B Natural products CC(=O)OC12CCC(C(=O)OC)=CCC11C(=O)OC(C)(C=CC=C(C)C(O)=O)C2CC1 VDGOFNMYZYBUDT-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 description 1
- AUJXLBOHYWTPFV-UHFFFAOYSA-N quinomycin A Natural products CN1C(=O)C(C)NC(=O)C(NC(=O)C=2N=C3C=CC=CC3=NC=2)COC(=O)C(C(C)C)N(C)C(=O)C2N(C)C(=O)C(C)NC(=O)C(NC(=O)C=3N=C4C=CC=CC4=NC=3)COC(=O)C(C(C)C)N(C)C(=O)C1CSC2SC AUJXLBOHYWTPFV-UHFFFAOYSA-N 0.000 description 1
- CGJMVNVWQHPASW-UHFFFAOYSA-N quinoxaline-2-carboxamide Chemical compound C1=CC=CC2=NC(C(=O)N)=CN=C21 CGJMVNVWQHPASW-UHFFFAOYSA-N 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 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
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000004320 sodium erythorbate Substances 0.000 description 1
- 235000010352 sodium erythorbate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 1
- 229950007866 tanespimycin Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- GXNFPEOUKFOTKY-LPHQIWJTSA-N ubiquinone-6 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O GXNFPEOUKFOTKY-LPHQIWJTSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- PZKISQRTNNHUGF-UHFFFAOYSA-N vitexine Natural products OC1C(O)C(O)C(CO)OC1OC1=C(O)C=C(O)C2=C1OC(C=1C=CC(O)=CC=1)=CC2=O PZKISQRTNNHUGF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 1
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 1
Images
Description
[白内障]
本明細書において「白内障」とは、水晶体に混濁を生じる疾患一般を意図する。白内障によって水晶体に生じる混濁には、例えば、皮質混濁、核混濁、後嚢下混濁、皮質スポーク状混濁、前嚢下混濁、線維ひだ、水隙、核周囲の徹照下点状混濁、水疱、点状混濁、冠状混濁などの類型がある。また、本明細書において「白内障」とは、加齢白内障の他に、併発白内障(糖尿病白内障、先天白内障、外傷性白内障、アトピー白内障、放射線白内障、ステロイド白内障など)などの病型を総称した疾患を意図する。
本明細書において「予防剤」とは、予防効果をもたらす薬剤を意図する。予防効果とは、以下に例示される効果を意図するが、これらに限定されるものではない。
(1)予防剤を投与しなかった場合と比較して、疾患に係る1つ以上の症状の発症を防止する、またはリスクを低減する。
(2)予防剤を投与しなかった場合と比較して、疾患に係る1つ以上の症状の再発を防止する、またはリスクを低減する。
(3)予防剤を投与しなかった場合と比較して、疾患に係る1つ以上の症状の徴候が生じることを防止する、またはリスクを低減する。
本明細書において「治療剤」とは、治療効果をもたらす薬剤を意図する。治療効果とは、以下に例示される効果を意図するが、これらに限定されるものではない。
(1)治療剤を投与しなかった場合と比較して、疾患に係る1つ以上の症状の重症度を低減する。
(2)治療剤を投与しなかった場合と比較して、疾患に係る1つ以上の症状の重症度の増加、または進行を防止する。
(3)治療剤を投与しなかった場合と比較して、疾患に係る1つ以上の症状の重症度の増加速度、または進行速度を低減する。
[2−1.HIF経路阻害剤]
本明細書において、HIF経路とは、HIF(Hypoxia Inducible Factor;低酸素誘導因子)またはHIFを構成するサブユニットが関与している、シグナル伝達経路一般を意味する。ここで、HIFのファミリーには、HIF−1、HIF−2およびHIF−3が含まれる。また、HIFのサブユニットのファミリーには、HIF−1α、HIF−1β、HIF−2α、HIF−2β、HIF−3αおよびHIF−3βが含まれる。したがって、一実施形態において、上記HIF経路は、上述したHIFおよびHIFのサブユニットのうち、1種以上が関与しているシグナル伝達経路である。
次に、本発明が開示しようとする技術思想について、簡単に説明する。本発明者らは、従前、ガラクトース添加培地を用いたex vivo糖尿病白内障モデルを利用して、白内障を予防および/または治療する薬剤について、探求していた。そして、白内障の発症および/または進行に、HIF経路が関わっていることを、今回新たに見出した。
本発明の好ましい実施形態に係る白内障の予防剤または治療剤は、HIF−1α経路阻害剤を有効成分とする。より好ましくは、上記HIF−1α経路阻害剤は、HIF−1α阻害剤である。これは、HIFに関連するタンパク質の中では、HIF−1αが最も研究が進んでおり、主に癌治療の分野において、臨床段階にある、または、医薬品として承認を受けているHIF−1α阻害剤が多数存在するためである。
・YC-1([5-(1-benzylindazol-3-yl)furan-2-yl]methanol)
・2-Methoxyestradiol((17β)-2-Methoxyestra-1,3,5(10)-triene-3,17-diol)
・Chrysin(5,7-Dihydroxyflavone)
・CAY10585(Methyl 3-({[4-(adamantan-1-yl)phenoxy]acetyl}amino)-4-hydroxybenzoate)
・Dimethyl-bisphenol A(4,4'-(2,2-Propanediyl)diphenol)
・BAY87-2243(1-cyclopropyl-4-[4-[[5-methyl-3-[3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl]-1H-pyrazol-1-yl]methyl]-2-pyridinyl]-piperazine)
・KC7F2(3,3'-(Disulfanediyldi-2,1-ethanediyl)bis(2,5-dichlorobenzenesulfonamide))
・Echinomycin(N-[(1R,4S,7R,11S,14R,17S,20R,24S)-2,4,12,15,17,25-hexamethyl-29-methylsulfanyl-3,6,10,13,16,19,23,26-octaoxo-11,24-di(propan-2-yl)-7-(quinoxaline-2-carbonylamino)-9,22-dioxa-28-thia-2,5,12,15,18,25-hexazabicyclo[12.12.3]nonacosan-20-yl]quinoxaline-2-carboxamide)
・gn44028(N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1,4-dihydroindeno[1,2-c]pyrazol-3-amine)
・TAT-cyclo-CLLFVY(ペプチド;CAS番号:1446322-66-2;配列番号1、2)
・PX12(2-(sec-Butyldisulfanyl)-1H-imidazole)
・VH-298((2S,4R)-1-((S)-2-(1-cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide)
・GL331((5S,5aS,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-5-(4-nitroanilino)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one)
・FK228((1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone)
・Topotecan((S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride)
・Taxol((-)-(1S,2S,3R,4S,5R,7S,8S,10R,13S)-4,10-Diacetoxy-2-benzoyloxy-5,20-epoxy-1,7-dihydroxy-9-oxotax-11-en-13-yl(2R,3S)-3-benzoylamino-2-hydroxy-3-phenylpropionate)
・Vincristine((3aR,3a1R,4R,5S,5aR,10bR)-methyl 4-acetoxy-3a-ethyl-9-((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1H-3,7-methano[1]azacycloundecino[5,4-b]indol-9-yl)-6-formyl-5-hydroxy-8-methoxy-3a,3a1,4,5,5a,6,11,12-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate)
・CCI-779((1R,2R,4S)-4-{(2R)-2-[(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontin-3-yl]propyl}-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate)
・RAD001(dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone)
・Imatinib(4-(4-Methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]benzamide monomethanesulfonate)
・Erlotinib(N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine)
・Gefinitib(N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine)
・Cetuximab(抗体;CAS番号205923-56-4;重鎖は配列番号3、軽鎖は配列番号4(いずれの配列も、出典:https://www.ebi.ac.uk/chembl/compound/inspect/CHEMBL1201577(2017年9月4日閲覧)))
・103D5R(PubChem CID:11267663)
・Radicicol((1aR,2E,4E,14R,15aR)-8-chloro-9,11-dihydroxy-14-methyl-1a,14,15,15a-tetrahydro-6H-oxireno[e][2]benzoxacyclotetradecine-6,12(7H)-dione)
・17AAG([(3S,5S,6R,7S,8E,10R,11S,12E,14E)-21-(allylamino)-6-hydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-17-azabicyclo[16.3.1]docosa-8,12,14,18,21-pentaen-10-yl]carbamate)
・KF58333(PubChem CID:9690135)
・SCH66336(4-(2-{4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]piperidin-1-yl}-2-oxoethyl)piperidine-1-carboxamide)
・Novobiocin([(3R,4S,5R,6R)-5-hydroxy-6-[4-hydroxy-3-[[4-hydroxy-3-(3-methylbut-2-enyl)benzoyl]amino]-8-methyl-2-oxochromen-7-yl]oxy-3-methoxy-2,2-dimethyloxan-4-yl] carbamate)
・PX-478(4-[Bis(2-chloroethyl)nitroryl]phenylalanine dihydrochloride)
・Pleurotin(PubChem CID:13994131)
・Actinomycin D(2-amino-N,N'-bis[(6S,9R,10S,13R,18aS)-6,13-diisopropyl-2,5,9-trimethyl-1,4,7,11,14-pentaoxohexadecahydro-1H-pyrrolo[2,1-i][1,4,7,10,13]oxatetraazacyclohexadecin-10-yl]-4,6-dimethyl-3-oxo-3H-phenoxazine-1,9-dicarboxamide)
・Glucosylceramide(N-[(2S,3R,4E)-1-(β-D-Glucopyranosyloxy)-3-hydroxy-4-octadecen-2-yl]icosanamide)
・cycloheximide(4-[(2R)-2-[(1S,3S,5S)-3,5-Dimethyl-2-oxocyclohexyl]-2-hydroxyethyl]piperidine-2,6-dione)
・nsc-606985(PubChem CID:3246702)
・nsc-639174(PubChem CID:3246719)
・DX 52-1(CAS番号:96251-59-1)
・Vitexin((1S)-1,5-Anhydro-1-[5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-8-yl]-D-glucitol)
・Daprodustat(N-[(1,3-Dicyclohexyl-2,4,6-trioxohexahydro-5-pyrimidinyl)carbonyl]glycine)
・Apigenin(5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one)
・DMOG(2-(carboxymethylamino)-2-oxoacetic acid)
・Molidustat(2-[6-(4-Morpholinyl)-4-pyrimidinyl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one)
・FG-2216(2-[(1-chloro-4-hydroxyisoquinoline-3-carbonyl)amino]acetic acid)
・MK-8617(N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide)
・IOX2(2-[(1-benzyl-4-hydroxy-2-oxoquinoline-3-carbonyl)amino]acetic acid)
・PX-12(2-(butan-2-yldisulfanyl)-1H-imidazole)
・Roxadustat(N-[(4-Hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl)carbonyl]glycine)
・TC-S 7009(N-(3-Chloro-5-fluorophenyl)-4-nitro-2,1,3-benzoxadiazol-5-amine)
・17-AG([(3R,5R,6R,7S,8E,10S,11R,12Z,14E)-21-amino-6-hydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-17-azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate)
・17-DMAG([(3R,5S,6R,7S,8E,10S,11S,12Z,14E)-21-[2-(dimethylamino)ethylamino]-6-hydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-17-azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate)
・Acriflavine(acridine-3,6-diamine;10-methylacridin-10-ium-3,6-diamine;chloride)
・Aminoflavone(5-Amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one)
・Temozolomide(3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide)
・Bortezomib([(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid)
・Camptothecin((S)-4-ethyl-4-hydroxy-1H-Pyrano(3',4':6,7)indolizino(1,2-b)quinoline-3,14(4H,12H)-dione)
・CLT003([2,6-Diisopropylphenyl])-5-amino-1 H-isoindole1 ,3- dione)
・Cucurbitacin-B([(E,6R)-6-[(2S,8S,9R,10R,13R,14S,16R,17R)-2,16-dihydroxy-4,4,9,13,14-pentamethyl-3,11-dioxo-2,7,8,10,12,15,16,17-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-6-hydroxy-2-methyl-5-oxohept-3-en-2-yl] acetate)
・Cyclo-CLLFVY(配列番号5;[Miranda E et al. (2013) "A Cyclic Peptide Inhibitor of HIF-1 Heterodimerization That Inhibits Hypoxia Signaling in Cancer Cells", Jounal of the American Chemical Society, Vol.135(Issue 28) pp.10418-10425]を参照)
・Cyclo-CLLRMY(配列番号6;[Miranda E et al., Op. cit.]を参照)
・Cyclo-CRLMVL(配列番号7;[Miranda E et al., Op. cit.]を参照)
・Daunorubicin((7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione)
・Digoxin (3-[(3S,5R,8R,9S,10S,12R,13S,14S,17R)-3-[(2R,4S,5S,6R)-5-[(2S,4S,5S,6R)-5-[(2S,4S,5S,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-12,14-dihydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]-2H-furan-5-one)
・Doxorubicin ((7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione)
・ENMD-1198((13R)-2-methoxy-13-methyl-7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthrene-3-carboxamide)
・ENMD-1200([Georgina N et al. (2015) "HIF-1α pathway: role, regulation and intervention for cancer therapy", Acta Pharmaceutica Sinica B, Vol.5(Issue 5), p.378-389]を参照)
・ENMD-1237([Georgina N et al., Op. cit.]を参照)
・Epirubicin((7S,9S)-7-[(2R,4S,5R,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione)
・EZN-2208([Georgina N et al., Op. cit.]を参照)
・FM19G11([2-(4-methylphenyl)-2-oxoethyl] 3-[(2,4-dinitrobenzoyl)amino]benzoate)
・Geldanamycin([(3R,5S,6R,7S,8E,10S,11S,12Z,14E)-6-hydroxy-5,11,21-trimethoxy-3,7,9,15-tetramethyl-16,20,22-trioxo-17-azabicyclo[16.3.1]docosa-1(21),8,12,14,18-pentaen-10-yl] carbamate)
・Idarubicin((7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-8,10-dihydro-7H-tetracene-5,12-dione)
・Irinotecan([1,4’-bipiperidine]-1’-carboxylicacid, (4S)-4,11-diethyl-3,4,12,14- tetrahydro-4-hydroxy-3,14-dioxo- 1H-pyrano[3’,4’:6,7]indolizino[1,2-b] quinolin-9-yl ester, monohydrochloride)
・Laurenditerpenol((1S)-3-methyl-6-[4-[(2R,3R,4S)-1,2,4-trimethyl-7-oxabicyclo[2.2.1]heptan-3-yl]butan-2-yl]cyclohex-2-en-1-ol)
・LW6(3-(2-(4-Adamantan-1-yl-phenoxy)-acetylamino)-4-hydroxybenzoic acid methyl ester)
・NSC-134754(3-ethyl-9,10-dimethoxy-2-(1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)-4,6,7,11b-tetrahydro-1H-benzo[a]quinolizine;hydrobromide)
・Ouabain(3-[(1R,3S,5S,8R,9S,10R,11R,13R,14S,17R)-1,5,11,14-tetrahydroxy-10-(hydroxymethyl)-13-methyl-3-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2H-furan-5-one)
・PD-184161(5-bromo-2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide)
・Proscillaridin(5-[(3S,8R,9S,10R,13R,14S,17R)-14-hydroxy-10,13-dimethyl-3-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy-1,2,3,6,7,8,9,11,12,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl]pyran-2-one)
・EZN-2968(HIF1a anti-sense oligonucleotide)([Greenberger LM (2008) "A RNA antagonist of hypoxia-inducible factor-1α, EZN-2968, inhibits tumor cell growth", Molecular Cancer Therapeutics, Vol.7(Issue 11), pp.3598-3608];配列番号8)
・Q6(2-[(2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaenyl]-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-1,4-dione)
・Q39((3-(4-bromophenyl)-2-(ethylsulfonyl)-6-methylquinoxaline 1,4-dioxide)
・SN-38(4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione)
・SR16388(3-(carboxymethyl)-3-hydroxypentanedioic acid;(7R,8S,9S,13S,14S,17E)-17-[2-[2-(dimethylamino)ethoxy]ethylidene]-7,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-ol)
・Vorinostat(N'-hydroxy-N-phenyloctanediamide)
・Perifosine((1,1-dimethylpiperidin-1-ium-4-yl) octadecyl phosphate)
・NSC644221(N-[2-(dimethylamino)ethyl]-9-nitrodibenzo-p-dioxin-1-carboxamide;hydrochloride)
・PD98059(2-(2-amino-3-methoxyphenyl)chromen-4-one)
・Miltefosine(hexadecyl 2-(trimethylazaniumyl)ethyl phosphate)
・Romidepsin((1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone)
・LY294002(2-Morpholin-4-yl-8-phenylchromen-4-one)
・Wortmannin((1R,3R,5S,9R,18S)-18-(Methoxymethyl)-1,5-dimethyl-6,11,16-trioxo-13,17-dioxapentacyclo[10.6.1.02,10.05,9015,19]-nonadeca-2(10),12(19),14-trien-3-yl-aceta)
・NSC686288(5-Amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methyl-4H-chromen-4-one)
・Temsirolimus((1R,2R,4S)-4-{(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,35R)-1,18-Dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl}-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate)
・Everolimus((1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-Dihydroxy-12-{(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone)
・Rapamycin((3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone))
・Cyclosporine A((3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone)
・pseudolaric acid B((2E,4E)-5-[(1R,7S,8R,9R)-4,7-Bis(methoxycarbonyl)-9-methyl-11-oxo-10-oxatricyclo[6.3.2.01,7]tridec-3-en-9-yl]-2-methyl-2,4-pentadienoic acid)
・Genistein(5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one)
・Fludarabine((2R,3S,4S,5R)-2-(6-amino-2-fluoropurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol)。
[4−1.投与形態および剤型]
本発明の一実施形態に係る白内障の予防剤または治療剤は、被験体に対して投与される。一実施形態において、上記被験体は、ヒトである。他の実施形態において、上記被験体は、ヒト以外の動物である。ヒト以外の動物の例としては、ヒト以外の哺乳類(ウシ、ブタ、ヒツジ、ヤギ、ウマ、イヌ、ネコ、ウサギ、マウス、ラットなど)が挙げられる。
本発明の一実施形態に係る白内障の予防剤または治療剤は、有効成分としてHIF経路阻害剤を含んでいる。本明細書において、「有効成分」とは、1つ以上の症状に対して予防効果または治療効果をもたらすことのできる物質を意図する。上記白内障の予防剤または治療剤に含まれる有効成分は、1種類であっても、2種類以上であってもよい。
本発明の一実施形態に係る白内障の予防剤または治療剤は、上述した有効成分、および、上述した有効成分以外の成分を原料として、公知の手法により製剤することができる。
6週齢のSDラット(三協ラボサービス製)の左右の眼球から、水晶体を摘出した。左右両眼から摘出した水晶体を、M199培地(SIGMA Aldrich製)に30mMのガラクトースを添加した培地にて3日間培養し、糖尿病白内障を発症させたモデルとした。その後、左眼の水晶体を、30mMのガラクトースおよび40μMの2-Methoxyeatradiol(HIF−1α阻害剤)を添加した培地に移した。一方、右眼の水晶体は培地を変更しなかった。
図4から明らかなように、2-Methoxyeatradiolを添加していない培地で培養した水晶体では、皮質部の白濁化が進行している。一方、2-Methoxyeatradiolを添加した培地で培養した水晶体では、皮質部の白濁が軽減されていた。このことから、2-Methoxyeatradiolには、白内障の治療効果があることが示唆される。
HIF経路阻害剤を25μMのYC-1(HIF−1α阻害剤)に変更した以外は、実施例1と同様の条件により、水晶体を培養した。培地変更時(培養開始から3日目)、および培地変更から3日目(培養開始から6日目)に、上記水晶体をそれぞれ培地から取り出し、SZX12(Olympas製)により20倍に拡大した顕微鏡写真を撮影した。それぞれの写真を図5に示す。
図5から明らかなように、YC-1を添加していない培地で培養した水晶体では、皮質部の白濁化が進行している。一方、YC-1を添加した培地で培養した水晶体では、皮質部の白濁が軽減されていた。このことから、YC-1には、白内障の治療効果があることが示唆される。
実施例1で培地に添加した2-Methoxyeatradiolと、実施例2で培地に添加したYC-1とは、HIF経路を阻害する(HIF−1αを阻害する)という機能上の共通点を有している。一方、これらの化学構造は、互いに大きく異なっている(下記化学式を参照)。このことから、HIF経路阻害剤に、白内障の治療効果があることが示唆される。
Claims (6)
- [5-(1-benzylindazol-3-yl)furan-2-yl]methanolを有効成分として含んでいる、白内障の予防剤または治療剤。
- 上記白内障は、糖尿病白内障である、請求項1に記載の白内障の予防剤または治療剤。
- 2−メトキシエストラジオールを有効成分として含んでいる、糖尿病白内障の予防剤または治療剤。
- 剤型が点眼剤である、請求項1〜3のいずれか1項に記載の白内障の予防剤または治療剤。
- 白内障の予防剤または治療剤を製造するための、[5-(1-benzylindazol-3-yl)furan-2-yl]methanolの使用。
- 糖尿病白内障の予防剤または治療剤を製造するための、2−メトキシエストラジオールの使用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017181717A JP6923917B2 (ja) | 2017-09-21 | 2017-09-21 | 白内障の予防剤および治療剤、ならびに、これらを製造するためのhif経路阻害剤の使用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017181717A JP6923917B2 (ja) | 2017-09-21 | 2017-09-21 | 白内障の予防剤および治療剤、ならびに、これらを製造するためのhif経路阻害剤の使用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019055925A JP2019055925A (ja) | 2019-04-11 |
JP6923917B2 true JP6923917B2 (ja) | 2021-08-25 |
Family
ID=66107087
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017181717A Active JP6923917B2 (ja) | 2017-09-21 | 2017-09-21 | 白内障の予防剤および治療剤、ならびに、これらを製造するためのhif経路阻害剤の使用 |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP6923917B2 (ja) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2305308A1 (en) * | 2003-04-18 | 2011-04-06 | Advanced Medicine Research Institute | Remedies for diseases to be applied to eye |
JP2011153156A (ja) * | 2011-05-12 | 2011-08-11 | Saisentan Igaku Kenkyusho:Kk | サーチュインの活性化剤を含む各種眼疾患治療用組成物 |
-
2017
- 2017-09-21 JP JP2017181717A patent/JP6923917B2/ja active Active
Also Published As
Publication number | Publication date |
---|---|
JP2019055925A (ja) | 2019-04-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2013299627B2 (en) | Methods of treating cancer using 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione | |
US10292962B2 (en) | Pharmaceutical combination comprising metformin and dihydroquercetin and its use for the treatment of cancer | |
CA3077362A1 (en) | Treatment of inflammatory disorders | |
JP7082162B2 (ja) | マイボーム機能不全の治療剤 | |
ES2743493T3 (es) | Composición para el tratamiento de células madre cancerosas | |
EP3458448B1 (en) | Fasn inhibitors for use in treating non-alcoholic steatohepatitis | |
KR20210071974A (ko) | 사이토카인 방출 증후군을 치료하는 방법 | |
RU2749952C2 (ru) | Депо-препарат, содержащий сложный эфир лимонной кислоты | |
Luo et al. | P-selectin glycoprotein ligand-1 deficiency leads to cytokine resistance and protection against atherosclerosis in apolipoprotein E deficient mice | |
TW201733574A (zh) | 脈絡膜新生血管抑制劑或隱結抑制劑及其評價或篩選方法 | |
US20200352937A1 (en) | Combination comprising at least one spliceosome modulator and at least one inhibitor chosen from bcl2 inhibitors, bcl2/bclxl inhibitors, and bclxl inhibitors and methods of use | |
KR20210045364A (ko) | 악성 림프증식성 장애를 치료하는 방법 | |
KR20190018486A (ko) | 암의 예방 및/또는 치료를 위한 화합물, 조성물 및 방법 | |
CN105616400A (zh) | 一类牛蒡子苷元氨基甲酸酯衍生物在制备用于治疗阿尔茨海默病的药物中的用途 | |
EP3220908B1 (en) | Compositions and methods for treating endometriosis | |
KR20200096781A (ko) | 말초 t-세포 림프종 및 피부 t-세포 림프종을 치료하기 위한 조성물 및 방법 | |
KR20200118840A (ko) | 신규한 APE1/Ref-1 저해제를 사용한 눈 질환의 표적화 | |
JP6923917B2 (ja) | 白内障の予防剤および治療剤、ならびに、これらを製造するためのhif経路阻害剤の使用 | |
JP6918839B2 (ja) | 概日時計の乱れに関連するマイクロバイオームの調節異常を処置するための方法及び医薬組成物 | |
WO2018079149A1 (ja) | 白内障の予防剤、治療剤、およびこれらを製造するためのhat阻害剤の使用 | |
JP6509244B2 (ja) | 水晶体硬化抑制剤 | |
WO2019039525A1 (ja) | Axl阻害剤を有効成分として含むがん治療剤 | |
US10098860B2 (en) | Bezafibrate for the treatment of cancer | |
TWI650141B (zh) | 包含奎寧鹽懸浮液的用於抗癌治療的局部給藥用注射劑組合物 | |
US20200281918A1 (en) | Calcium release-activated calcium channel modulators for treating hematological and solid cancers |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200413 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210413 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210603 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20210713 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210721 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6923917 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |