WO2007013147A1 - Inhibiteur de l’angiogenèse et agent de régression vasculaire - Google Patents
Inhibiteur de l’angiogenèse et agent de régression vasculaire Download PDFInfo
- Publication number
- WO2007013147A1 WO2007013147A1 PCT/JP2005/013713 JP2005013713W WO2007013147A1 WO 2007013147 A1 WO2007013147 A1 WO 2007013147A1 JP 2005013713 W JP2005013713 W JP 2005013713W WO 2007013147 A1 WO2007013147 A1 WO 2007013147A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- vascular
- dihydroxyphenylalanine
- hydrogen atom
- angiogenesis inhibitor
- angiogenesis
- Prior art date
Links
- 230000002792 vascular Effects 0.000 title claims abstract description 49
- 229940121369 angiogenesis inhibitor Drugs 0.000 title claims abstract description 44
- 239000004037 angiogenesis inhibitor Substances 0.000 title claims abstract description 44
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 38
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 title claims abstract description 37
- 230000001373 regressive effect Effects 0.000 title abstract 3
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical class OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- QLKZYHAMOAGABF-QMMMGPOBSA-N (2s)-2-(3-aminopropanoylamino)-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound NCCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C(O)=C1 QLKZYHAMOAGABF-QMMMGPOBSA-N 0.000 claims abstract description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 60
- 210000003556 vascular endothelial cell Anatomy 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 38
- 239000000126 substance Substances 0.000 claims description 35
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 125000000539 amino acid group Chemical group 0.000 claims description 19
- 210000004087 cornea Anatomy 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- 102000001938 Plasminogen Activators Human genes 0.000 claims description 16
- 108010001014 Plasminogen Activators Proteins 0.000 claims description 16
- 239000011159 matrix material Substances 0.000 claims description 16
- 229940127126 plasminogen activator Drugs 0.000 claims description 16
- 238000012216 screening Methods 0.000 claims description 16
- 238000012360 testing method Methods 0.000 claims description 16
- 108091005804 Peptidases Proteins 0.000 claims description 13
- 239000004365 Protease Substances 0.000 claims description 13
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 11
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 11
- 230000010261 cell growth Effects 0.000 claims description 10
- 230000035755 proliferation Effects 0.000 claims description 9
- 230000035605 chemotaxis Effects 0.000 claims description 8
- -1 β-alanyl Chemical group 0.000 claims description 8
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 7
- 230000026721 endothelial cell chemotaxis Effects 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- 102000013566 Plasminogen Human genes 0.000 claims description 4
- 108010051456 Plasminogen Proteins 0.000 claims description 4
- 229960003067 cystine Drugs 0.000 claims description 2
- 239000013598 vector Substances 0.000 claims description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 2
- 108700004568 N-beta-alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine Proteins 0.000 abstract description 50
- 230000033115 angiogenesis Effects 0.000 description 44
- 230000000694 effects Effects 0.000 description 43
- 210000004204 blood vessel Anatomy 0.000 description 34
- 150000001875 compounds Chemical class 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 24
- 208000011688 Generalised anxiety disease Diseases 0.000 description 19
- 208000029364 generalized anxiety disease Diseases 0.000 description 19
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 13
- 230000009471 action Effects 0.000 description 12
- 102000035195 Peptidases Human genes 0.000 description 11
- 210000002889 endothelial cell Anatomy 0.000 description 11
- 229940024606 amino acid Drugs 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 238000012258 culturing Methods 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108010010803 Gelatin Proteins 0.000 description 8
- 238000010586 diagram Methods 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 239000008273 gelatin Substances 0.000 description 8
- 229920000159 gelatin Polymers 0.000 description 8
- 235000019322 gelatine Nutrition 0.000 description 8
- 235000011852 gelatine desserts Nutrition 0.000 description 8
- 229910001961 silver nitrate Inorganic materials 0.000 description 8
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 7
- 229910002091 carbon monoxide Inorganic materials 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 7
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 7
- 238000013268 sustained release Methods 0.000 description 7
- 239000012730 sustained-release form Substances 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 206010012689 Diabetic retinopathy Diseases 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 6
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 210000002919 epithelial cell Anatomy 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 210000004379 membrane Anatomy 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 210000003786 sclera Anatomy 0.000 description 6
- 239000013589 supplement Substances 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 102000001301 EGF receptor Human genes 0.000 description 5
- 108060006698 EGF receptor Proteins 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 108091000080 Phosphotransferase Proteins 0.000 description 5
- 102000003923 Protein Kinase C Human genes 0.000 description 5
- 108090000315 Protein Kinase C Proteins 0.000 description 5
- 210000003711 chorioallantoic membrane Anatomy 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 102000020233 phosphotransferase Human genes 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 4
- 241000287828 Gallus gallus Species 0.000 description 4
- 208000010412 Glaucoma Diseases 0.000 description 4
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 4
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 4
- CAWNOJXNAUEIGB-UHFFFAOYSA-N cytogenin Chemical compound C1=C(CO)OC(=O)C=2C1=CC(OC)=CC=2O CAWNOJXNAUEIGB-UHFFFAOYSA-N 0.000 description 4
- 210000002308 embryonic cell Anatomy 0.000 description 4
- 229960002897 heparin Drugs 0.000 description 4
- 229920000669 heparin Polymers 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000002054 transplantation Methods 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- 230000029663 wound healing Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100037787 Protein-tyrosine kinase 2-beta Human genes 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000013592 cell lysate Substances 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- AZFLJNIPTRTECV-FUMNGEBKSA-N dienogest Chemical compound C1CC(=O)C=C2CC[C@@H]([C@H]3[C@@](C)([C@](CC3)(O)CC#N)CC3)C3=C21 AZFLJNIPTRTECV-FUMNGEBKSA-N 0.000 description 3
- 229960003309 dienogest Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 201000001371 inclusion conjunctivitis Diseases 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 235000008729 phenylalanine Nutrition 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 206010044325 trachoma Diseases 0.000 description 3
- 229960004441 tyrosine Drugs 0.000 description 3
- NGGMYCMLYOUNGM-UHFFFAOYSA-N (-)-fumagillin Natural products O1C(CC=C(C)C)C1(C)C1C(OC)C(OC(=O)C=CC=CC=CC=CC(O)=O)CCC21CO2 NGGMYCMLYOUNGM-UHFFFAOYSA-N 0.000 description 2
- LSIXBBPOJBJQHN-UHFFFAOYSA-N 2,3-Dimethylbicyclo[2.2.1]hept-2-ene Chemical compound C1CC2C(C)=C(C)C1C2 LSIXBBPOJBJQHN-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 102000009088 Angiopoietin-1 Human genes 0.000 description 2
- 108010048154 Angiopoietin-1 Proteins 0.000 description 2
- 102000019025 Calcium-Calmodulin-Dependent Protein Kinases Human genes 0.000 description 2
- 108010026870 Calcium-Calmodulin-Dependent Protein Kinases Proteins 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010055665 Corneal neovascularisation Diseases 0.000 description 2
- 101100481404 Danio rerio tie1 gene Proteins 0.000 description 2
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 2
- 244000187656 Eucalyptus cornuta Species 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 101100481406 Mus musculus Tie1 gene Proteins 0.000 description 2
- 208000022873 Ocular disease Diseases 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 102000003425 Tyrosinase Human genes 0.000 description 2
- 108060008724 Tyrosinase Proteins 0.000 description 2
- 206010047571 Visual impairment Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 206010064930 age-related macular degeneration Diseases 0.000 description 2
- 230000006229 amino acid addition Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 210000001142 back Anatomy 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 201000000159 corneal neovascularization Diseases 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000005038 ethylene vinyl acetate Substances 0.000 description 2
- 208000024519 eye neoplasm Diseases 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- NGGMYCMLYOUNGM-CSDLUJIJSA-N fumagillin Chemical compound C([C@H]([C@H]([C@@H]1[C@]2(C)[C@H](O2)CC=C(C)C)OC)OC(=O)\C=C\C=C\C=C\C=C\C(O)=O)C[C@@]21CO2 NGGMYCMLYOUNGM-CSDLUJIJSA-N 0.000 description 2
- 229960000936 fumagillin Drugs 0.000 description 2
- 238000007804 gelatin zymography Methods 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 208000014617 hemorrhoid Diseases 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 201000003142 neovascular glaucoma Diseases 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 2
- 208000004644 retinal vein occlusion Diseases 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000012723 sample buffer Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000001356 surgical procedure Methods 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
- 230000004614 tumor growth Effects 0.000 description 2
- 210000003606 umbilical vein Anatomy 0.000 description 2
- 208000029257 vision disease Diseases 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 230000004393 visual impairment Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WWERAMQGVZVWQW-LURJTMIESA-N (2S)-3-(3,4-dihydroxyphenyl)-2-nitramidopropanoic acid Chemical compound [N+](=O)([O-])N[C@H](C(=O)O)CC1=CC=C(O)C(O)=C1 WWERAMQGVZVWQW-LURJTMIESA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- VIYKYVYAKVNDPS-HKGPVOKGSA-N (2s)-2-azanyl-3-[3,4-bis(oxidanyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 VIYKYVYAKVNDPS-HKGPVOKGSA-N 0.000 description 1
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-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
- UPXRTVAIJMUAQR-UHFFFAOYSA-N 4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)OC(C)(C)C)CC1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-UHFFFAOYSA-N 0.000 description 1
- VVTNSTLJOVCBDL-UHFFFAOYSA-N 4-[[3,5-bis(trimethylsilyl)benzoyl]amino]benzoic acid Chemical compound C[Si](C)(C)C1=CC([Si](C)(C)C)=CC(C(=O)NC=2C=CC(=CC=2)C(O)=O)=C1 VVTNSTLJOVCBDL-UHFFFAOYSA-N 0.000 description 1
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 102000009075 Angiopoietin-2 Human genes 0.000 description 1
- 108010048036 Angiopoietin-2 Proteins 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 108010087765 Antipain Proteins 0.000 description 1
- 241000239290 Araneae Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 101001067249 Bos taurus Plasminogen Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000032544 Cicatrix 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
- 108010049894 Cyclic AMP-Dependent Protein Kinases 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
- 229920002307 Dextran Polymers 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
- 102000000564 Elongation Factor 2 Kinase Human genes 0.000 description 1
- 108010016831 Elongation Factor 2 Kinase Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102100021808 Eukaryotic elongation factor 2 kinase Human genes 0.000 description 1
- 101710110154 Eukaryotic elongation factor 2 kinase Proteins 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102000013382 Gelatinases Human genes 0.000 description 1
- 108010026132 Gelatinases Proteins 0.000 description 1
- 229930183217 Genin Natural products 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010076557 Matrix Metalloproteinase 14 Proteins 0.000 description 1
- 102100030216 Matrix metalloproteinase-14 Human genes 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010027457 Metastases to liver Diseases 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
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- MSHZHSPISPJWHW-UHFFFAOYSA-N O-(chloroacetylcarbamoyl)fumagillol Chemical compound O1C(CC=C(C)C)C1(C)C1C(OC)C(OC(=O)NC(=O)CCl)CCC21CO2 MSHZHSPISPJWHW-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 201000002154 Pterygium Diseases 0.000 description 1
- 206010037649 Pyogenic granuloma Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 201000007527 Retinal artery occlusion Diseases 0.000 description 1
- 208000006268 Sarcoma 180 Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010042033 Stevens-Johnson syndrome Diseases 0.000 description 1
- 231100000168 Stevens-Johnson syndrome Toxicity 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- ZKHQWZAMYRWXGA-KNYAHOBESA-N [[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] dihydroxyphosphoryl hydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)O[32P](O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KNYAHOBESA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 210000004712 air sac Anatomy 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 230000006427 angiogenic response Effects 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- SDNYTAYICBFYFH-TUFLPTIASA-N antipain Chemical compound NC(N)=NCCC[C@@H](C=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SDNYTAYICBFYFH-TUFLPTIASA-N 0.000 description 1
- 210000002403 aortic endothelial cell Anatomy 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical group NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 1
- 150000001576 beta-amino acids Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000034196 cell chemotaxis Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229930191753 cochlioquinone Natural products 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 208000021921 corneal disease Diseases 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000004299 exfoliation Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 229960004184 ketamine hydrochloride Drugs 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000029849 luteinization Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000012423 maintenance 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000013586 microbial product Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 229950010895 midostaurin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000008722 morphological abnormality Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- BSIZUMJRKYHEBR-QGZVFWFLSA-N n-hydroxy-2(r)-[[(4-methoxyphenyl)sulfonyl](3-picolyl)amino]-3-methylbutanamide hydrochloride Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N([C@H](C(C)C)C(=O)NO)CC1=CC=CN=C1 BSIZUMJRKYHEBR-QGZVFWFLSA-N 0.000 description 1
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
- 230000030505 negative regulation of chemotaxis Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 230000007727 signaling mechanism Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 108700026239 src Genes Proteins 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000004382 visual function Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- Angiogenesis inhibitors and vascular regression agents are included in angiogenesis inhibitors and vascular regression agents.
- the present invention relates to an angiogenesis inhibitor and a vascular regression agent.
- the present invention also relates to a method for screening an angiogenesis inhibitor.
- vascular endogenesis refers to a phenomenon in which new blood vessels, that is, new blood vessels, are formed from existing blood vessels.
- RTK receptor tyrosine kinase
- Angiopoietin 1 (Ang-1) is known to act on vascular endothelial cells through binding to Tie-2 to induce differentiation of juvenile blood vessels built by VEGF into more mature blood vessels.
- Ang-1 Angiopoietin 1
- Angiopoietin 2 (Ang— 2) is a physiological inhibitor in the Ang-1 / Tie-2 system. It is thought that there is, it works competitively with Ang_l and controls angiogenesis, morphological maintenance, etc. (PC Maisonpierre et al., Science, 277: 55-60 (1997)).
- Angiogenesis is observed in various physiological and pathological states in the living body.
- Angiogenesis in the physiological state is observed during luteinization, placenta formation, and the like.
- angiogenesis in a pathological state has been observed in inflammation, wound healing, tumor growth, etc.
- angiogenesis associated with diabetic retinopathy, post-lens fibrosis, corneal transplantation, etc. Glaucoma, eye tumors, trachoma, etc.
- the dermatology area for example, psoriasis, pyogenic granuloma, etc.
- pediatric area for example, hemangioma, fibroangioma, etc.
- Is for example, hypertrophic scars, granulations, etc., in the internal medicine region, for example, rheumatoid arthritis, edema sclerosis, etc., and for heart diseases, for example, atherosclerosis, etc.
- a pathological increase is observed.
- abnormal angiogenesis in diabetic retinopathy and trachoma drives many people blind, and in rheumatoid arthritis, abnormal angiogenesis in the joints destroys the cartilage in the joints. Wake up and annoy many people.
- angiogenesis is caused by various inflammatory diseases (rheumatic arthritis, psoriasis, etc.), various diseases in ophthalmology (diabetic retinopathy, retinopathy of prematurity, senile macular degeneration, retinal vein occlusion, later Lens fibroproliferation, angiogenesis associated with corneal transplantation, glaucoma, eye tumors, etc.) and various tumors.
- ophthalmology diabetic retinopathy, retinopathy of prematurity, senile macular degeneration, retinal vein occlusion, later Lens fibroproliferation, angiogenesis associated with corneal transplantation, glaucoma, eye tumors, etc.
- corneal diseases Stevens-Johnson syndrome and related diseases
- ocular acne and related diseases alkalis, acids, surfactants, various solvents, volatile gases, and other various cytotoxic substances.
- the angiogenesis inhibitors developed so far can be classified as follows.
- angiogenesis inhibitors have insufficient activity and have side effects such as toxicity, they are satisfactory as preventive or therapeutic agents for diseases involving angiogenesis. Development of a substance having an angiogenesis-inhibiting action superior to that of spiders is desired. In particular, in the field of ophthalmology, drugs must always be used with the goal of maintaining visual function, and the development of safe drugs that do not adversely affect other eye tissues is expected.
- corneal neovascularization is known to be involved in allograft rejection during corneal transplant surgery (Jpn. J. Ophthalmol., 38 (3), 311-316 (1994)), it is thought that rejection of a graft can be suppressed by inhibiting angiogenesis after corneal transplantation.
- the potential for treatment of ocular diseases with neovascularization with interferon is age-related macular degeneration (Fung, WE, J. ophthalmol., 112, 349 (1991)), neovascular glaucoma (Miller, JW et al., Ophthalmology) , 100, 9, (1992)), and diabetic retinopathy (Wakelee_Lynch, J.
- N_ ⁇ -alanyl_5_S-glutathionyl_3,4-dihydroxyphenylalanine is a known substance (Patent Document 3), and 5-S-GAD is It is known to have antitumor action (Patent Documents 3 and 4), apoptosis-inducing action (Patent Document 5), osteoclast formation inhibitory action (Patent Document 5), and the like.
- Non-Patent Document 1 Ingber D et al., “Nature”, 1990, No. 348, No. 6301, p.555-557
- Non-Patent Document 2 Jung HJ et al., “Bioorganic & Medicinal Chemistry”, 2003, No. 11, No. 22, ⁇ .4743-4747
- Non-Patent Document 3 Nakamura (Nakamura) ES, etc., “Cancer Science”, 2004, No. 95, No. 1, ⁇ .25-31
- Non-Patent Document 4 Penn JS et al., “Investigative Ophthalmology and Visual Science”, 2003, 4th 4th, p.5423-5429
- Non-Patent Document 5 Ozaki H et al., “American Journal of Pathology”, 2000, No. 156, No. 2, ⁇ .697-707
- Patent Document 1 JP-A-1 279828
- Patent Document 2 Japanese Patent Laid-Open No. 2003-26696
- Patent Document 3 Japanese Patent Laid-Open No. 8-337594
- Patent Document 4 Japanese Patent Laid-Open No. 2001-213799
- Patent Document 5 Japanese Patent Laid-Open No. 2001-226283
- An object of the present invention is to provide a novel angiogenesis inhibitor and a vascular regression agent.
- Another object of the present invention is to provide a screening method for a novel angiogenesis inhibitor.
- the present invention provides the following angiogenesis inhibitors, vascular regression agents, and methods for screening for angiogenesis inhibitors.
- R 1 represents a hydrogen atom or an arbitrary amino acid residue
- R 2 represents a hydrogen atom or the following formula ( ⁇ ):
- R 3 represents a hydrogen atom or any amino acid residue
- R 4 represents a hydroxyl group or any amino acid residue
- n represents 1 or 2.
- An angiogenesis inhibitor comprising, as an active ingredient, a 3,4-dihydroxyphenyllauran derivative represented by the formula: or a pharmaceutically acceptable salt thereof.
- the angiogenesis inhibitor according to the above (1) or (2) which is an ocular angiogenesis inhibitor.
- R 1 represents a hydrogen atom or any amino acid residue
- R 2 represents a hydrogen atom or the following formula ( ⁇ ):
- R 3 represents a hydrogen atom or an arbitrary amino acid residue
- R 4 represents a hydroxyl group or any Amino acid residue
- n represents 1 or 2.
- a vascular regression agent comprising, as an active ingredient, a 3,4-dihydroxyphenyllauranin derivative represented by the formula: or a pharmaceutically acceptable salt thereof.
- the vascular regression agent according to (5) or (6) above which is an ocular vascular regression agent.
- vascular retraction agent which is a corneal vascular retraction agent.
- Test substance is vascular regression, vascular endothelial cell growth inhibitory, vascular endothelial cell luminal formation inhibitory, vascular endothelial cell chemotaxis inhibitory, matrix meta-mouth protease inhibitory, plasminogen activator Step of determining whether or not it has vector inhibitory activity and receptor type tyrosine kinase inhibitory activity
- b Has vascular regression, inhibits proliferation of vascular endothelial cells, inhibits luminal formation of vascular endothelial cells, inhibits chemotaxis of vascular endothelial cells, inhibits matrix metamouth protease, plasminogen Screening for substances that have no inhibitory activity on the inhibitor and receptor type tyrosine kinase
- the angiogenesis inhibitor and the vascular regression agent provided by the present invention can inhibit angiogenesis based on a mechanism different from conventional angiogenesis inhibitors.
- angiogenesis inhibitors have an inhibitory effect on vascular endothelial cell proliferation, an inhibitory effect on vascular endothelial cell lumen formation, an inhibitory action on vascular endothelial cell chemotaxis, an inhibitory action on matrix metabolite protease, a plasminogen It exerts angiogenesis inhibitory action based on one or more kinds of actions such as inhibitory action of cuticle and receptor type tyrosine kinase.
- the angiogenesis inhibitor and the vascular regression agent of the present invention have an inhibitory action on vascular endothelial cell proliferation, an inhibitory action on luminal formation of vascular endothelial cells, an inhibitory action on chemotaxis of vascular endothelial cells, and an inhibition of matrix metamouth protease
- it does not have any of the actions, plasminogen activator beta inhibitory action and receptor type tyrosine kinase inhibitory action, it can inhibit angiogenesis based on the vascular regression action. Therefore, the angiogenesis inhibitor and the vascular regression agent of the present invention can be administered for a long time without causing the possibility of delaying wound healing caused by excessively suppressing the proliferation of vascular endothelial cells.
- Fig. 1 shows the results of measuring the number of cells by the Coulter Counter method after culturing HUVEC in the presence of 5-S-GAD. b) shows the results of measuring the mitochondrial metabolic activity by the MTT method after culturing HUVEC in the presence of 5-S-GAD.
- FIG. 2 is a diagram showing the results of measuring the number of cells by the Coulter counter method after culturing HUVEC in the presence of 5_S-GAD.
- FIG. 3 is a diagram showing the results of observation of tube formation after culturing HUVEC in the presence of 5_S-GAD.
- FIG. 4 shows the results of measuring extracellular plasminogen activity after culturing HUVEC in the presence of 5-S-GAD
- FIG. 4 (b) shows the results of measuring cell adhesion plasminogen activator activity after culturing HUVEC in the presence of 5-S-GAD.
- FIG. 5 is a diagram showing the results of detecting MMP-2 precursor and MMP-9 precursor after culturing HUVEC in the presence of 5_S-GAD.
- FIG. 6 is a diagram showing the results of measuring cell chemotaxis after culturing HUVEC in the presence of 5-S-GAD.
- FIG. 7 is a diagram showing the results of detecting PKA activity, PKC activity, eE F 2K activity and PTK activity after treating a cell lysate with 5-S-GAD.
- FIG. 8 is a graph showing the results of measuring EGF receptor tyrosine kinase activity after treating the membrane fraction with 5-S-GAD.
- FIG. 9 is a diagram showing the results of detecting VEGF receptor tyrosine kinase activity after treating the membrane fraction with 5-S-GAD.
- Fig. 10 shows blood vessels that are directed to the corneal epithelial cell exfoliated part from the outer edge of the cornea in the 5-S-GAD administered group or the control group after exfoliating the corneal epithelial cells of the sputum and stimulating with silver nitrate It is a figure which shows the result of having observed the newborn.
- FIG. 11 is a diagram showing the results of measuring the number of new blood vessels after 5-S-GAD administration by the mouse dorsal subcutaneous method.
- FIG. 12 is a view showing the state (thickness) of an existing blood vessel after administration of 5-S-GAD.
- FIG. 13 (a) is a diagram showing the results of observing the state of blood vessels after 5-S-GAD treatment by the chicken embryo chorioallantoic membrane method, and FIG. It is a figure which shows the result of having evaluated the presence or absence of the newborn inhibitory effect.
- Arbitrary amino acid residues represented by R 3 or R 4 include any type of amino acid residues.
- Examples of amino acid residues represented by R 1 R 3 or R 4 include ⁇ -amino acid residues. Groups, ⁇ -amino acid residues, ⁇ -amino acid residues, neutral amino acids (monoamino mono-functional norlevonic acid such as glycine, phosphorus, leucine), acidic amino acids (glutamic acid, aspartic acid, etc.) Minodicarboxylic acid) residues, basic amino acids (diaminomonocarboxylic acids such as arginine and phenylalanine) and the like.
- the binding mode of any amino acid residue represented by R 1 R 3 or R 4 is an amide bond.
- the amino acid residue represented by R 1 is preferably a ⁇ -alanine residue, and the amino acid residue represented by R 3 is preferably a glutamic acid residue, represented by R 4.
- the amino acid residue is preferably a glycine residue, and ⁇ is preferably 1.
- the 3,4-dihydroxyphenylalanine derivative (compound (1)) represented by formula (I) is preferably ⁇ - ⁇ -alanyl-5-S glutathionyl-3,4-dihydroxy. It is phenylalanine (5-S-GAD), ⁇ -alanil-3,4-dihydroxyphenylalanine-AD) or 5-S cystinelu 3,4-dihydroxyphenylalanine (5-S-CD).
- compound (I) is 5-S-GAD
- R 1 is a; 3-alanine residue
- R 2 is a group represented by the formula (II)
- R 3 is a gnoretamine residue
- R 4 is glycine.
- n 1, when compound (I) is ⁇ -AD, R 1 is an alanine residue, R 2 is a hydrogen atom, and compound (I) is 5 —S—CD, R 1 is a hydrogen atom, R 2 is a group represented by the formula ( ⁇ ), R 3 is a hydrogen atom, R 4 is a hydroxyl group, and n is 1.
- an asymmetric carbon exists in the compound (I), the configuration of the asymmetric carbon is not particularly limited, and may be either S or R configuration.
- compound (I) exists as an isomer based on one or more asymmetric carbons, compound (I) can be any stereoisomerically pure isomer (optical isomer, diastereoisomer). Etc.), a mixture of arbitrary isomers, a racemate and the like.
- Examples of the pharmaceutically acceptable salt of compound (I) include acid addition salts, base addition salts, amino acid addition salts, and the like.
- acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate, formate, acetate, oxalate, benzoate, methanesulfonate, ⁇ _Toluene sulfonate, maleate, fumarate, tartrate, citrate, succinate, organic acid salts such as lactate, etc.
- base addition salts include sodium salt, potassium, for example Metal salts such as salts, magnesium salts, calcium salts, and amine salts such as ammonium salts, methylamine salts, and triethylamine salts.
- amino acid addition salts include glycine, phenylalanine, aspartic acid, and glutamic acid. With Salting can be mentioned.
- Compound (I) is produced, for example, using 3, 4-dihydroxyphenylalanine (Dopa) as a starting material and utilizing amino acid condensation synthesis method, enzyme treatment method, liquid phase peptide synthesis method, etc. This comes out.
- Dopa 4-dihydroxyphenylalanine
- a specific production method of the compound (I) is as follows.
- a certain compound (I) can be produced.
- 1N hydrochloric acid is added to the reaction mixture, and after extraction with ethyl acetate under acidic conditions, the ethyl acetate layer is concentrated under reduced pressure. This can be done by collecting the precipitated crystals and subjecting them to HPLC treatment.
- R 1 is a hydrogen atom and R 2 is a group represented by the formula (II)
- Compound (I) can be produced. Purification of compound (I) from the reaction solution can be performed by HPLC treatment.
- n is as defined above.
- S-GAD is the force to collect body fluid after wounding and rearing adult Scarlet fly, homogenized and used as a raw material, which is separated by ion column chromatography and reversed-phase HP LC. It can also be obtained by subjecting to fractionation and collecting a fraction having antibacterial activity.
- Compound (I) has an angiogenesis inhibitory action and a vascular regression action.
- Compound (I) can relieve blood vessels and inhibit angiogenesis based on a vascular retraction effect.
- the angiogenesis inhibitory action of compound (I) is not limited to the action based on the vascular regression action.
- Compound (I) inhibits the proliferation of vascular endothelial cells, inhibits the formation of lumens of vascular endothelial cells, inhibits the chemotaxis of vascular endothelial cells, inhibits matrix meta-mouth protease, and inhibits plasminogen activator. And angiogenesis can be inhibited on the basis of the vascular retraction action, although it does not have any action of inhibiting the receptor tyrosine kinase. Therefore, Compound (I) has an excessive effect on inhibiting the proliferation of vascular endothelial cells. Therefore, it can be administered for a long period of time without the risk of causing a delay in wound healing.
- the angiogenesis inhibitor and the vascular regression agent of the present invention may be composed only of the compound (I), but usually usually together with one or more pharmaceutically acceptable carriers and Z or additives. Formulated according to law. When formulating, the compounding amount of compound (I) can be adjusted as appropriate.
- Examples of the pharmaceutically acceptable carrier include water, pharmaceutically acceptable organic solvents, collagen, polybutyl alcohol, polybutyl pyrrolidone, carboxyvinyl polymer, sodium alginate, water-soluble dextran. , Sodium carboxymethyl starch, pectin, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petroleum jelly, paraffin, stearyl alcohol, stearic acid, human serum anolebumin, mannitol, sorbitol, ratatoose Etc.
- additives used in the formulation include excipients, binders, lubricants, dispersants, suspending agents, emulsifiers, buffers, antioxidants, preservatives, and isotonic agents. PH regulators, solubilizers, stabilizers, and the like. These additives can be appropriately selected according to the dosage unit form of the preparation.
- routes of administration include oral administration and parenteral administration such as intracerebral, intraperitoneal, intraoral, intratracheal, intrarectal, subcutaneous, intramuscular and intravenous.
- routes of administration include oral administration and parenteral administration such as intracerebral, intraperitoneal, intraoral, intratracheal, intrarectal, subcutaneous, intramuscular and intravenous.
- examples include tablets, granules, capsules, powders, solutions, suspensions, syrups, sprays, ribosomes, emulsions, suppositories, injections, eye drops, ointments, tapes.
- oral administration and parenteral administration such as intracerebral, intraperitoneal, intraoral, intratracheal, intrarectal, subcutaneous, intramuscular and intravenous.
- examples include tablets, granules, capsules, powders, solutions, suspensions, syrups, sprays, ribosomes, emulsions, suppositories, injections
- tissue in which the angiogenesis inhibitor and the vascular regression agent of the present invention can exert an angiogenesis inhibitory effect and vascular regression activity is not particularly limited, but it is excellent in the eye, particularly in the cornea. Angiogenesis inhibitory action and vascular regression action can be exerted.
- the angiogenesis inhibitor and the vascular regression agent of the present invention are used as injections, and directly injected into a diseased tissue such as cornea or vitreous body or adjacent tissue with a thin injection needle. You can do it. It can also be administered as an intraocular perfusate using a pump or the like. Further, by pre-impregnating the angiogenesis inhibitor and the vascular regression agent of the present invention as components of contact lenses, administration to the eye including the cornea can be performed.
- the sclera is a thin avascular layer of highly ordered collagen network surrounding most of the vertebrate eye circumference. Because the sclera is avascular, injections that do not inherently pose a risk of bleeding can be quickly lost from the eye. Thus, the sclera can be used as a natural drug storage location. In addition, by using the sclera as a natural drug storage location, it is possible to supply drugs to the underlying tissue.
- the angiogenesis inhibitor and the vascular regression agent of the present invention are, for example, incorporated into a sustained-release polymer pellet or microcapsule to form a sustained-release agent, and the sustained-release agent is surgically inserted into the tissue to be treated. Can be transplanted.
- sustained-release polymers include ethylene vinyl acetate, polyhydrometatalylate, polyacrylamide, polyvinyl pyrrolidone, methyl cellulose, lactic acid polymer, and lactic acid / glycolic acid copolymer.
- biodegradable polymers Lactic acid polymers and lactic acid glycolic acid copolymers are preferred. Examples that can be referred to when using sustained-release agents include the use of inserts and implants (US Pat. No.
- An insert is a device inserted on the eye, such as on the conjunctival layer, which generally consists of a polymer matrix containing the active compound.
- the angiogenesis inhibitor and the vascular regression agent of the present invention can be administered to mammals including humans.
- the dose of the angiogenesis inhibitor or the vascular regression agent of the present invention should be appropriately increased or decreased according to the conditions such as the age, sex, weight, symptoms, and administration route of the patient.
- the drug of the above dosage may be administered every day or may be administered at intervals of several days, for example:!
- the angiogenesis inhibitor or vascular regression agent of the present invention can be used in combination with other drugs, and the dosage in that case is the same as above.
- the angiogenesis inhibitor and the vascular regression agent of the present invention may be used for diseases involving angiogenesis, such as , Diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis, ocular diseases such as corneal neovascularization, solid tumors It can be used as a prophylactic or therapeutic agent for cancer diseases such as hemangioma, tumor growth and metastasis.
- diseases involving angiogenesis such as , Diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis, ocular diseases such as corneal neovascularization, solid tumors
- cancer diseases such as hemangioma, tumor growth
- the test substance is a vascular regression action, a vascular endothelial cell proliferation inhibitory action, a vascular endothelial cell lumen formation inhibitory action, a vascular endothelial cell chemotaxis inhibitory action, a matrix metamouth.
- a protease inhibitory action a plasminogen activator inhibitory action and a receptor tyrosine kinase inhibitory action can be determined by known methods of in vitro or in vivo systems. In in vitro methods, for example, vascular endothelial cells derived from human, ushi, mouse, rat, etc.
- a membrane fraction of a cell expressing a desired receptor (for example, a host cell into which an expression vector having a desired receptor gene has been introduced) can be used.
- mammals such as ushi, hidge, goat, horse, pig, usagi, inu, cat, rat and mouse can be used as model animals.
- test substance when the test substance can reduce, for example, the number of blood vessels, the thickness of the blood vessels, the length of the blood vessels, etc., it is possible to determine that the test substance has a vascular retraction action. it can.
- the concentration of the test substance is usually 10 ⁇ M or less, preferably 50 ⁇ ⁇ or less, more preferably 100 a ⁇ or less, the test is conducted when the growth of vascular endothelial cells is not inhibited. It can be determined that the substance has no vascular endothelial cell growth inhibitory action.
- the concentration of the test substance is usually 10 ⁇ or less, preferably 50 ⁇ or less, more preferably 100 ⁇ or less, the lumen formation of vascular endothelial cells is not inhibited. Sometimes it can be determined that the test substance has no inhibitory effect on the formation of vascular endothelial cells.
- the concentration of the test substance is usually 10 ⁇ or less, preferably 50 ⁇ or less, more preferably 100 ⁇ or less, vascular endothelial cell chemotaxis is achieved. Can be discriminated as having no inhibitory effect on the chemotaxis of vascular endothelial cells.
- the concentration of the test substance is usually 10 ⁇ M or less, preferably 50 ⁇ or less, more preferably 100 ⁇ or less, when the matrix metaprotease activity is not inhibited.
- concentration of the test substance is usually 10 ⁇ M or less, preferably 50 ⁇ or less, more preferably 100 ⁇ or less, when the matrix metaprotease activity is not inhibited.
- the test substance does not have a matrix meta-oral protease inhibitory action.
- “Matrix meta-oral protease” includes various types of matrix meta-oral proteases as long as they are related to angiogenesis. For example, the gelatinase group ( ⁇ ⁇ -2, ⁇ -9) that degrades the basement membrane. ), MP-3, MMP-14, etc. that activate these are included.
- plasminogen activator activity is inhibited when the concentration of the test substance is usually 10 ⁇ M or less, preferably 50 ⁇ or less, more preferably 100 ⁇ or less. If not, it can be determined that the test substance has no plasminogen activator inhibitory action.
- the concentration of the test substance is usually 10 / ig / mL or less, preferably 50 ⁇ g / mL or less, more preferably 100 ⁇ g / mL or less, receptor type 1 tyrosine kinase activity. Can be discriminated as having no inhibitory effect on the receptor type thymosine kinase.
- “Receptor-type thymosine kinase” includes various types of receptor-type thyrosin kinase as long as it is involved in angiogenesis. For example, EGF receptor, FGF receptor, VEGF receptor (Flt _ l, Flk_ l), PDGF receptor, etc.
- the screening method of the present invention has a vascular retraction effect, inhibits the proliferation of vascular endothelial cells, inhibits luminal formation of vascular endothelial cells, inhibits chemotaxis of vascular endothelial cells, inhibits matrix meta-mouth protease N- ⁇ -alanyl-5 _S _Dartathonyl-3,4-dihydroxyphenylalanine-like angiogenesis inhibition of substances that do not have plasminogen activator inhibitory activity or receptor tyrosine kinase inhibitory action It can be screened as a substance.
- ⁇ _ ⁇ -Varanyl-1 5 _ S _Dartathonyl-3, 4-dihydroxyphenylalanine-like angiogenesis inhibitor means 5-S— Like GAD, blood vessel endothelial cell growth inhibitory action, blood Inhibition of luminal formation of vascular endothelial cells, inhibition of chemotaxis of vascular endothelial cells, inhibition of matrix metalloprotease, inhibition of plasminogen activator and inhibitor of receptor type 1 tyrosine kinase Despite not having it, it is a substance that can inhibit angiogenesis based on vascular regression.
- a 5-S-GAD-like angiogenesis inhibitor can be administered for a long period of time because there is no risk of causing delayed wound healing caused by excessively suppressing the proliferation of vascular endothelial cells.
- Example 1 is known literature (Nakamura M, Katsuki Y, Shibutani Y, Oikawa T. Dienogest, a synthetic steroid, suppresses both embryonic and tumor-cell-induced angiogenes is.Eur J Pharmacol.386, 33-40 (1999). ).
- HUVEC human umbilical vein endothelial cells (10 3 cells / well) was seeded on a gelatin-coated 24-well plate and cultured at 37 ° C, 5% CO for 4 hours.
- HUVEC culture complete medium (MCDB131 (Sigma), 10% fetal bovine serum, 1% antibiotic (10,000 U / ml penicillin and 10,000 ⁇ g / ml streptomycin mixture) (Manufactured by GIBCO)), 10 ⁇ gZmL endothelial cell growth supplement (Upstate Biotechnology Sento), 10ng / mL epidermal growth factor, 10 ⁇ g / mL heparin) It was. Then, 5-S-GAD (0 xM, 0. ⁇ , 0. ⁇ , ⁇ , ⁇ , ⁇ ) was added, and further cultured at 37 ° C, 5% CO for 72 hours. After culture, trypsin HUVEC
- Fig. 1 (a) The results are shown in Fig. 1 (a).
- HUVE C was cultured in the same manner as described above using a complete medium with a concentration of 1% fetal bovine serum, and the number of cells was measured by a Coulter counter method. The result is shown in figure 2.
- HUVEC (10 4 cells / well) was seeded in a gelatin-coated 96-well plate and cultured at 37 ° C and 5% CO for 4 months. Then, 5-S-GAD (0 M, 0.01 / iM, 0. ⁇ , 1 / i
- Mitochondrial metabolic activity was measured by the MTT method. The results are shown in Fig. 1 (b). As shown in Fig. 1 and Fig. 2, 5-S-GAD did not affect HU VEC proliferation at concentrations below ⁇ ⁇ .
- Example 2 is a known document (Oikawa T, Sasaki M, Inose M, Shimamura M, Kuboki H, Hi rano S, Kumagai H, Ishizuka M, Takeuchi T. Effects of cytogenin, a novel microbial product, on embryonic and tumor cell. -induced angiogenic responses in vivo. Anticancer Res. 17, 1881-1886 (1997)).
- FIG. 3 A, B, C, and D show the results when the concentration of 5-S-GAD is 0 ⁇ M, 1 ⁇ , 10 ⁇ M, and 100 ⁇ , respectively.
- 5-S-GAD did not inhibit HUVEC tube formation at concentrations below 100 ⁇ ⁇ .
- Example 3 is a known literature (Nakamura M, Katsuki Y, Shibutani Y, Oikawa T. Dienogest, a synthetic steroid, suppresses both embryonic and tumor—cell—induced angiogenes is. Eur J Pharmacol. 386, 33-40 (1999). ).
- Plasminogen activator activity includes ubiquitinogen (bovine plasminogen) and H—D—Val—Leu—Lys—p—nitroanilide 0 ⁇ 1 M Tris / HCl
- the sample was added to (pH 7.4), incubated at 37 ° C, and quantified by measuring the released P-nitrotrolide based on the absorbance at 405 nm.
- 5-S-GAD did not inhibit plasminogen activator activity at concentrations below 100 ⁇ .
- Example 4 is known literature (Nakamura M, Katsuki Y, Shibutani Y, Oikawa T. Dienogest, a synthetic steroid, suppresses both embryonic and tumor-cell-induced angiogenes is. Eur J Pharmacol. 386, 33-40 (1999). ).
- MCDB131 manufactured by Sigma
- 10 ⁇ g / mL endothelial cell growth supplement manufactured by Upstate Biotechnology
- 10 gZmL ⁇ , 5 A medium supplemented with S-GAD (0 M, 0.01 ⁇ M, 0.1 ⁇ M, 1 ⁇ M, ⁇ , 100 ⁇ ) was added and cultured for 18 hours.
- the culture supernatant was collected and centrifuged, and the ⁇ -2 activity and 9-9 activity of the supernatant were analyzed by a gelatin-zymography method.
- the gelatin zymography method is a method for detecting the activity of MMP by utilizing gelatin, which is a denatured product of collagen, as a substrate for many MMPs.
- gelatin is mixed with SDS-polyacrylamide electrophoresis gel and a sample containing MMP is separated on this gel and then subjected to an enzymatic reaction, MMP moves through the gel by a fixed distance depending on the size of the molecule. Place It stays in and breaks down the gelatin. Therefore, after the reaction, when the gel is dyed with a protein stain, only the portion where MMP is present is dyed and becomes a transparent gel, and the activity of MMP is detected. The results are shown in FIG.
- Example 5 is a known literature (Oikawa T, Murakami K, Sano M, Shibata J, Wierzba K, Yamada Y. A potential use of a synthetic retinoid TAC-101 as an orally active agent t hat blocks angiogenesis in liver metastases of Human stomach cancer cells. Jpn J Cancer Res., 92, 1225-1234 (2001)).
- HUVEC (4.5 X 10 5 cells / mL, 2 mU) was seeded on a 35 mm culture dish (IWAKI) and cultured for 24 hours, and then 0.1% sushi serum was added to MCDB131 (Sigma).
- Culture medium supplemented with albumin, 10 ig / mL endothelial cell growth supplement, 10 ig / mL heparin and 5-S-GA ⁇ (0 ⁇ , 0. ⁇ , 0.
- Example 6 is a known document (Fukazawa H, Li PM, Mizuno S, Uehara Y. Method for simu Itaneous detection of protein kinase A, protein kinase C, protein tyrosine kinase, an d calmodulin-dependent protein kinase activities.Analy Biochem., 212, 106-110 (199
- Mouse NIH3T3 cells expressing the v_src oncogene were treated with hypotonic buffer (ImM Hepes-NaOH (pH7.4), 5 mM MgCl, 25 ⁇ g / mL antipain, leupe).
- hypotonic buffer ImM Hepes-NaOH (pH7.4), 5 mM MgCl, 25 ⁇ g / mL antipain, leupe).
- the cell lysate was prepared by stirring for 1 minute with a vortex mixer. The cell lysate was centrifuged at 500 ⁇ g for 5 minutes at 4 ° C., and the centrifuged supernatant was recovered as the enucleated fraction. Add an appropriate amount of reagent to the enucleated fraction, protein concentration lmg / mL, 20 mM Hepes—NaOH (pH 7.
- PKA protein kinase 8
- PLC protein kinase ⁇
- eEF _ 2KJ eEF-2 kinase (eukaryotic elongation factor 2 kinase; calmodulin-dependent protein kinase ⁇ )
- ⁇ indicates the position of tyrosine kinase.
- the disappearance of the band represents inhibition of activity.
- Example 7 is a known document (Hanai N, Nores G, Torres-Mendez C, Hakomori S. Modifie d ganglioside as a possiole modulator of transmembrane signaling mechanism through growth factor receptors: a preliminary note. Biochem Biophys Res Commun, 147, 1 27-134 (1987); Bertics PJ, Gill GN. Self-phosphoylation enhances the protein-tyr osine kinase activity of the epidermal growth factor receptor. J Biol Chem, 260, 146 42-14647 (1985)) It was.
- a membrane fraction was prepared from A431 (human epidermoid carcinoma) cells. 15 ⁇ L reaction
- EGF EGF receptor tyrosine kinase inhibitor AG1 478 (0. 001, 0. l ig / mL), 25.
- 5 ⁇ L [ ⁇ - 32 P]
- a TP 5 iCi / assay; l / iM
- the reaction was stopped and the supernatant was spotted on P81 cellulose paper (Whatman) After washing, the radioactivity was measured with a scintillation counter 1. The results are shown in FIG.
- 5-S-GAD did not inhibit EGF receptor tyrosin kinase activity at concentrations below ⁇ .
- Example 8 is from Koyaguchi (Sawano A, Takahashi T, Yamagucni S, Shibuya M. Tne pho sphorylated 1169-tyrosine containing region of flt-l kinase (VEGFR-l) is a major binding site for PL and gamma. Biochem Biophys Res Commun., 238, 487-491 (1997) was used as a reference.
- kinase assay buffer (5 OmM HEPES (pH7.4)) supplemented with 5_S_GAD (10xgZmL, 100 ⁇ gZmU or VEGF receptor tyrosine kinase inhibitor SU4984 (1 ⁇ g / mL, 10 ⁇ g / mL) , 0.1% Triton X-100, lOmM MnCl, 2mM MgCl,
- the disappearance of the band represents inhibition of VEGF receptor tyrosine kinase activity.
- the corneal epithelial cells in the silver nitrate application part were peeled off to expose the corneal surface, and silver nitrate filter paper was applied to the corneal surface for 1 minute 30 seconds. Immediately after application, it was washed with 10 mL of physiological saline. Immediately after that, 5 _S _GAD (5 _S _GAD administration group) or physiological saline (control group) was applied to each cornea using 50 ⁇ L of both corneas using an Eppendorf micropipette. An ointment (manufactured by Santen Pharmaceutical) was administered. Two weeks from the next day, 50 ⁇ L each of 5_S-GAD or physiological saline was instilled into the corneas of each group 4 times a day.
- neovascular model hemorrhoids 7 days before, 5 _S _GAD or physiological saline was applied to both corneas 50 times a day for 4 times a day, and neovascular model hemorrhoids were prepared by the method described above. Used to observe angiogenesis over time. At that time, the number of new blood vessels in the sample eye of each group was counted and scored as follows.
- ⁇ The number of blood vessels that do not reach the corneal epithelial cell exfoliation part from the outer edge of the cornea (however, blood vessels having a length of 1/4 or more of the distance from the outer edge of the cornea to the center of the cornea were targeted).
- Table 1 shows the scores after 1 week and 3 weeks in each group.
- Tumor cells S180; Sarcoma 180 tumor cell line) 0.1 5 mL (2 X 10 7 ) with a Millipore filter (pore size: 0.45 xm, Mil lipore) on both sides of the Millipore ring (Millipore) Cell Z chamber 1) was injected. Air was injected into the dorsum of the anaesthetized mouse (15-week-old female ICR mouse) subcutaneously from the dorsum. The skin was incised and a chamber was inserted into the head of the air injection part, and the insertion site was closed. One implant 1, 2, 3, 4 day chamber, site genin (C yt 0 g en i n ) (100mg / kg body weight) or 5- S- GAD (12.
- site genin C yt 0 g en i n
- the ip was administered.
- the back of an anesthetized mouse was incised around the chamber, and the skin was peeled off.
- a rubber packing of the same type as the ring was placed on the skin-contacting part of the chamber.
- the number of new blood vessels having a length of 3 mm or more was measured with a stereomicroscope. The results are shown in FIG.
- FIG. 12 administration of 5-S-GAD made existing blood vessels thinner.
- Figure 12 (a) is PBS treatment, (b) is cytogenin treatment, (c) is 5-S-GAD (200mg / kg) treatment, (d) is 5-S-GAD (50mg / kg). Represents a process.
- the chicken embryo chorioallantoic membrane (CAM) method was performed as follows.
- 5-S-GAD inhibited angiogenesis in chicken embryos. Further, as shown in FIG. 13 (b), the inhibition of angiogenesis by 5-S-GAD was dose-dependent.
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
La présente invention concerne un nouvel inhibiteur de l’angiogenèse et un nouvel agent de régression vasculaire. L’inhibiteur de l’angiogenèse et l’agent de régression vasculaire comprennent chacun un dérivé de la 3,4-dihydroxyphénylalanine tel que N-β-alanyl-5-S-glutathionyl-3,4-dihydroxyphénylalanine, β-alanyl-3,4-dihydroxyphénylalanine et 5-S-cystéinyl-3,4-dihydroxyphénylalanine ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/JP2005/013713 WO2007013147A1 (fr) | 2005-07-27 | 2005-07-27 | Inhibiteur de l’angiogenèse et agent de régression vasculaire |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/JP2005/013713 WO2007013147A1 (fr) | 2005-07-27 | 2005-07-27 | Inhibiteur de l’angiogenèse et agent de régression vasculaire |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007013147A1 true WO2007013147A1 (fr) | 2007-02-01 |
Family
ID=37683055
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2005/013713 WO2007013147A1 (fr) | 2005-07-27 | 2005-07-27 | Inhibiteur de l’angiogenèse et agent de régression vasculaire |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2007013147A1 (fr) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01279828A (ja) * | 1988-01-19 | 1989-11-10 | Takeda Chem Ind Ltd | 脈管形成阻止剤 |
JPH08337594A (ja) * | 1995-06-13 | 1996-12-24 | Sanwa Kagaku Kenkyusho Co Ltd | 新規化合物及びその用途 |
JP2001213799A (ja) * | 2000-01-28 | 2001-08-07 | Inst Of Physical & Chemical Res | 抗腫瘍剤 |
JP2001226283A (ja) * | 2000-02-17 | 2001-08-21 | Inst Of Physical & Chemical Res | 5−s−gadを有効成分とするアポトーシス誘導剤 |
JP2001278785A (ja) * | 2000-03-30 | 2001-10-10 | Inst Of Physical & Chemical Res | 骨疾患の治療剤 |
WO2003070269A1 (fr) * | 2002-02-18 | 2003-08-28 | Cevec Pharmaceuticals Gmbh | Traitement de maladies de l'oeil, de l'oreille interne et du systeme nerveux central |
JP2005213159A (ja) * | 2004-01-27 | 2005-08-11 | Inbiotex:Kk | 血管新生阻害剤及び血管退縮剤 |
-
2005
- 2005-07-27 WO PCT/JP2005/013713 patent/WO2007013147A1/fr active Application Filing
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01279828A (ja) * | 1988-01-19 | 1989-11-10 | Takeda Chem Ind Ltd | 脈管形成阻止剤 |
JPH08337594A (ja) * | 1995-06-13 | 1996-12-24 | Sanwa Kagaku Kenkyusho Co Ltd | 新規化合物及びその用途 |
JP2001213799A (ja) * | 2000-01-28 | 2001-08-07 | Inst Of Physical & Chemical Res | 抗腫瘍剤 |
JP2001226283A (ja) * | 2000-02-17 | 2001-08-21 | Inst Of Physical & Chemical Res | 5−s−gadを有効成分とするアポトーシス誘導剤 |
JP2001278785A (ja) * | 2000-03-30 | 2001-10-10 | Inst Of Physical & Chemical Res | 骨疾患の治療剤 |
WO2003070269A1 (fr) * | 2002-02-18 | 2003-08-28 | Cevec Pharmaceuticals Gmbh | Traitement de maladies de l'oeil, de l'oreille interne et du systeme nerveux central |
JP2005213159A (ja) * | 2004-01-27 | 2005-08-11 | Inbiotex:Kk | 血管新生阻害剤及び血管退縮剤 |
Non-Patent Citations (2)
Title |
---|
KILARSKI W. ET AL.: "Inactivation of Src family kinases inhibits angiogenesis in vivo: implications for mechanism involving organization of the actin cytoskeleton.", EXPERIMENTAL CELL RESEARCH, vol. 291, pages 70 - 82, XP001183269 * |
ZHENG Z. ET AL.: "Selective Inhibition of Src Protein Tyrosine Kinase by Analogues if 5-S-Glutathionyl-beta-alanyl-L-dopa.", CHEM.PHARM.BULL., vol. 46, no. 12, pages 1950 - 1951, XP002991712 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102014883B1 (ko) | 근위축성 측삭 경화증 치료용 신규 조성물 | |
JP2019069942A (ja) | ペプチド治療薬およびその使用方法 | |
CA3135553C (fr) | Compositions d'acides amines et utilisations associees | |
US10633324B2 (en) | Compounds, compositions, and methods for the treatment of inflammatory, degenerative, and neurodegenerative diseases | |
US20210038677A1 (en) | Methods and compositions for preventing or treating leber's hereditary optic neuropathy | |
US20200325148A1 (en) | Compositions and methods of treatment for neurological disorders comprising motor neuron diseases | |
WO2020081923A1 (fr) | Inhibiteurs de sarm1 en combinaison avec nad+ ou un précurseur de nad+ | |
JP2008247900A (ja) | TGF−β活性化反応阻害物質 | |
RU2591210C2 (ru) | Соединения и способы лечения боли и других расстройств | |
KR20220119032A (ko) | 알츠하이머 질환 치료용 화합물 | |
US20210275480A1 (en) | Compositions and methods for the reduction or treatment of fibrosis | |
US20210145797A1 (en) | Compositions for treating skin | |
RU2304444C1 (ru) | Пептид, обладающий стресспротекторным действием, фармацевтическая композиция на его основе и способ ее применения | |
BR112019027707A2 (pt) | método para o tratamento de demência, uso de um antagonista de receptor 5-ht6 puro para o tratamento de demência e composição farmacêutica | |
EP2714028A1 (fr) | Inhibiteurs du transporteur de d-sérine en tant que compositions pharmaceutiques pour le traitement de troubles du système visuel | |
KR102501677B1 (ko) | 프리마퀸 디포스페이트와 그 타겟으로 usp1의 혈관누수차단 효과 | |
JP2005213159A (ja) | 血管新生阻害剤及び血管退縮剤 | |
WO2007013147A1 (fr) | Inhibiteur de l’angiogenèse et agent de régression vasculaire | |
JP7097444B2 (ja) | 脳小血管病の治療用医薬の製造における化合物の使用 | |
CN101293831B (zh) | 3-羟基脂肪酸及其衍生物在制备钙离子通道调节剂中的用途 | |
JP2006508047A (ja) | 新血管新生に関連する状態を治療する方法及び配合物 | |
TW201904569A (zh) | 膀胱過動的預防劑或治療劑 | |
WO2023134732A9 (fr) | Prévention ou traitement de maladies cardiovasculaires à l'aide de promédicaments d'aspirine et d'autres ains à forte pénétration | |
Zhang et al. | Irisin attenuates acute glaucoma-induced neuroinflammation by activating microglia-integrin αVβ5/AMPK and promoting autophagy | |
JP3750983B2 (ja) | 骨疾患の治療剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 05767031 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: JP |