CN106074546A - Rui Te Xining is as indoleamine 2, the purposes of 3 dioxygenase 1 inhibitor - Google Patents
Rui Te Xining is as indoleamine 2, the purposes of 3 dioxygenase 1 inhibitor Download PDFInfo
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- CN106074546A CN106074546A CN201610419182.5A CN201610419182A CN106074546A CN 106074546 A CN106074546 A CN 106074546A CN 201610419182 A CN201610419182 A CN 201610419182A CN 106074546 A CN106074546 A CN 106074546A
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- 239000003112 inhibitor Substances 0.000 title abstract description 9
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 title abstract description 4
- 102000016680 Dioxygenases Human genes 0.000 title abstract 3
- 108010028143 Dioxygenases Proteins 0.000 title abstract 3
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 claims abstract description 40
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- 229940043367 IDO1 inhibitor Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 230000006698 induction Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000002177 Cataract Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 206010040047 Sepsis Diseases 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 208000023965 endometrium neoplasm Diseases 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 230000036772 blood pressure Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 2
- 230000001404 mediated effect Effects 0.000 abstract description 2
- 229930014626 natural product Natural products 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- YGPSJZOEDVAXAB-QMMMGPOBSA-N L-kynurenine Chemical compound OC(=O)[C@@H](N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-QMMMGPOBSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- ZADWXFSZEAPBJS-JTQLQIEISA-N 1-methyl-L-tryptophan Chemical group C1=CC=C2N(C)C=C(C[C@H](N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-JTQLQIEISA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 101710120843 Indoleamine 2,3-dioxygenase 1 Proteins 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 3
- 229960000907 methylthioninium chloride Drugs 0.000 description 3
- 238000005497 microtitration Methods 0.000 description 3
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- ZADWXFSZEAPBJS-UHFFFAOYSA-N racemic N-methyl tryptophan Natural products C1=CC=C2N(C)C=C(CC(N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-UHFFFAOYSA-N 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- RAEOYMOPVHBBKE-UHFFFAOYSA-N 2-[2-(methylamino)benzoyl]-4,9-dihydro-3h-pyrido[3,4-b]indol-1-one Chemical compound CNC1=CC=CC=C1C(=O)N1C(=O)C(NC=2C3=CC=CC=2)=C3CC1 RAEOYMOPVHBBKE-UHFFFAOYSA-N 0.000 description 2
- -1 Acyl kynurenin Chemical compound 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
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- 150000001875 compounds Chemical class 0.000 description 2
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- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 2
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- 210000004881 tumor cell Anatomy 0.000 description 2
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229930195573 Amycin Natural products 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 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
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- FBKMWOJEPMPVTQ-UHFFFAOYSA-N N'-(3-bromo-4-fluorophenyl)-N-hydroxy-4-[2-(sulfamoylamino)ethylamino]-1,2,5-oxadiazole-3-carboximidamide Chemical compound NS(=O)(=O)NCCNC1=NON=C1C(=NO)NC1=CC=C(F)C(Br)=C1 FBKMWOJEPMPVTQ-UHFFFAOYSA-N 0.000 description 1
- BYHJHXPTQMMKCA-QMMMGPOBSA-N N-formyl-L-kynurenine Chemical compound [O-]C(=O)[C@@H]([NH3+])CC(=O)C1=CC=CC=C1NC=O BYHJHXPTQMMKCA-QMMMGPOBSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 229960004799 tryptophan 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention passes through natural product Rui Te Xining or its pharmaceutically acceptable salt as indoleamine 2, the purposes of 3 dioxygenases 1 inhibitor (IDO1), Rui Te Xining is for indoleamine 2, the inhibitory action of 3 dioxygenases 1, IDO1 facilitation in disease development is hindered and/or destroys, thus the disease mediated for treatment IDO1 provides good prospect.
Description
Technical field
The present invention relates to Rui Te Xining (rhetsinine) as indole amine 2,3-dioxygenase-1(IDO1) new application
And the application in the disease of preparation treatment IDO1 mediation.
Background technology
Indole amine 2,3-dioxygenase-1 [EC 1.13.11.17] (IDO1) be a kind of at intracellular, monomer containing blood red
Cellulose protein, catalysis l-tryptophan (Trp) catabolism becomes the first step of kynurenine pathway.IDO1 metabolite, N-first
Acyl kynurenin (N-formylkynurenine), is metabolized to other bioactive molecule further.IDO1 has at multiple tissues
Express, including lung, small intestinal, Placenta Hominis, spleen and nervus centralis.IDO1 in many cell types can by inflammatory cytokine (as
Interferon gamma, escherichia coli endotoxin and tumor necrosis factor-alpha etc.) stimulate cause expression.IDO1 also offers carefully at host antigen
Born of the same parents (APC), Monocyte-macrophages and tumor cell are expressed.
IDO1 is as immunosuppressant and a kind of important mechanisms of toleration, anti-at autoimmune disease, transplant rejection
Play an important role in Ying.IDO1, by consuming the concentration of local T rp, suppresses T cell and the activity of NK cell, induces modulability
The formation of T cell.By these mechanism, IDO provides the immunoreation of feedback control.Research find, if IDO ovarian cancer,
High expressed in colorectal cancer and other tumor cells, then tumour patient prognosis is poor, thus it can play the prediction of oncotherapy
Effect.
IDO1 can also work as target spot in kinds of tumors.Such as, swollen in ovarian cancer, colorectal cancer and endometrium
In tumor, IDO1 expression raises.In preclinical model, IDO1 promotes the life of tumor by suppression anti tumor immune response
Long.In these models, micromolecular inhibitor IDO1 can recover immunologic tumor rejection phenomenon and improve Common Chemotherapy medicine
Activity.These data support that IDO1 inhibitor, as new type anticancer medicine, can be combined with existing therapy.Except treatment cancer,
IDO1 inhibitor to other diseases, as sepsis induction hypotension, schizophrenia, Alzheimer's disease and parkinson disease,
Cataract also functions to effect.These find the development interest promoted IDO inhibitor medicine, particularly cancer immunotherapy.?
Widely studied IDO inhibitor is 1-methyl-tryptophan.It is nearest it is demonstrated experimentally that 1-methyl-tryptophan can be with substantial amounts of clinic
Relevant chemotherapy drugs in combination uses, and plays synergism.1-methyl-tryptophan and cyclophosphamide, cisplatin, amycin or Ramulus et folium taxi cuspidatae
The combination of alcohol can cure the mouse breast cancer model of neu induction.
At present, international market has a few class IDO1 inhibitor in clinical experiment, such as Novel IDO 1 inhibitor INCB024360
By Incyte company exploitation treatment late malignant tumour.But, IDO1 inhibitor quantity generally is the most less, and laboratory or
Clinical effectiveness still has much room for improvement.
Summary of the invention
One aspect of the present invention relates to Rui Te Xining or its pharmaceutically acceptable salt as a kind of indoleamine 2,3-pair of oxygenation
The purposes of enzyme-1 inhibitor (IDO1).
Another aspect of the present invention provides Rui Te Xining or its pharmaceutically acceptable salt in the disease of preparation treatment IDO1 mediation
The sick application in medicine.
In some embodiments, the disease of described IDO1 mediation refers to the disease of IDO1 up-regulated, including but do not limit
In, tumor, sepsis induction hypotension, schizophrenia, Alzheimer's disease and parkinson disease and cataract.
In some embodiments, described tumor is selected from ovarian cancer, colorectal cancer and endometrial tumors.Real at some
Executing in mode, described disease does not include tumor.
The structural formula in Rui Te Xining is shown below, existing document show its have antineoplastic action (Wang Qizhi etc., in
Pharmaceutical university of state journal, 6 (40), 240-241；, and there is reduction blood viscosity and analgesic activity 2009).Rui Te Xining can lead to
Crossing proper method well known by persons skilled in the art to prepare, a kind of exemplary preparation method sees Chinese patent application and announces CN
102093357A。
The present invention expects that " pharmaceutically acceptable salt " in Rui Te Xining also has identical activity.Generally, this salt is such as
By by the suitable alkali of these compounds of free acid or alkali form and stoichiometric amount or acid in water or in organic solvent
Or prepare in both mixture.Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred
's.The example of acid-addition salts includes inorganic acid addition salt such as, hydrochlorate, hydrobromate, hydriodate, sulfate, nitrate,
And organic acid addition salt, such as such as acetate, maleate, fumarate, citrate, oxalates, succinate, tartaric acid
Salt, malate, mandelate and tosilate.The example of base addition salts include inorganic salt such as sodium, potassium, calcium, ammonium, magnesium,
Aluminum and lithium salts；And organic base such as ethylenediamine, ethanolamine, N, N-dialkylethanolamines, triethanolamine, glycosamine and basic amine group
Hydrochlorate.
Present invention demonstrates the Rui Te Xining inhibitory action for IDO-1, IDO1 is sent out in disease
Raw developing facilitation carries out hindering and/or destroying, thus the disease mediated for treatment IDO1 provides good prospect.
Detailed description of the invention
The present invention now will be in conjunction with following experiment explaination further, it should be noted that these experimental examples should not be construed as right
The restriction of the present invention.
Kynurenin Specification Curve of Increasing
1. the 0.5M kaliumphosphate buffer (pH 6.5) of standard medium (200 μ L): 20 μ L, final concentration of 50 mM；20μL
0.2M ascorbic acid, final concentration of 20 mM；The 0.5mM methylene blue of 4 μ L, final concentration of 10 μMs；The 5mg/ml peroxide of 4 μ L
Change hydrogen enzyme, final concentration of 100 μ g/ml；The dd-H of 132 μ L2O；The kynurenin solution of 20 μ L, final concentration is respectively 0, and 1,
5,7.5,10,25,50,75 and 100 mM.
2. after adding the 1M NaOH solution of 40 μ L, centrifugal culture medium (11,500rpm, 4 ° of C, 15min).
3. the supernatant of 200 μ L is transferred on 96 hole microtitration plates, measures fluorescence intensity (λ ex 360nm, λ em
480nm)。
Quantification of protein
Protein IDO1 content is measured by BCA method.Solution absorption value is measured, subsequently with bovine serum albumin at λ max 570nm
White standard curve (0-2 mg/ml) checks, to obtain protein concentration.
Activity experiment
1. the 0.5M kaliumphosphate buffer (pH 6.5) of standard test culture medium (200 μ L): 20 μ L, final concentration of 50 mM；20
The 0.2M ascorbic acid of μ L, final concentration of 20 mM；The 0.5mM methylene blue of 4 μ L, final concentration of 100 μ g/ml；20 μ L's
2mM L-tryptophan, final concentration of 200 μMs；The dd-H of 112 μ L2O；The IDO1 of 20 μ L, final concentration of 0 to 10 μ g/ml.
2. comparison: with the dd-H of 20 μ L2O substitutes IDO1.
3., after adding the 1M NaOH solution of 40 μ L, 60 ° of C of mixture hatch 15min, with by N-formoxyl kynurenin water
Solve as kynurenin.It is centrifuged culture medium (11,500rpm, 4 ° of C, 15min) subsequently.
4. the supernatant of 200 μ L is transferred on 96 hole microtitration plates, measures fluorescence intensity (λ ex 360nm, λ em
480nm)。
Inhibition test
1. the 0.5M kaliumphosphate buffer (pH 6.5) of standard test culture medium (200 μ L): 20 μ L, final concentration of 50 mM；20
The 0.2M ascorbic acid of μ L, final concentration of 20 mM；The 0.5mM methylene blue of 4 μ L, final concentration of 10 μMs；The 5mg/ml of 4 μ L
Catalase, final concentration of 100 μ g/ml；The dd-H of 112 μ L2O；The 4mM L-tryptophan of 10 μ L, final concentration of 200 μ
M；The 5 μ g/ml IDO1 of 20 μ L and 10 μ l inhibitor (1-methyl-L-tryptophan) solution in DMSO, final concentration is respectively
For 0,0.1,0.5 and 1mM.
2. comparison is (i): with the dd-H of 10 μ L2O substitutes L-Trp.
3. comparison is (ii): with the dd-H of 30 μ L2O substitutes L-Trp and IDO1.
4., after adding the 1M NaOH solution of 40 μ L, 60 ° of C of mixture hatch 15min, with by N-formoxyl kynurenin water
Solve as kynurenin.It is centrifuged culture medium (11,500rpm, 4 ° of C, 15min) subsequently.
5. the supernatant of 200 μ L is transferred on 96 hole microtitration plates, measures fluorescence intensity (λ ex 360nm, λ em
480nm)。
6. calculating suppression ratio with formula (100-(A/Bx100)), wherein A represents the activity of IDO1, B when there is inhibitor
Represent the activity of IDO1 when there is not inhibitor.The results are shown in Table 1.
The inhibitory action in table 1. Rui Te Xining
| Compound name | IC50(uM) | Hillslope | R square |
| Rui Te Xining | 1.145 | -1.241 | 0.9369 |
Claims (6)
1. Rui Te Xining or its pharmaceutically acceptable salt are as the purposes of indole amine 2,3-dioxygenase-1 inhibitor.
2. Rui Te Xining or the application in the medicine of the disease of preparation treatment IDO1 mediation of its pharmaceutically acceptable salt.
Application the most according to claim 2, the disease of wherein said IDO1 mediation refers to the disease of IDO1 up-regulated.
4., according to the application described in Claims 2 or 3, the disease of wherein said IDO1 mediation is low selected from tumor, sepsis induction
Blood pressure, schizophrenia, Alzheimer's disease and parkinson disease and cataract.
Application the most according to claim 4, wherein said tumor is selected from swollen in ovarian cancer, colorectal cancer and endometrium
Tumor.
Application the most according to claim 4, wherein said disease does not include tumor.
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| CN201610419182.5A CN106074546A (en) | 2016-06-13 | 2016-06-13 | Rui Te Xining is as indoleamine 2, the purposes of 3 dioxygenase 1 inhibitor |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024012554A1 (en) * | 2022-07-14 | 2024-01-18 | 上海日馨医药科技股份有限公司 | Tpk agonist and method for treating neurodegenerative diseases using same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093357A (en) * | 2011-01-12 | 2011-06-15 | 江苏省中国科学院植物研究所 | Novel indoletriazole alkaloid as well as preparation method and antifungal application thereof |
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2016
- 2016-06-13 CN CN201610419182.5A patent/CN106074546A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093357A (en) * | 2011-01-12 | 2011-06-15 | 江苏省中国科学院植物研究所 | Novel indoletriazole alkaloid as well as preparation method and antifungal application thereof |
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| CUN-JING YU等: "Oren-gedoku-to and its Constituents with Therapeutic Potential in Alzheimer"s Disease Inhibit Indoleamine 2, 3-Dioxygenase Activity In Vitro", 《JOURNAL OF ALZHEIMER’S DISEASE》 * |
| 王奇志等: "吲哚喹唑啉类生物碱瑞特西宁的抗肿瘤活性研究", 《中草药》 * |
| 钱平、杨秀伟: "左金方的生物碱类成分及其对肿瘤细胞的细胞毒活性", 《中草药》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2024012554A1 (en) * | 2022-07-14 | 2024-01-18 | 上海日馨医药科技股份有限公司 | Tpk agonist and method for treating neurodegenerative diseases using same |
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