CN111568894A - Use of 2- (ethylaminomethyl) -5- (phenyl) furan for the preparation of a medicament for inhibiting TLR7/8 - Google Patents
Use of 2- (ethylaminomethyl) -5- (phenyl) furan for the preparation of a medicament for inhibiting TLR7/8 Download PDFInfo
- Publication number
- CN111568894A CN111568894A CN202010418422.6A CN202010418422A CN111568894A CN 111568894 A CN111568894 A CN 111568894A CN 202010418422 A CN202010418422 A CN 202010418422A CN 111568894 A CN111568894 A CN 111568894A
- Authority
- CN
- China
- Prior art keywords
- compound
- tlr7
- ethylaminomethyl
- substituted
- use according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 title claims abstract description 30
- 102100039390 Toll-like receptor 7 Human genes 0.000 title claims abstract description 30
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title claims abstract description 12
- MAIIHHHSKYEHIH-UHFFFAOYSA-N n-[(5-phenylfuran-2-yl)methyl]ethanamine Chemical compound O1C(CNCC)=CC=C1C1=CC=CC=C1 MAIIHHHSKYEHIH-UHFFFAOYSA-N 0.000 title description 2
- 238000002360 preparation method Methods 0.000 title description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 18
- -1 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound Chemical class 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 206010061218 Inflammation Diseases 0.000 claims abstract description 10
- 230000004054 inflammatory process Effects 0.000 claims abstract description 10
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 8
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 22
- 201000001421 hyperglycemia Diseases 0.000 claims description 18
- 230000037361 pathway Effects 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 claims description 3
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 claims description 3
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 229940001468 citrate Drugs 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
- 238000000338 in vitro Methods 0.000 claims description 2
- 229940001447 lactate Drugs 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000005341 metaphosphate group Chemical group 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 19
- 230000004663 cell proliferation Effects 0.000 abstract description 15
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 abstract description 11
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 9
- 230000003013 cytotoxicity Effects 0.000 abstract description 9
- 108090000623 proteins and genes Proteins 0.000 abstract description 9
- 229940125971 TLR7/8 inhibitor Drugs 0.000 abstract description 8
- 229960000905 indomethacin Drugs 0.000 abstract description 7
- 102000003945 NF-kappa B Human genes 0.000 abstract description 6
- 108010057466 NF-kappa B Proteins 0.000 abstract description 6
- 230000010261 cell growth Effects 0.000 abstract description 6
- 201000011510 cancer Diseases 0.000 abstract description 4
- 208000015181 infectious disease Diseases 0.000 abstract description 4
- 230000002411 adverse Effects 0.000 abstract description 3
- 230000000770 proinflammatory effect Effects 0.000 abstract description 3
- 229940125904 compound 1 Drugs 0.000 description 29
- 229940125782 compound 2 Drugs 0.000 description 24
- 102000002689 Toll-like receptor Human genes 0.000 description 17
- 108020000411 Toll-like receptor Proteins 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- 229940124613 TLR 7/8 agonist Drugs 0.000 description 10
- 239000006228 supernatant Substances 0.000 description 9
- FBFJOZZTIXSPPR-UHFFFAOYSA-N 1-(4-aminobutyl)-2-(ethoxymethyl)imidazo[4,5-c]quinolin-4-amine Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CCCCN)C3=C(N)N=C21 FBFJOZZTIXSPPR-UHFFFAOYSA-N 0.000 description 8
- 239000000556 agonist Substances 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 230000001270 agonistic effect Effects 0.000 description 5
- 239000002158 endotoxin Substances 0.000 description 5
- 229920006008 lipopolysaccharide Polymers 0.000 description 5
- 108010087230 Sincalide Proteins 0.000 description 4
- 238000010609 cell counting kit-8 assay Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000003032 molecular docking Methods 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 229950010550 resiquimod Drugs 0.000 description 3
- BXNMTOQRYBFHNZ-UHFFFAOYSA-N resiquimod Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CC(C)(C)O)C3=C(N)N=C21 BXNMTOQRYBFHNZ-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 102000028391 RNA cap binding Human genes 0.000 description 2
- 108091000106 RNA cap binding Proteins 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 231100000313 clinical toxicology Toxicity 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 102000002467 interleukin receptors Human genes 0.000 description 2
- 108010093036 interleukin receptors Proteins 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 230000004044 response Effects 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
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- RVCKCEDKBVEEHL-UHFFFAOYSA-N 2,3,4,5,6-pentachlorobenzyl alcohol Chemical compound OCC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl RVCKCEDKBVEEHL-UHFFFAOYSA-N 0.000 description 1
- RHKWIGHJGOEUSM-UHFFFAOYSA-N 3h-imidazo[4,5-h]quinoline Chemical class C1=CN=C2C(N=CN3)=C3C=CC2=C1 RHKWIGHJGOEUSM-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 208000002633 Febrile Neutropenia Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 206010049151 Neutropenic sepsis Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010084455 Zeocin Proteins 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 102000027412 enzyme-linked receptors Human genes 0.000 description 1
- 108091008592 enzyme-linked receptors Proteins 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009650 gentamicin protection assay Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000008088 immune pathway Effects 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002314 neuroinflammatory effect Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- CWCMIVBLVUHDHK-ZSNHEYEWSA-N phleomycin D1 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC[C@@H](N=1)C=1SC=C(N=1)C(=O)NCCCCNC(N)=N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C CWCMIVBLVUHDHK-ZSNHEYEWSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000003041 virtual screening Methods 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of a 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound or a medicinal salt thereof in preparing a medicament for inhibiting TLR7/8, which is characterized in that the 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound is shown as the following formula I:
the 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound has TLR7/8 inhibitor effect, and can inhibit tumor treatment by inhibiting TLR7/8Hyperglycemia due to therapy and its associated adverse consequences, such as infection and non-malignant tumor-related death, cell proliferation rate>80%, the cytotoxicity is lower, and the normal growth of cells is not influenced; the anti-inflammatory effect is better than that of indometacin, the anti-inflammatory activity is better, the cytotoxicity is lower, NF-kB can be blocked by inhibiting TLR7/8, the expression of proinflammatory genes is inhibited, and the aim of treating inflammation is fulfilled.
Description
Technical Field
The invention relates to a TLRs receptor inhibitor, in particular to an application of a 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound or a medicinal salt thereof in preparing a medicament for inhibiting TLR 7/8.
Background
TLRs (Toll-like receptors) receptors are members of the interleukin receptor (IL-1R) superfamily, mainly play a role in the innate immune system, are single, transmembrane, non-catalytic receptors and recognize structure-specific molecules derived from microorganisms. Among them, TLR7 not only recognizes small molecule compounds with antiviral and antitumor effects such as imidazoquinoline analogs, but also recognizes viral ssRNA, activates MyD88 signal pathway, activates immune cells, and promotes the expression of downstream cytokines such as IFN, TNF-alpha, IL-12, etc., thereby mediating the immune regulation of the body and the regulation of tumor cells. TLR7 agonists can activate both innate and cell-regulated immune pathways. However, activation of the endogenous immune system through TLR7 is one of the pathogenesis causes of insulin resistance, diabetes and atherosclerosis.
Hyperglycemia is a major side effect of tumors and tumor therapy, and the occurrence of hyperglycemia is not related to diabetes. Glucose is the only energy source for tumor cells. The hyperglycemic state can be used as a nutrient medium to promote the growth of tumor cells, so that the tumor cells have more sufficient energy to complete the rapid proliferation. Hyperglycemia can lead to a range of adverse outcomes, such as infection and non-malignant tumor-related death. Hyperglycemia increases the risk of clinical toxicity, neutropenia, neutropenic fever, sepsis and neuropathy. Hyperglycemia in the course of tumor treatment is also one of the clinical toxicities that lead to delayed chemotherapy efficacy, reducing the patient's response to chemotherapeutic drugs.
Hyperglycemia in turn can activate the TLR pathway. Chronic hyperglycemia is associated with inflammation (high NO levels) and oxidative stress. The neuroinflammatory state caused by hyperglycemia activates the NF- κ B pathway, which in turn activates microglia and astrocytes, resulting in brain-related neuropathological responses.
Therefore, the side effects brought by the activation of NF-kB pathway by TLRs and the relation between TLR and NF-kB pathway activation and hyperglycemia and inflammation promote the further research of TLR inhibitors.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Disclosure of Invention
The invention aims to provide application of a 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound or a pharmaceutically acceptable salt thereof in preparing a medicament for inhibiting TLR7/8, which can solve the problem that the existing TLR agonist has side effects.
To achieve the above objects, the present invention provides the use of a 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting TLR7/8, the 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound being represented by formula I below:
wherein R1 is selected from any one of the following substituents:
r2 is selected from any one or more of the following substituents:
-Cl、-Br、-OH、
in a preferred embodiment, the medicament is used for in vitro anti-inflammatory, MyD88 pathway inhibition, NF-kB pathway inhibition.
In a preferred embodiment, the above-mentioned medicament is for the treatment and/or prevention of inflammation, hyperglycemia.
In a preferred embodiment, the hyperglycemia is hyperglycemia due to tumor treatment.
In a preferred embodiment, the pharmaceutically acceptable salts include, but are not limited to, carbonate, hydrochloride, sulfate, sulfite, maleate, succinate, hydrobromide, nitrate, phosphate, metaphosphate, perchlorate, and one or more of formate, acetate, propionate, malonate, acrylate, succinate, oxalate, D or L malate, fumarate, benzoate, hydroxybutyrate, phthalate, methanesulfonate, ethanesulfonate, sulfonate, salicylate, tartrate, citrate, lactate, mandelate.
In a preferred embodiment, R1 is selected from any one of the following substituents:
in a preferred embodiment, R2 is selected from any one of the following substituents:
-Cl、-Br、-OH、
in a preferred embodiment, the compound of formula I above is a compound of formula 1 below:
in a preferred embodiment, the compound of formula I above is a compound of formula 2 below:
compared with the prior art, the invention has the following beneficial effects:
(1) both compound 1 and compound 2 form hydrogen bonds with Asp555, Thr586, but unlike TLR7/8 agonists, the hydrogen bond strength is not as strong as agonists such as R848(resiquimod, raemont); in addition, the binding mode of the TLR7/8 inhibitor molecule compound 1 and the TLR7/8 agonist is obviously different from that of the TLR7/8 agonist, almost all the TLR7/8 inhibitor molecule compound 1 and the TLR 368 inhibitor molecule compound 2 are combined with TLR7/8 protein in the X-axis direction, and interact with adjacent loops of 2-3 TLR7/8 molecules, like a cap binding mode, and are firmly buckled on a first-site position, so that a relatively conservative system structure is formed, and a dimer system formed by overlapping two TLRs 7/8 is difficult to form.
(2) The test principle of the inhibitor is that the inhibitor is firstly added to cultivate cells, then the agonist is added, then the agonistic effect is tested, and if the agonistic effect is not generated, the inhibitory activity is shown. The agonistic effect of CL097 is 100%, the percentage of the agonistic effect of TLR7/8 of compound 1 or compound 2 is low, which indicates that the 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound or the pharmaceutically acceptable salt thereof has TLR7/8 inhibitor effect, better effect than TLR7/8 agonist CL097, and can block hyperglycemia caused by tumor treatment and adverse effects thereof, such as infection and non-malignant tumor-related death, by inhibiting TLR 7/8. Meanwhile, the cell proliferation rate of the compound 1 and the compound 2 is more than 80 percent, which indicates that the 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound or the medicinal salt thereof has low cytotoxicity and does not influence the normal growth of cells.
(3) The invention uses LPS to stimulate cells to generate inflammation, then adds anti-inflammatory compound, measures NO concentration and finally determines anti-inflammatory effect. The anti-inflammatory effect of the compound 1 is better than that of indometacin, the cell proliferation rate of the compound is higher than that of negative control, the 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound or the medicinal salt thereof has better anti-inflammatory activity and lower cytotoxicity, and NF-kB can be blocked by inhibiting TLR7/8, so that the expression of proinflammatory genes is inhibited, and the aim of treating inflammation is fulfilled.
In conclusion, the 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound of formula I or a pharmaceutically acceptable salt thereof has TLR7/8 inhibitory activity, is low in cytotoxicity, does not have the side effects of existing TLR agonists, and does not affect normal growth of cells while being capable of treating inflammation and hyperglycemia.
Drawings
FIG. 1 is a graph of the effect of compound 1, compound 2 and a control compound TLR7/8 activator on the inhibitory activity of TLR7/8 protein in HEK293 cells and the rate of cell proliferation as determined by CCK-8.
Figure 2 is a schematic representation of molecular docking of compound 1 with TLR7/8 protein.
Figure 3 is a schematic representation of molecular docking of compound 2 with TLR7/8 protein.
Figure 4 is the effect of compound 1, compound 2 and the control anti-inflammatory compound indomethacin on NO inhibitory activity.
Detailed Description
The following detailed description of the present invention is provided in conjunction with the accompanying drawings, but it should be understood that the scope of the present invention is not limited to the specific embodiments.
According to computer-aided drug design, virtual screening is carried out in the first round, drug formation experience evaluation is carried out in the second round, synthesis feasibility evaluation is carried out in the third round, lead compounds 1 and compounds 2 are purchased in the fourth round, and finally pharmacological experiment confirmation is carried out on the compounds 1 and the compounds 2.
Example 1
Effect of Compound 1, Compound 2 and control Compound TLR7/8 activator on the inhibitory Activity of TLR7/8 protein in HEK293 cells and cell proliferation Rate determined by CCK-8
The scheme is as follows: HEK-BlueTMhTLR7 cells (HEK 293 cells transfected with humanized TLR7, from InvivoGen) were seeded in 96-well plates at a density of 4 × 104Agonist CL097(5 μ M) and test compound 1 or compound 2(40 μ M) were added overnight per well to give a supernatant. The resulting supernatant was aspirated by pipette, the supernatant (20. mu.L) was assayed by Quanti-blue (OD 630nm), and the residue was assayed for cell proliferation rate by CCK-8. If the cell proliferation rate is high, the cytotoxicity is low, and the cells can grow normally.
Index of Quanti-Blue value (A-B)/(C-B); wherein A: average value of the wells to be measured; b: an average value of the cell-containing matrix; c: positive control (CL 097).
The method comprises the following operation steps:
① HEK-TLR7/8 cell line of HEK293 line was seeded in 96-well plate, 4 × 104One/well/100. mu.L. Test Compound 1 or test Compound 2 (40. mu.M, 100. mu.L), 37 ℃ with 5% CO was added2And staying overnight;
50mL of DMEM medium: 5mL of FBS (10%), 500. mu.L of PS (100X), 100. mu.L of Normocin (0.01%), 500. mu.L of L-glutamine, 50. mu.L of Zeocin (100mg/mL) and 50. mu.L of Blastin (10 mg/mL).
② on the next day, 20 mu L of supernatant is taken and added with QUANTI-Blue to 200 mu L for color development (630 nm).
③ adding TLR7/8 agonist CL097 (purchased from InvivoGen company) into the original 96 pore plate at 5 μ M/pore; the next day, 20. mu.L of supernatant was added with QUANTI-Blue to 200. mu.L, and color development (630nm) was performed.
Fourthly, adding 10 mu L of reagent CCK-8 into the residual liquid, detecting the cell proliferation rate (450nm), and calculating the formula as follows:
the principle of the embodiment is as follows: the inhibitory effect of compound 1 and compound 2 was tested by measuring TLR7/8 agonist activity. If TLR7/8 is inhibited, its downstream agonistic activity is reduced.
In FIG. 1, the ordinate represents the cell proliferation rate and TLR7/8 inhibitory effect, the better the TLR7/8 inhibitory effect, the lower the bar graph. As can be seen from FIG. 1, the agonist effect of the positive control CL097 is 100%, and the percentage of the agonist effect of the TLR7/8 of the compound 1 or the compound 2 is low, which indicates that the two compounds have the TLR7/8 inhibitor effect and the effect is better than that of the TLR7/8 agonist CL 097. In addition, compound 1 has a superior inhibitory effect to compound 2. The cell proliferation effect of compound 1 and compound 2 was simultaneously measured to detect the cytotoxicity of compound 1 and compound 2. The cell proliferation rate of the compound 1 and the compound 2 is more than 80 percent, which indicates that the two compounds have low cytotoxicity and do not influence the normal growth of cells. The compound 1 and the compound 2 can block hyperglycemia caused by tumor treatment, such as infection and non-malignant tumor related death, by inhibiting TLR 7/8.
The molecular docking is illustrated in conjunction with fig. 2 and 3. For TLR7/8 inhibitor molecules compound 1 and compound 2, the inhibitor of interest was able to stably bind to TLR7/8 from a binding pattern. Both compound 1 and compound 2 form hydrogen bonds with Asp555, Thr586, but unlike TLR7/8 agonists, hydrogen bond strength is not as strong as those of R848; in addition, the binding mode of the TLR7/8 inhibitor molecule compound 1 and the TLR7/8 agonist is obviously different from that of the TLR7/8 agonist, almost all the TLR7/8 inhibitor molecule compound 1 and the TLR 368 inhibitor molecule compound 2 are combined with TLR7/8 protein in the X-axis direction, and interact with adjacent loops of 2-3 TLR7/8 molecules, like a cap binding mode, and are firmly buckled on a first-site position, so that a relatively conservative system structure is formed, and a dimer system formed by overlapping two TLRs 7/8 is difficult to form.
Example 2
NO Activity assay and cell survival assay for Compound 1/Compound 2
The scheme is that RAW264.7 cells are inoculated in a 96-well plate, and the density is 4 × 104One well, 1.5h later compound 1, compound 2 or indomethacin (40 μ M) and Lipopolysaccharide (LPS) (1 μ g/mL, 10 μ L/well) were added. After 24h, the NO concentration was measured by Griess reagent (540 nm); cell growth was measured by MTT (200. mu.L, 0.5mg/mL, 450 nm).
The method comprises the following operation steps:
① RAW264.7 cells were cultured in DMEM medium (10% FBS + 1% penicillin/streptomycin), 37 ℃ and 5% CO2Inoculating to 96-well plate (5 × 10) after cell growth is stable4One/well), overnight.
② after addition of compound (40. mu.M, 100. mu.L) LPS (1. mu.g/mL, 10. mu.L/well) was added.
③ taking 50 μ L of cell supernatant on the next day, and simultaneously drawing a standard curve by using a Griess kit (nitric oxide kit, purchased from Biyuntian Biotechnology Co., Ltd.).
And fourthly, removing the supernatant, adding 200 mu L (0.5mg/mL) of MTT [3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide ] into the supernatant, blackening the cells after 4h, sucking the supernatant, adding 150 mu L of DMSO into the residue, shaking the mixture for 15min to dissolve the residue, and detecting the NO inhibition rates of the compound 1, the compound 2 and the anti-inflammatory compound indometacin at 450nm, 490 nm, 520 nm and 570nm respectively. The calculation formula is as follows:
the measurement principle of the embodiment is as follows: the cells are stimulated to produce inflammation with LPS, then anti-inflammatory compounds are added, the NO concentration is measured, and finally the anti-inflammatory effect is determined. Indomethacin is a recognized anti-inflammatory compound and is also a commonly used anti-inflammatory positive control. FIG. 2 is a graph showing the anti-inflammatory activity of NO and the cell proliferation rate, wherein the ordinate represents the cell proliferation rate and the NO inhibition rate, the better the anti-inflammatory effect, and the higher the columnar shape. As can be seen from FIG. 2, compound 1 in this example has better anti-inflammatory effect than indomethacin, and higher cell proliferation rate than that of the negative control, indicating that compound 1 has better anti-inflammatory activity and lower cytotoxicity.
TLRs clear pathogens and produce toxic inflammatory mediators, which are produced in excessive amounts and cause a number of side effects. The compound 1 and the compound 2 can block NF-kB by inhibiting TLR7/8, thereby inhibiting the expression of proinflammatory genes and further achieving the purpose of treating inflammation.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (9)
- Use of a 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting TLR7/8, wherein the 2- (substituted ethylaminomethyl) -5- (substituted phenyl) furan compound is represented by formula I below:
wherein R1 is selected from any one of the following substituents:
r2 is selected from any one of the following substituents:-Cl、-Br、-OH、
- 2. the use according to claim 1, wherein the medicament is for anti-inflammatory, MyD88 pathway inhibition, NF- κ B pathway inhibition in vitro.
- 3. Use according to claim 1, characterized in that the medicament is for the treatment and/or prevention of inflammation, hyperglycemia.
- 4. Use according to claim 3, characterized in that the hyperglycemia is hyperglycemia as a result of tumor therapy.
- 5. The use according to claim 1, wherein the pharmaceutically acceptable salts include, but are not limited to, one or more of carbonate, hydrochloride, sulfate, sulfite, maleate, succinate, hydrobromide, nitrate, phosphate, metaphosphate, perchlorate, formate, acetate, propionate, malonate, acrylate, succinate, oxalate, D or L malate, fumarate, benzoate, hydroxybutyrate, phthalate, methanesulfonate, ethanesulfonate, sulfonate, salicylate, tartrate, citrate, lactate, mandelate.
- 6. The use according to claim 1, wherein R1 is selected from any one of the following substituents:
- 7. the use according to claim 1, wherein R2 is selected from any one or more of the following substituents:-Cl、-Br、-OH、
- 8. use according to claim 6, wherein the compound of formula I is a compound of formula 1 below:
- 9. use according to claim 7, wherein the compound of formula I is a compound of formula 2 below:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010418422.6A CN111568894B (en) | 2020-05-18 | 2020-05-18 | Use of 2- (ethylaminomethyl) -5- (phenyl) furan for the preparation of a medicament for inhibiting TLR7/8 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010418422.6A CN111568894B (en) | 2020-05-18 | 2020-05-18 | Use of 2- (ethylaminomethyl) -5- (phenyl) furan for the preparation of a medicament for inhibiting TLR7/8 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111568894A true CN111568894A (en) | 2020-08-25 |
| CN111568894B CN111568894B (en) | 2021-07-27 |
Family
ID=72109405
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010418422.6A Expired - Fee Related CN111568894B (en) | 2020-05-18 | 2020-05-18 | Use of 2- (ethylaminomethyl) -5- (phenyl) furan for the preparation of a medicament for inhibiting TLR7/8 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111568894B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004060884A1 (en) * | 2002-12-26 | 2004-07-22 | Aventis Pharmaceuticals Inc. | [4-(3-aminomethylphenyl) piperidin-1-yl]- [5-(2-fluorophenylethynyl)furan-2-yl]-methanone as an inhibitor of mast cell tryptase |
| WO2010020556A1 (en) * | 2008-08-22 | 2010-02-25 | Evotec Neurosciences Gmbh | New bradykinin b1 antagonists |
| CN103012381A (en) * | 2013-01-10 | 2013-04-03 | 山东大学 | Benzofuran compound, preparation method thereof and application of benzofuran compound in preparation of antiarrhythmic drugs |
| JP2014118401A (en) * | 2012-12-19 | 2014-06-30 | Kowa Company Ltd | Furan derivative having tlr inhibition effect |
| CN105193811A (en) * | 2014-06-25 | 2015-12-30 | 中国药科大学 | SGLT2 inhibitor and application thereof |
| CN107827877A (en) * | 2017-11-21 | 2018-03-23 | 陕西师范大学 | Dialkyl amido quinazoline compounds and its application in antineoplastic is prepared |
| CN108947912A (en) * | 2018-07-31 | 2018-12-07 | 中国人民解放军总医院 | A kind of antitumoral compounds targeting Neddylation access |
-
2020
- 2020-05-18 CN CN202010418422.6A patent/CN111568894B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004060884A1 (en) * | 2002-12-26 | 2004-07-22 | Aventis Pharmaceuticals Inc. | [4-(3-aminomethylphenyl) piperidin-1-yl]- [5-(2-fluorophenylethynyl)furan-2-yl]-methanone as an inhibitor of mast cell tryptase |
| WO2010020556A1 (en) * | 2008-08-22 | 2010-02-25 | Evotec Neurosciences Gmbh | New bradykinin b1 antagonists |
| JP2014118401A (en) * | 2012-12-19 | 2014-06-30 | Kowa Company Ltd | Furan derivative having tlr inhibition effect |
| CN103012381A (en) * | 2013-01-10 | 2013-04-03 | 山东大学 | Benzofuran compound, preparation method thereof and application of benzofuran compound in preparation of antiarrhythmic drugs |
| CN105193811A (en) * | 2014-06-25 | 2015-12-30 | 中国药科大学 | SGLT2 inhibitor and application thereof |
| CN107827877A (en) * | 2017-11-21 | 2018-03-23 | 陕西师范大学 | Dialkyl amido quinazoline compounds and its application in antineoplastic is prepared |
| CN108947912A (en) * | 2018-07-31 | 2018-12-07 | 中国人民解放军总医院 | A kind of antitumoral compounds targeting Neddylation access |
Non-Patent Citations (3)
| Title |
|---|
| IRENE CUADRADO ET AL.: "Semisynthesis and Inhibitory Effects of Solidagenone Derivatives on TLR-Mediated Inflammatory Responses", 《MOLECULES》 * |
| JOHN P VASILAKOS ET AL.: "The use of Toll-like receptor 7/8 agonists as vaccine adjuvants", 《EXPERT REV. VACCINES》 * |
| 宋英: "TLＲ4 和 TLＲ7 /8 在肿瘤免疫豁免中的不同机制", 《四川师范大学学报( 自然科学版)》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111568894B (en) | 2021-07-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI689514B (en) | Compounds, compositions, and methods for the treatment of disease | |
| US8030318B2 (en) | Fused bicyclic inhibitors of HCV | |
| CN104781239B (en) | For treating the alkyl derivative of virus infection and other disease | |
| CA2875970C (en) | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases | |
| CA3055076C (en) | Glucocorticoid receptor modulators to treat cervical cancer | |
| US20070066632A1 (en) | Fused bicyclic inhibitors of TGFbeta | |
| US9284315B2 (en) | Three-ring PI3K and/or mTOR inhibitor | |
| CA3095699A1 (en) | Combination product of bcl-2 inhibitor and chemotherapeutic agent and use thereof in the prevention and/or treatment of diseases | |
| US11166943B2 (en) | Combination therapy using azabicyclo compound for cancer | |
| AU2016204054A1 (en) | Effect potentiator for antitumor agents | |
| CN107243008B (en) | Novel application of pyrazolo [1,5-a ] pyridine compound and composition for treating mycobacterium abscesses infection | |
| CN111568894B (en) | Use of 2- (ethylaminomethyl) -5- (phenyl) furan for the preparation of a medicament for inhibiting TLR7/8 | |
| US11219619B2 (en) | Therapeutic agent for hepatocellular carcinoma | |
| US11572359B2 (en) | PARP/PI3K double-target inhibit containing pyridopyrimidine structure | |
| AU2019265011A1 (en) | Inhibitors of the RAS oncoprotein, methods of making and methods of use thereof | |
| US20230100235A1 (en) | Anticancer agent composition | |
| CN108456670B (en) | Use of a magnetic field confining device for the preparation of a product for assisting chemotherapy | |
| CN118436650A (en) | Pharmaceutical composition composed of compound LYW-2 and clinical chemotherapy medicament and application thereof | |
| US11548891B1 (en) | Quaternary ammonium salts of phenanthroindolizidine and phenanthroquinolizidine alkaloids as hypoxia-targeted anticancer agents | |
| CN110893192A (en) | Pharmaceutical composition for treating nasopharyngeal carcinoma | |
| WO2023131305A1 (en) | Combination of prmt5 inhibitor and anti-cancer therapeutic agent | |
| WO2007077861A1 (en) | NF-κB INHIBITOR | |
| CN116396229A (en) | Preparation of quinazoline compound and anti-tumor application thereof | |
| CN112457246A (en) | Dopamine D1 receptor antagonists and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210727 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |