CA3137869A1 - Protein kinase inhibitors and uses thereof for the treatment of diseases and conditions - Google Patents
Protein kinase inhibitors and uses thereof for the treatment of diseases and conditions Download PDFInfo
- Publication number
- CA3137869A1 CA3137869A1 CA3137869A CA3137869A CA3137869A1 CA 3137869 A1 CA3137869 A1 CA 3137869A1 CA 3137869 A CA3137869 A CA 3137869A CA 3137869 A CA3137869 A CA 3137869A CA 3137869 A1 CA3137869 A1 CA 3137869A1
- Authority
- CA
- Canada
- Prior art keywords
- mhz
- nmr
- mmol
- cdc13
- ppm
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 201000010099 disease Diseases 0.000 title claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 20
- 238000011282 treatment Methods 0.000 title abstract description 12
- 239000003909 protein kinase inhibitor Substances 0.000 title description 8
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 6
- 101001089266 Homo sapiens Receptor-interacting serine/threonine-protein kinase 3 Proteins 0.000 claims abstract description 99
- 102100033729 Receptor-interacting serine/threonine-protein kinase 3 Human genes 0.000 claims abstract description 99
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 27
- 102000020233 phosphotransferase Human genes 0.000 claims abstract description 27
- 102000001253 Protein Kinase Human genes 0.000 claims abstract description 25
- 108060006633 protein kinase Proteins 0.000 claims abstract description 25
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 17
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims description 60
- 241000712431 Influenza A virus Species 0.000 claims description 49
- 230000000694 effects Effects 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- -1 carrier Substances 0.000 claims description 8
- 208000027866 inflammatory disease Diseases 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 239000002671 adjuvant Substances 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- 239000003381 stabilizer Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910014033 C-OH Inorganic materials 0.000 claims description 3
- 229910014570 C—OH Inorganic materials 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 abstract description 60
- 230000001225 therapeutic effect Effects 0.000 abstract description 12
- 108010079933 Receptor-Interacting Protein Serine-Threonine Kinase 2 Proteins 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 5
- 230000003412 degenerative effect Effects 0.000 abstract description 5
- 230000009977 dual effect Effects 0.000 abstract description 2
- 102100022502 Receptor-interacting serine/threonine-protein kinase 2 Human genes 0.000 abstract 3
- 101150041968 CDC13 gene Proteins 0.000 description 152
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 152
- 239000007787 solid Substances 0.000 description 125
- 238000005481 NMR spectroscopy Methods 0.000 description 84
- 239000011541 reaction mixture Substances 0.000 description 62
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 55
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 54
- 239000000243 solution Substances 0.000 description 53
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 50
- 238000005160 1H NMR spectroscopy Methods 0.000 description 49
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 48
- 239000000741 silica gel Substances 0.000 description 45
- 229910002027 silica gel Inorganic materials 0.000 description 45
- 238000004440 column chromatography Methods 0.000 description 43
- 210000004027 cell Anatomy 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- 230000021597 necroptosis Effects 0.000 description 27
- 229910052786 argon Inorganic materials 0.000 description 25
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 20
- 238000003786 synthesis reaction Methods 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 241000700605 Viruses Species 0.000 description 18
- 230000030833 cell death Effects 0.000 description 17
- 208000015181 infectious disease Diseases 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 102000003390 tumor necrosis factor Human genes 0.000 description 16
- 239000007832 Na2SO4 Substances 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 230000006907 apoptotic process Effects 0.000 description 15
- 230000005764 inhibitory process Effects 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- 239000012267 brine Substances 0.000 description 14
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 230000037361 pathway Effects 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- WDHAAJIGSXNPFO-UHFFFAOYSA-N 8h-pyrido[2,3-d]pyrimidin-7-one Chemical compound N1=CN=C2NC(=O)C=CC2=C1 WDHAAJIGSXNPFO-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 231100000419 toxicity Toxicity 0.000 description 9
- 230000001988 toxicity Effects 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000034994 death Effects 0.000 description 8
- 231100000517 death Toxicity 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- 238000004020 luminiscence type Methods 0.000 description 8
- 230000001338 necrotic effect Effects 0.000 description 8
- 230000001717 pathogenic effect Effects 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 210000004072 lung Anatomy 0.000 description 7
- 230000007170 pathology Effects 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- 208000004852 Lung Injury Diseases 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 206010069363 Traumatic lung injury Diseases 0.000 description 6
- 231100000516 lung damage Toxicity 0.000 description 6
- 231100000515 lung injury Toxicity 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000011535 reaction buffer Substances 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- KBFYJXMMAXTGQP-UHFFFAOYSA-N 6-chloro-4-(methylamino)pyridine-3-carbaldehyde Chemical compound CNC1=CC(Cl)=NC=C1C=O KBFYJXMMAXTGQP-UHFFFAOYSA-N 0.000 description 5
- 201000001320 Atherosclerosis Diseases 0.000 description 5
- 101001011663 Homo sapiens Mixed lineage kinase domain-like protein Proteins 0.000 description 5
- 101001125026 Homo sapiens Nucleotide-binding oligomerization domain-containing protein 2 Proteins 0.000 description 5
- 102100030177 Mixed lineage kinase domain-like protein Human genes 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000006721 cell death pathway Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- RRCMGJCFMJBHQC-UHFFFAOYSA-N (2-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1Cl RRCMGJCFMJBHQC-UHFFFAOYSA-N 0.000 description 4
- WGUCZWYLSKPURM-UHFFFAOYSA-N 4-(methylamino)-2-methylsulfanylpyrimidine-5-carbaldehyde Chemical compound CNC1=NC(SC)=NC=C1C=O WGUCZWYLSKPURM-UHFFFAOYSA-N 0.000 description 4
- NYQBZJFZEZEXFP-UHFFFAOYSA-N 6-bromo-2-chloroquinazoline Chemical compound C1=C(Br)C=CC2=NC(Cl)=NC=C21 NYQBZJFZEZEXFP-UHFFFAOYSA-N 0.000 description 4
- DHKLJXPNLNWRLZ-UHFFFAOYSA-N 6-bromo-N-[4-[2-(diethylamino)ethoxy]phenyl]quinazolin-2-amine Chemical compound BrC=1C=C2C=NC(=NC2=CC=1)NC1=CC=C(C=C1)OCCN(CC)CC DHKLJXPNLNWRLZ-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 102100029441 Nucleotide-binding oligomerization domain-containing protein 2 Human genes 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 102000013070 Receptor-Interacting Protein Serine-Threonine Kinase 2 Human genes 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- YVBIXOXCIOUBMY-UHFFFAOYSA-N [6-chloro-4-(methylamino)pyridin-3-yl]methanol Chemical compound CNC1=CC(Cl)=NC=C1CO YVBIXOXCIOUBMY-UHFFFAOYSA-N 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000012054 celltiter-glo Methods 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 239000002158 endotoxin Substances 0.000 description 4
- SNNHLSHDDGJVDM-UHFFFAOYSA-N ethyl 4-chloro-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1Cl SNNHLSHDDGJVDM-UHFFFAOYSA-N 0.000 description 4
- DEAFVBVKIMXSND-UHFFFAOYSA-N ethyl 6-chloro-4-(methylamino)pyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)C=C1NC DEAFVBVKIMXSND-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 206010022000 influenza Diseases 0.000 description 4
- 229940043355 kinase inhibitor Drugs 0.000 description 4
- 229920006008 lipopolysaccharide Polymers 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- OSDVLFXRFXCYML-UHFFFAOYSA-N methyl 2-[3-[tert-butyl(dimethyl)silyl]oxyphenyl]acetate Chemical compound COC(=O)CC1=CC=CC(O[Si](C)(C)C(C)(C)C)=C1 OSDVLFXRFXCYML-UHFFFAOYSA-N 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 230000001960 triggered effect Effects 0.000 description 4
- 230000035899 viability Effects 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WZJSEOATGOTFNY-UHFFFAOYSA-N 4-(3-nitrophenyl)-1,4-thiazinane 1,1-dioxide Chemical compound [O-][N+](=O)C1=CC=CC(N2CCS(=O)(=O)CC2)=C1 WZJSEOATGOTFNY-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- HCYCPZFHVYEOER-UHFFFAOYSA-N 6-bromo-N-(3-methylsulfonylphenyl)quinazolin-2-amine Chemical compound BrC=1C=C2C=NC(=NC2=CC=1)NC1=CC(=CC=C1)S(=O)(=O)C HCYCPZFHVYEOER-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 102000004091 Caspase-8 Human genes 0.000 description 3
- 108090000538 Caspase-8 Proteins 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- CIKTYIPDZNLIDJ-UHFFFAOYSA-N N-[4-[2-(diethylamino)ethoxy]phenyl]formamide Chemical compound C(C)N(CCOC1=CC=C(C=C1)NC=O)CC CIKTYIPDZNLIDJ-UHFFFAOYSA-N 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000006978 adaptation Effects 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 230000005754 cellular signaling Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001952 enzyme assay Methods 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 230000004968 inflammatory condition Effects 0.000 description 3
- 230000010354 integration Effects 0.000 description 3
- 238000012417 linear regression Methods 0.000 description 3
- OONQSUFLXZFOLA-UHFFFAOYSA-N n-(3-methylsulfonylphenyl)formamide Chemical compound CS(=O)(=O)C1=CC=CC(NC=O)=C1 OONQSUFLXZFOLA-UHFFFAOYSA-N 0.000 description 3
- ZCDBTQNFAPKACC-UHFFFAOYSA-N n-(6-propan-2-ylsulfonylquinolin-4-yl)-1,3-benzothiazol-5-amine Chemical compound C1=C2SC=NC2=CC(NC2=CC=NC3=CC=C(C=C32)S(=O)(=O)C(C)C)=C1 ZCDBTQNFAPKACC-UHFFFAOYSA-N 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- UKYCKUPXBPLXBA-UHFFFAOYSA-N (2-chloro-4-methylphenyl)boronic acid Chemical compound CC1=CC=C(B(O)O)C(Cl)=C1 UKYCKUPXBPLXBA-UHFFFAOYSA-N 0.000 description 2
- LYUPJHVGLFETDG-UHFFFAOYSA-N 1-phenylbutan-2-ol Chemical compound CCC(O)CC1=CC=CC=C1 LYUPJHVGLFETDG-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- AABYCBJQCOPZML-UHFFFAOYSA-N 3-(1,1-dioxo-1,4-thiazinan-4-yl)aniline Chemical compound NC1=CC=CC(N2CCS(=O)(=O)CC2)=C1 AABYCBJQCOPZML-UHFFFAOYSA-N 0.000 description 2
- LFJGGGIWERIGNX-UHFFFAOYSA-N 4-[2-(diethylamino)ethoxy]aniline Chemical compound CCN(CC)CCOC1=CC=C(N)C=C1 LFJGGGIWERIGNX-UHFFFAOYSA-N 0.000 description 2
- FGONQMFYFJRAIG-UHFFFAOYSA-N 4-amino-2-methylsulfanylpyrimidine-5-carbaldehyde Chemical compound CSC1=NC=C(C=O)C(N)=N1 FGONQMFYFJRAIG-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 2
- 125000006414 CCl Chemical group ClC* 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- 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 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- VDDZMXQAZJMGPK-UHFFFAOYSA-N ethyl 4-(methylamino)-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1NC VDDZMXQAZJMGPK-UHFFFAOYSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000004816 latex Substances 0.000 description 2
- 229920000126 latex Polymers 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- IUUDCMFVEMKOBT-UHFFFAOYSA-N n-(4-methylsulfonylphenyl)formamide Chemical compound CS(=O)(=O)C1=CC=C(NC=O)C=C1 IUUDCMFVEMKOBT-UHFFFAOYSA-N 0.000 description 2
- CBKFHSNATJJWQK-UHFFFAOYSA-N n-pyridin-3-ylformamide Chemical compound O=CNC1=CC=CN=C1 CBKFHSNATJJWQK-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- UMLDUMMLRZFROX-UHFFFAOYSA-N pyridin-2-ylboronic acid Chemical compound OB(O)C1=CC=CC=N1 UMLDUMMLRZFROX-UHFFFAOYSA-N 0.000 description 2
- NIOSVSUQTYFZQG-UHFFFAOYSA-N quinazolin-2-amine Chemical compound C1=C=CC=C2[N]C(N)=NC=C21 NIOSVSUQTYFZQG-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000003362 replicative effect Effects 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 230000001932 seasonal effect Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- GCSOXUVISUKQBS-UHFFFAOYSA-N tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC(N)=C1 GCSOXUVISUKQBS-UHFFFAOYSA-N 0.000 description 2
- NZFUVIYLYULVSP-UHFFFAOYSA-N tert-butyl 4-(5-aminopyridin-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CN=CC(N)=C1 NZFUVIYLYULVSP-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- LHHZRIYUOZPKSG-UHFFFAOYSA-N 1-(3-nitrophenyl)piperazine Chemical compound [O-][N+](=O)C1=CC=CC(N2CCNCC2)=C1 LHHZRIYUOZPKSG-UHFFFAOYSA-N 0.000 description 1
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- MBNPJRQKQLLRIS-UHFFFAOYSA-N 3-methylsulfonylaniline Chemical compound CS(=O)(=O)C1=CC=CC(N)=C1 MBNPJRQKQLLRIS-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229940123169 Caspase inhibitor Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 102000010170 Death domains Human genes 0.000 description 1
- 108050001718 Death domains Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins Proteins 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 208000015872 Gaucher disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101000799140 Homo sapiens Activin receptor type-1 Proteins 0.000 description 1
- 101001109145 Homo sapiens Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- 108091054729 IRF family Proteins 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000016854 Interferon Regulatory Factors Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 208000010557 Lipid storage disease Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 208000015439 Lysosomal storage disease Diseases 0.000 description 1
- CRZQGDNQQAALAY-UHFFFAOYSA-N Methyl benzeneacetate Chemical compound COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 108700011067 Necrosome Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241001458120 Orophe Species 0.000 description 1
- 241000712464 Orthomyxoviridae Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 208000024571 Pick disease Diseases 0.000 description 1
- 206010035737 Pneumonia viral Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 101710092489 Protein kinase 2 Proteins 0.000 description 1
- 101710092490 Protein kinase 3 Proteins 0.000 description 1
- 101150025038 RIPK3 gene Proteins 0.000 description 1
- 102100022501 Receptor-interacting serine/threonine-protein kinase 1 Human genes 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000005475 Vascular calcification Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 230000010398 acute inflammatory response Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 210000001552 airway epithelial cell Anatomy 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 150000001720 carbohydrates Chemical class 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
- 238000004113 cell culture Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000004715 cellular signal transduction Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- NMMPMZWIIQCZBA-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylethanamine Chemical compound [Pd+]Cl.NCCC1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 NMMPMZWIIQCZBA-UHFFFAOYSA-M 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 208000028919 diffuse intrinsic pontine glioma Diseases 0.000 description 1
- 208000026144 diffuse midline glioma, H3 K27M-mutant Diseases 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 210000005081 epithelial layer Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- AAUBVINEXCCXOK-UHFFFAOYSA-N ethyl 4,6-dichloropyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=C(Cl)C=C1Cl AAUBVINEXCCXOK-UHFFFAOYSA-N 0.000 description 1
- QINRQIZOBCQKAZ-UHFFFAOYSA-N ethyl 4-amino-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1N QINRQIZOBCQKAZ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001723 extracellular space Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000009215 host defense mechanism Effects 0.000 description 1
- 102000054953 human ACVR1 Human genes 0.000 description 1
- 102000050354 human NOD2 Human genes 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 208000014416 lysosomal lipid storage disease Diseases 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- ZLZZAXUKBHFTHA-UHFFFAOYSA-N n,n-diethyl-2-(4-nitrophenoxy)ethanamine Chemical compound CCN(CC)CCOC1=CC=C([N+]([O-])=O)C=C1 ZLZZAXUKBHFTHA-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 229940127255 pan-caspase inhibitor Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000008741 proinflammatory signaling process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical group N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 208000009421 viral pneumonia Diseases 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000001262 western blot Methods 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Rheumatology (AREA)
- Psychiatry (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962848719P | 2019-05-16 | 2019-05-16 | |
| US201962848648P | 2019-05-16 | 2019-05-16 | |
| US62/848,648 | 2019-05-16 | ||
| US62/848,719 | 2019-05-16 | ||
| PCT/US2020/032784 WO2020232190A1 (en) | 2019-05-16 | 2020-05-14 | Protein kinase inhibitors and uses thereof for the treatment of diseases and conditions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3137869A1 true CA3137869A1 (en) | 2020-11-19 |
Family
ID=70919255
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3137869A Pending CA3137869A1 (en) | 2019-05-16 | 2020-05-14 | Protein kinase inhibitors and uses thereof for the treatment of diseases and conditions |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20220194937A1 (enExample) |
| EP (2) | EP4480485A3 (enExample) |
| JP (2) | JP7546603B2 (enExample) |
| AU (1) | AU2020275304B2 (enExample) |
| CA (1) | CA3137869A1 (enExample) |
| WO (1) | WO2020232190A1 (enExample) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11174255B2 (en) * | 2017-05-15 | 2021-11-16 | University Of Houston System | Pyrido[2,3-d]pyrimidin-7-ones and related compounds as inhibitors of protein kinases |
| US20220194937A1 (en) * | 2019-05-16 | 2022-06-23 | University Of Houston System | Protein kinase inhibitors and uses thereof for the treatment of diseases and conditions |
| CN113072471B (zh) * | 2021-03-02 | 2022-09-16 | 四川美大康华康药业有限公司 | 一种利非司特中间体及其制备方法 |
| WO2024097805A1 (en) * | 2022-11-01 | 2024-05-10 | Trustees Of Tufts College | Mixed lineage kinase domain like pseudokinase (mlkl) activators |
| WO2024199388A1 (zh) * | 2023-03-29 | 2024-10-03 | 微境生物医药科技(上海)有限公司 | 作为myt1抑制剂的化合物 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL117923A (en) * | 1995-05-03 | 2000-06-01 | Warner Lambert Co | Anti-cancer pharmaceutical compositions containing polysubstituted pyrido¬2,3-d¾pyrimidine derivatives and certain such novel compounds |
| WO1999009030A1 (en) * | 1997-08-20 | 1999-02-25 | Warner-Lambert Company | Naphthyridinones for inhibiting protein tyrosine kinase and cell cycle kinase mediated cellular proliferation |
| HUP0203803A3 (en) * | 2000-01-27 | 2004-09-28 | Warner Lambert Co | Pyridopyrimidinone derivatives for treatment of neurodegenerative disease |
| WO2014031571A1 (en) * | 2012-08-21 | 2014-02-27 | Icahn School Of Medicine At Mount Sinai | Treatment of viral infections |
| WO2015179436A1 (en) * | 2014-05-19 | 2015-11-26 | Sanford-Burnham Medical Research Institute | Inflammation therapy using mekk3 inhibitors or blocking peptides |
| US11174255B2 (en) * | 2017-05-15 | 2021-11-16 | University Of Houston System | Pyrido[2,3-d]pyrimidin-7-ones and related compounds as inhibitors of protein kinases |
| US20220194937A1 (en) * | 2019-05-16 | 2022-06-23 | University Of Houston System | Protein kinase inhibitors and uses thereof for the treatment of diseases and conditions |
-
2020
- 2020-05-14 US US17/595,406 patent/US20220194937A1/en active Pending
- 2020-05-14 EP EP24191377.1A patent/EP4480485A3/en active Pending
- 2020-05-14 JP JP2021568650A patent/JP7546603B2/ja active Active
- 2020-05-14 AU AU2020275304A patent/AU2020275304B2/en active Active
- 2020-05-14 WO PCT/US2020/032784 patent/WO2020232190A1/en not_active Ceased
- 2020-05-14 CA CA3137869A patent/CA3137869A1/en active Pending
- 2020-05-14 EP EP20729566.8A patent/EP3968991B1/en active Active
-
2024
- 2024-08-27 JP JP2024145040A patent/JP2024170457A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU2020275304A1 (en) | 2021-12-16 |
| JP2024170457A (ja) | 2024-12-10 |
| WO2020232190A1 (en) | 2020-11-19 |
| EP3968991C0 (en) | 2024-07-31 |
| EP4480485A3 (en) | 2025-02-26 |
| US20220194937A1 (en) | 2022-06-23 |
| JP2022533182A (ja) | 2022-07-21 |
| EP3968991A1 (en) | 2022-03-23 |
| JP7546603B2 (ja) | 2024-09-06 |
| AU2020275304B2 (en) | 2025-01-23 |
| EP3968991B1 (en) | 2024-07-31 |
| EP4480485A2 (en) | 2024-12-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2020275304B2 (en) | Protein kinase inhibitors and uses thereof for the treatment of diseases and conditions | |
| JP6759514B2 (ja) | ブロモドメインに対して活性な化合物 | |
| AU2017268536B2 (en) | Novel compounds and compositions for inhibition of FASN | |
| TWI222971B (en) | Antagonists of MCP-1 function and methods of use thereof | |
| KR101530117B1 (ko) | 야누스 키나제 억제제 화합물 및 방법 | |
| JP2021152064A (ja) | 乳酸脱水素酵素の小分子阻害剤及びその使用方法 | |
| CN108794411B (zh) | 某些化学实体、组合物及方法 | |
| CN114555588B (zh) | 作为axl抑制剂的喹唑啉类化合物 | |
| AU2018300123B2 (en) | New heteroaryl amide derivatives as selective inhibitors of histone deacetylases 1 and 2 (HDAC1-2) | |
| JP2023512038A (ja) | 化合物及びその使用 | |
| US11066370B2 (en) | Kinase inhibitor compounds, compositions, and methods of treating cancer | |
| WO2016026445A1 (zh) | 作为fgfr激酶抑制剂的吲唑类化合物及其制备和应用 | |
| CN107709320A (zh) | 一种吡啶并氮杂环化合物及其制备方法和用途 | |
| TW201113267A (en) | Quinazolines as potassium ion channel inhibitors | |
| US20240327403A1 (en) | PYRIDO[2,3-d]PYRIMIDIN-7-ONES AND RELATED COMPOUNDS AS INHIBITORS OF PROTEIN KINASES | |
| WO2014079232A1 (zh) | 7-氧代吡啶并嘧啶类化合物及其药用组合物和应用 | |
| KR20170045308A (ko) | 인간 면역결핍 바이러스 복제의 억제제로서 이미다조[1,2-a]피리딘 유도체 | |
| CN106795152B (zh) | 蛋白激酶抑制剂 | |
| CN106986832A (zh) | Vegfr3抑制剂 | |
| CN114981256B (zh) | 干扰素基因刺激物sting的单环激动剂 | |
| CN106146493A (zh) | 吡唑并[3,4-b]吡啶类和吲唑类化合物的制备方法和用途 | |
| EP2716632A1 (en) | Inhibitors of viral replication, their process of preparation and their therapeutical uses | |
| CN115003383B (zh) | 干扰素基因刺激物sting的双环激动剂 | |
| KR102288434B1 (ko) | 신규한 (이소프로필-트리아졸릴)피리디닐 치환된 벤조옥사지논 또는 벤조티아지논 유도체 및 이의 용도 | |
| Meng et al. | Design, synthesis and dipeptidyl peptidase 4 inhibition of novel aminomethyl biaryl derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20240501 |