CN112513044B - 吡咯并[1,2-b]哒嗪衍生物 - Google Patents
吡咯并[1,2-b]哒嗪衍生物 Download PDFInfo
- Publication number
- CN112513044B CN112513044B CN201980046945.8A CN201980046945A CN112513044B CN 112513044 B CN112513044 B CN 112513044B CN 201980046945 A CN201980046945 A CN 201980046945A CN 112513044 B CN112513044 B CN 112513044B
- Authority
- CN
- China
- Prior art keywords
- inhibitors
- antagonists
- receptor
- modulators
- agonists
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- NISJKLIMPQPAQS-UHFFFAOYSA-N pyrrolo[1,2-b]pyridazine Chemical class C1=CC=NN2C=CC=C21 NISJKLIMPQPAQS-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 114
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 52
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 14
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 15
- 201000010099 disease Diseases 0.000 abstract description 9
- 239000003112 inhibitor Substances 0.000 description 290
- 239000005557 antagonist Substances 0.000 description 132
- 239000003446 ligand Substances 0.000 description 104
- -1 IL-1β Proteins 0.000 description 76
- 239000000556 agonist Substances 0.000 description 57
- 239000000243 solution Substances 0.000 description 47
- 229940044551 receptor antagonist Drugs 0.000 description 37
- 239000002464 receptor antagonist Substances 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 32
- 229940044601 receptor agonist Drugs 0.000 description 30
- 239000000018 receptor agonist Substances 0.000 description 30
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 30
- 108010012236 Chemokines Proteins 0.000 description 29
- 102000019034 Chemokines Human genes 0.000 description 29
- 125000000217 alkyl group Chemical group 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 239000004480 active ingredient Substances 0.000 description 27
- 229960000598 infliximab Drugs 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 108060003951 Immunoglobulin Proteins 0.000 description 25
- 238000009472 formulation Methods 0.000 description 25
- 102000018358 immunoglobulin Human genes 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 24
- 108010008165 Etanercept Proteins 0.000 description 21
- 229960000403 etanercept Drugs 0.000 description 21
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 20
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 20
- 229910052805 deuterium Inorganic materials 0.000 description 20
- 239000003826 tablet Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 17
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 17
- 229960002964 adalimumab Drugs 0.000 description 16
- 229960000106 biosimilars Drugs 0.000 description 16
- 229940043355 kinase inhibitor Drugs 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 15
- 229960001350 tofacitinib Drugs 0.000 description 15
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 15
- 239000004012 Tofacitinib Substances 0.000 description 14
- 229940121649 protein inhibitor Drugs 0.000 description 14
- 239000012268 protein inhibitor Substances 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 14
- 229960004641 rituximab Drugs 0.000 description 14
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 13
- 239000004615 ingredient Substances 0.000 description 13
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 13
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 13
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 13
- 101000977771 Homo sapiens Interleukin-1 receptor-associated kinase 4 Proteins 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 102100023533 Interleukin-1 receptor-associated kinase 4 Human genes 0.000 description 12
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229960003697 abatacept Drugs 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 229960001743 golimumab Drugs 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 229960002009 naproxen Drugs 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 108010002350 Interleukin-2 Proteins 0.000 description 11
- 102000000588 Interleukin-2 Human genes 0.000 description 11
- 108090001005 Interleukin-6 Proteins 0.000 description 11
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 11
- 108010029697 CD40 Ligand Proteins 0.000 description 10
- 102100032937 CD40 ligand Human genes 0.000 description 10
- 206010009900 Colitis ulcerative Diseases 0.000 description 10
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 10
- 108010036949 Cyclosporine Proteins 0.000 description 10
- 102100030694 Interleukin-11 Human genes 0.000 description 10
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 10
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 10
- 201000006704 Ulcerative Colitis Diseases 0.000 description 10
- 229960001265 ciclosporin Drugs 0.000 description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 10
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 10
- 229960002411 imatinib Drugs 0.000 description 10
- 229960004963 mesalazine Drugs 0.000 description 10
- 229960005027 natalizumab Drugs 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 229960004586 rosiglitazone Drugs 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 9
- 102000013691 Interleukin-17 Human genes 0.000 description 9
- 108050003558 Interleukin-17 Proteins 0.000 description 9
- 102000004889 Interleukin-6 Human genes 0.000 description 9
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 9
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 208000030159 metabolic disease Diseases 0.000 description 9
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 9
- 229960004866 mycophenolate mofetil Drugs 0.000 description 9
- 229940075993 receptor modulator Drugs 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 8
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 8
- 102100032818 Integrin alpha-4 Human genes 0.000 description 8
- 108010065805 Interleukin-12 Proteins 0.000 description 8
- 239000002139 L01XE22 - Masitinib Substances 0.000 description 8
- YALNUENQHAQXEA-UHFFFAOYSA-N N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester Chemical compound C1=CC2=CC(CN(CC)CC)=CC=C2C=C1COC(=O)NC1=CC=C(C(=O)NO)C=C1 YALNUENQHAQXEA-UHFFFAOYSA-N 0.000 description 8
- 102000003945 NF-kappa B Human genes 0.000 description 8
- 108010057466 NF-kappa B Proteins 0.000 description 8
- 108090000315 Protein Kinase C Proteins 0.000 description 8
- 102000003923 Protein Kinase C Human genes 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 description 8
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 229950010415 givinostat Drugs 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- WJEOLQLKVOPQFV-UHFFFAOYSA-N masitinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3SC=C(N=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 WJEOLQLKVOPQFV-UHFFFAOYSA-N 0.000 description 8
- 229960004655 masitinib Drugs 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 229960000485 methotrexate Drugs 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 239000003909 protein kinase inhibitor Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 229950010130 tamibarotene Drugs 0.000 description 8
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 8
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 7
- 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 7
- 208000011231 Crohn disease Diseases 0.000 description 7
- 102000003777 Interleukin-1 beta Human genes 0.000 description 7
- 108090000193 Interleukin-1 beta Proteins 0.000 description 7
- 102000019197 Superoxide Dismutase Human genes 0.000 description 7
- 108010012715 Superoxide dismutase Proteins 0.000 description 7
- YWBMODPHGARALU-SGIIKHNDSA-N acetic acid (2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound CC(O)=O.C([C@@H](C(=O)N[C@@H](CCSC)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 YWBMODPHGARALU-SGIIKHNDSA-N 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 description 7
- 239000006143 cell culture medium Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 210000003494 hepatocyte Anatomy 0.000 description 7
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- RRDUCQFUFXBIPW-UHFFFAOYSA-N pyrrolo[1,2-b]pyridazine-3-carbonitrile Chemical compound C1=C(C#N)C=NN2C=CC=C21 RRDUCQFUFXBIPW-UHFFFAOYSA-N 0.000 description 7
- 230000019491 signal transduction Effects 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 125000000547 substituted alkyl group Chemical group 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- LIFNDDBLJFPEAN-BPSSIEEOSA-N (2s)-4-amino-2-[[(2s)-2-[[2-[[2-[[(2s)-5-amino-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s)-2-[[(2s)-5-oxopyrrolidine-2-carbonyl]amino]propanoyl]amino]hexanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@@H]1CCC(=O)N1 LIFNDDBLJFPEAN-BPSSIEEOSA-N 0.000 description 6
- HMLGSIZOMSVISS-ONJSNURVSA-N (7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 description 6
- XPRDUGXOWVXZLL-UHFFFAOYSA-N 2-[[2-fluoro-4-(3-methoxyphenyl)phenyl]carbamoyl]cyclopentene-1-carboxylic acid Chemical compound COC1=CC=CC(C=2C=C(F)C(NC(=O)C=3CCCC=3C(O)=O)=CC=2)=C1 XPRDUGXOWVXZLL-UHFFFAOYSA-N 0.000 description 6
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 6
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 6
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 6
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 description 6
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 6
- 108010009685 Cholinergic Receptors Proteins 0.000 description 6
- 108010003422 Circulating Thymic Factor Proteins 0.000 description 6
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 6
- 101710114790 Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 6
- 108010092372 Granulocyte-Macrophage Colony-Stimulating Factor Receptors Proteins 0.000 description 6
- 102000016355 Granulocyte-Macrophage Colony-Stimulating Factor Receptors Human genes 0.000 description 6
- 239000007995 HEPES buffer Substances 0.000 description 6
- 239000008961 HMPL-004 Substances 0.000 description 6
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 6
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 6
- 108010041012 Integrin alpha4 Proteins 0.000 description 6
- 108010022222 Integrin beta1 Proteins 0.000 description 6
- 102000012355 Integrin beta1 Human genes 0.000 description 6
- 102000013462 Interleukin-12 Human genes 0.000 description 6
- 102000015696 Interleukins Human genes 0.000 description 6
- 108010063738 Interleukins Proteins 0.000 description 6
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 6
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 6
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 6
- 102000002689 Toll-like receptor Human genes 0.000 description 6
- 108020000411 Toll-like receptor Proteins 0.000 description 6
- 102000034337 acetylcholine receptors Human genes 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 229960001164 apremilast Drugs 0.000 description 6
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 6
- 229950000210 beclometasone dipropionate Drugs 0.000 description 6
- 229940125388 beta agonist Drugs 0.000 description 6
- 239000003124 biologic agent Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 229960003115 certolizumab pegol Drugs 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical group 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 102000002467 interleukin receptors Human genes 0.000 description 6
- 108010093036 interleukin receptors Proteins 0.000 description 6
- 229960000681 leflunomide Drugs 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000002503 metabolic effect Effects 0.000 description 6
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 6
- 229960003086 naltrexone Drugs 0.000 description 6
- 229960000381 omeprazole Drugs 0.000 description 6
- 108010046821 oprelvekin Proteins 0.000 description 6
- 229960001840 oprelvekin Drugs 0.000 description 6
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 6
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- NZCRJKRKKOLAOJ-XRCRFVBUSA-N rifaximin Chemical compound OC1=C(C(O)=C2C)C3=C4N=C5C=C(C)C=CN5C4=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O NZCRJKRKKOLAOJ-XRCRFVBUSA-N 0.000 description 6
- 229960003040 rifaximin Drugs 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 238000013456 study Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 125000003107 substituted aryl group Chemical group 0.000 description 6
- 229960001967 tacrolimus Drugs 0.000 description 6
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 6
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 6
- 229960002871 tenoxicam Drugs 0.000 description 6
- 229950010644 vidofludimus Drugs 0.000 description 6
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 5
- JJKOQZHWYLMASZ-FJWDNACWSA-N (3s,7r,8r,9s,10r,13s,14s,17r)-17-ethynyl-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-3,7,17-triol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3[C@@H](O)C=C21 JJKOQZHWYLMASZ-FJWDNACWSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 102000011185 B-lymphocyte antigen CD20 Human genes 0.000 description 5
- 108050001413 B-lymphocyte antigen CD20 Proteins 0.000 description 5
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 5
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 5
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 5
- 229940127590 IRAK4 inhibitor Drugs 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 102000051628 Interleukin-1 receptor antagonist Human genes 0.000 description 5
- 108700021006 Interleukin-1 receptor antagonist Proteins 0.000 description 5
- 102100036342 Interleukin-1 receptor-associated kinase 1 Human genes 0.000 description 5
- 108010065637 Interleukin-23 Proteins 0.000 description 5
- 102000003840 Opioid Receptors Human genes 0.000 description 5
- 108090000137 Opioid Receptors Proteins 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 108091008874 T cell receptors Proteins 0.000 description 5
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 5
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 5
- 102100040247 Tumor necrosis factor Human genes 0.000 description 5
- ZMJWRJKGPUDEOX-LMXUULCNSA-A alicaforsen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP([O-])(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)CO)[C@@H](OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([S-])(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C(N=C(N)C=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(N=C(N)C=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(N=C(N)C=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(NC(=O)C(C)=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C(N=C(N)C=C2)=O)OP([O-])(=S)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)C1 ZMJWRJKGPUDEOX-LMXUULCNSA-A 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 229960004238 anakinra Drugs 0.000 description 5
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- DREIJXJRTLTGJC-ZLBJMMTISA-N chembl3137308 Chemical compound C([C@H]1C[C@@](O)(C2)C3)C2C[C@H]3[C@H]1NC1=C2C=CNC2=NC=C1C(=O)N DREIJXJRTLTGJC-ZLBJMMTISA-N 0.000 description 5
- 125000003636 chemical group Chemical group 0.000 description 5
- 239000006184 cosolvent Substances 0.000 description 5
- 229930182912 cyclosporin Natural products 0.000 description 5
- 238000000502 dialysis Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 5
- 229960004770 esomeprazole Drugs 0.000 description 5
- 229960005293 etodolac Drugs 0.000 description 5
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 5
- 229960000556 fingolimod Drugs 0.000 description 5
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 5
- 102000006815 folate receptor Human genes 0.000 description 5
- 108020005243 folate receptor Proteins 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 229960004461 interferon beta-1a Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 5
- 229960004710 maraviroc Drugs 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229950005157 peficitinib Drugs 0.000 description 5
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 5
- 229960005205 prednisolone Drugs 0.000 description 5
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 5
- 229960004540 secukinumab Drugs 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 229960004914 vedolizumab Drugs 0.000 description 5
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 5
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 description 4
- LATZVDXOTDYECD-UFTFXDLESA-N 2,3-dihydroxybutanedioic acid (3S,4R)-3-ethyl-4-(1,5,7,10-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),3,7,9,11-pentaen-12-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide tetrahydrate Chemical compound O.O.O.O.OC(C(O)C(O)=O)C(O)=O.CC[C@@H]1CN(C[C@@H]1c1cnc2cnc3[nH]ccc3n12)C(=O)NCC(F)(F)F LATZVDXOTDYECD-UFTFXDLESA-N 0.000 description 4
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 4
- CAOTVXGYTWCKQE-UHFFFAOYSA-N 3-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)-1-adamantanecarboxamide Chemical compound C1=CC(Cl)=CC=C1C1(C2)CC(C3)(C(=O)NCC=4C=CN=CC=4)CC2CC3C1 CAOTVXGYTWCKQE-UHFFFAOYSA-N 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 4
- 102100022464 5'-nucleotidase Human genes 0.000 description 4
- XRVDGNKRPOAQTN-FQEVSTJZSA-N 5-[3-[(1s)-1-(2-hydroxyethylamino)-2,3-dihydro-1h-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-propan-2-yloxybenzonitrile Chemical compound C1=C(C#N)C(OC(C)C)=CC=C1C1=NC(C=2C=3CC[C@@H](C=3C=CC=2)NCCO)=NO1 XRVDGNKRPOAQTN-FQEVSTJZSA-N 0.000 description 4
- BNVPFDRNGHMRJS-UHFFFAOYSA-N 5-cyano-n-[2-(4,4-dimethylcyclohexen-1-yl)-6-(2,2,6,6-tetramethyloxan-4-yl)pyridin-3-yl]-1h-imidazole-2-carboxamide Chemical compound C1C(C)(C)CCC(C=2C(=CC=C(N=2)C2CC(C)(C)OC(C)(C)C2)NC(=O)C=2NC=C(N=2)C#N)=C1 BNVPFDRNGHMRJS-UHFFFAOYSA-N 0.000 description 4
- 102100022455 Adrenocorticotropic hormone receptor Human genes 0.000 description 4
- 108010028700 Amine Oxidase (Copper-Containing) Proteins 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WPTTVJLTNAWYAO-KPOXMGGZSA-N Bardoxolone methyl Chemical group C([C@@]12C)=C(C#N)C(=O)C(C)(C)[C@@H]1CC[C@]1(C)C2=CC(=O)[C@@H]2[C@@H]3CC(C)(C)CC[C@]3(C(=O)OC)CC[C@]21C WPTTVJLTNAWYAO-KPOXMGGZSA-N 0.000 description 4
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 description 4
- 102000010183 Bradykinin receptor Human genes 0.000 description 4
- 108050001736 Bradykinin receptor Proteins 0.000 description 4
- 108090000312 Calcium Channels Proteins 0.000 description 4
- 102000003922 Calcium Channels Human genes 0.000 description 4
- 229940122805 Cathepsin S inhibitor Drugs 0.000 description 4
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 4
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 4
- 108010078239 Chemokine CX3CL1 Proteins 0.000 description 4
- 101000573945 Coccidioides posadasii (strain C735) Neutral protease 2 homolog MEP2 Proteins 0.000 description 4
- 102000008954 Copper amine oxidases Human genes 0.000 description 4
- 108010074311 Corticotropin Receptors Proteins 0.000 description 4
- 229930105110 Cyclosporin A Natural products 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 4
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 4
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 4
- 102000013818 Fractalkine Human genes 0.000 description 4
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 4
- 102000009490 IgG Receptors Human genes 0.000 description 4
- 108010073807 IgG Receptors Proteins 0.000 description 4
- 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 4
- 229940122355 Insulin sensitizer Drugs 0.000 description 4
- 102100033016 Integrin beta-7 Human genes 0.000 description 4
- 102000003996 Interferon-beta Human genes 0.000 description 4
- 108090000467 Interferon-beta Proteins 0.000 description 4
- 102000008070 Interferon-gamma Human genes 0.000 description 4
- 108010074328 Interferon-gamma Proteins 0.000 description 4
- 102000000589 Interleukin-1 Human genes 0.000 description 4
- 101710199015 Interleukin-1 receptor-associated kinase 1 Proteins 0.000 description 4
- 108090000177 Interleukin-11 Proteins 0.000 description 4
- 102000004388 Interleukin-4 Human genes 0.000 description 4
- 108090000978 Interleukin-4 Proteins 0.000 description 4
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 4
- 102000010781 Interleukin-6 Receptors Human genes 0.000 description 4
- 102000042838 JAK family Human genes 0.000 description 4
- 108091082332 JAK family Proteins 0.000 description 4
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 4
- 102100034723 LanC-like protein 2 Human genes 0.000 description 4
- 101710195374 LanC-like protein 2 Proteins 0.000 description 4
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 102100037808 Mitogen-activated protein kinase 8 Human genes 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 4
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 4
- 102100037602 P2X purinoceptor 7 Human genes 0.000 description 4
- 101710189965 P2X purinoceptor 7 Proteins 0.000 description 4
- 108091008606 PDGF receptors Proteins 0.000 description 4
- 108091007960 PI3Ks Proteins 0.000 description 4
- 108010016731 PPAR gamma Proteins 0.000 description 4
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 4
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 4
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 4
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 4
- 102000015439 Phospholipases Human genes 0.000 description 4
- 108010064785 Phospholipases Proteins 0.000 description 4
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 4
- 108700023400 Platelet-activating factor receptors Proteins 0.000 description 4
- 101000944644 Rickettsia typhi (strain ATCC VR-144 / Wilmington) Co-chaperonin GroES Proteins 0.000 description 4
- 101150099493 STAT3 gene Proteins 0.000 description 4
- 229910004298 SiO 2 Inorganic materials 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 description 4
- 241000960389 Trichuris suis Species 0.000 description 4
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 description 4
- 229960004420 aceclofenac Drugs 0.000 description 4
- 239000003470 adrenal cortex hormone Substances 0.000 description 4
- 229960000548 alemtuzumab Drugs 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229960000074 biopharmaceutical Drugs 0.000 description 4
- 229950011318 cannabidiol Drugs 0.000 description 4
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 description 4
- 239000003557 cannabinoid Substances 0.000 description 4
- 229930003827 cannabinoid Natural products 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000000460 chlorine Chemical group 0.000 description 4
- 229910052801 chlorine Chemical group 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 208000020832 chronic kidney disease Diseases 0.000 description 4
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 4
- 229960002626 clarithromycin Drugs 0.000 description 4
- 229950001565 clazakizumab Drugs 0.000 description 4
- WDQPAMHFFCXSNU-BGABXYSRSA-N clofazimine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC(Cl)=CC=3)C(=N/C(C)C)/C=C2N1C1=CC=C(Cl)C=C1 WDQPAMHFFCXSNU-BGABXYSRSA-N 0.000 description 4
- 229960004287 clofazimine Drugs 0.000 description 4
- 230000001086 cytosolic effect Effects 0.000 description 4
- 229960001251 denosumab Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229960002344 dexamethasone sodium phosphate Drugs 0.000 description 4
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 description 4
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 4
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 229950004912 etrolizumab Drugs 0.000 description 4
- 229960005167 everolimus Drugs 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 229950006663 filgotinib Drugs 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Chemical group 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 239000003862 glucocorticoid Substances 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 4
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 239000002348 inosinate dehydrogenase inhibitor Substances 0.000 description 4
- 108010021315 integrin beta7 Proteins 0.000 description 4
- 102000006495 integrins Human genes 0.000 description 4
- 108010044426 integrins Proteins 0.000 description 4
- 229960003130 interferon gamma Drugs 0.000 description 4
- 229960001388 interferon-beta Drugs 0.000 description 4
- 229940100601 interleukin-6 Drugs 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 101150079478 jak1 gene Proteins 0.000 description 4
- XCIGZBVOUQVIPI-UHFFFAOYSA-N lanraplenib Chemical compound NC1=CN=CC(=N1)C=1N=C(C=2N(C1)C=CN2)NC2=CC=C(C=C2)N2CCN(CC2)C2COC2 XCIGZBVOUQVIPI-UHFFFAOYSA-N 0.000 description 4
- 229950007439 lenzilumab Drugs 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 229960001929 meloxicam Drugs 0.000 description 4
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 4
- 229960005249 misoprostol Drugs 0.000 description 4
- 230000002438 mitochondrial effect Effects 0.000 description 4
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 4
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 4
- 210000001616 monocyte Anatomy 0.000 description 4
- YDYLISNLJUDIGF-GXDYCHSMSA-N n-[(4r)-4-[(3r,5s,7r,8r,9s,10s,12s,13r,14s,17r)-3,7,12-tris(3-aminopropoxy)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentyl]octan-1-amine Chemical compound C([C@H]1C[C@H]2OCCCN)[C@H](OCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCNCCCCCCCC)[C@@]2(C)[C@@H](OCCCN)C1 YDYLISNLJUDIGF-GXDYCHSMSA-N 0.000 description 4
- RIJLVEAXPNLDTC-UHFFFAOYSA-N n-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide Chemical compound C1CC1C(=O)NC(=NN12)N=C1C=CC=C2C(C=C1)=CC=C1CN1CCS(=O)(=O)CC1 RIJLVEAXPNLDTC-UHFFFAOYSA-N 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 4
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 4
- 239000002457 oxidoreductase inhibitor Substances 0.000 description 4
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 4
- 239000003358 phospholipase A2 inhibitor Substances 0.000 description 4
- 102000030769 platelet activating factor receptor Human genes 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 229940076155 protein modulator Drugs 0.000 description 4
- 101150103875 purH gene Proteins 0.000 description 4
- 229960000885 rifabutin Drugs 0.000 description 4
- 229960001549 ropivacaine Drugs 0.000 description 4
- 108010038379 sargramostim Proteins 0.000 description 4
- 229960002530 sargramostim Drugs 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 125000005017 substituted alkenyl group Chemical group 0.000 description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 229960003989 tocilizumab Drugs 0.000 description 4
- GDHFOVCRYCPOTK-QBFSEMIESA-N (z)-2-cyano-3-cyclopropyl-3-hydroxy-n-[3-methyl-4-(trifluoromethyl)phenyl]prop-2-enamide Chemical compound C1=C(C(F)(F)F)C(C)=CC(NC(=O)C(\C#N)=C(/O)C2CC2)=C1 GDHFOVCRYCPOTK-QBFSEMIESA-N 0.000 description 3
- RVLCUCVJZVRNDC-IMJSIDKUSA-N 2-[(2s,5s)-5-methyl-3,6-dioxopiperazin-2-yl]acetic acid Chemical compound C[C@@H]1NC(=O)[C@H](CC(O)=O)NC1=O RVLCUCVJZVRNDC-IMJSIDKUSA-N 0.000 description 3
- AUZUGWXLBGZUPP-GXDHUFHOSA-N 2-[4-[(e)-(2-oxocyclohexylidene)methyl]phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1\C=C/1C(=O)CCCC\1 AUZUGWXLBGZUPP-GXDHUFHOSA-N 0.000 description 3
- JVCPIJKPAKAIIP-UHFFFAOYSA-N 2-amino-2-[2-[4-heptoxy-3-(trifluoromethyl)phenyl]ethyl]propane-1,3-diol Chemical compound CCCCCCCOC1=CC=C(CCC(N)(CO)CO)C=C1C(F)(F)F JVCPIJKPAKAIIP-UHFFFAOYSA-N 0.000 description 3
- XCHHJFVNQPPLJK-UHFFFAOYSA-N 2-carboxyphenolate;1h-imidazol-1-ium Chemical compound C1=CNC=N1.OC(=O)C1=CC=CC=C1O XCHHJFVNQPPLJK-UHFFFAOYSA-N 0.000 description 3
- UPMXNNIRAGDFEH-UHFFFAOYSA-N 3,5-dibromo-4-hydroxybenzonitrile Chemical compound OC1=C(Br)C=C(C#N)C=C1Br UPMXNNIRAGDFEH-UHFFFAOYSA-N 0.000 description 3
- LUNFNDILGRBFCA-MRVPVSSYSA-N 6-bromo-4-chloro-n-[(2r)-2-fluoro-3-hydroxy-3-methylbutyl]pyridine-3-carboxamide Chemical compound CC(C)(O)[C@H](F)CNC(=O)C1=CN=C(Br)C=C1Cl LUNFNDILGRBFCA-MRVPVSSYSA-N 0.000 description 3
- XWVFYJPQFMTKCQ-UHFFFAOYSA-N 6-bromo-4-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(Br)C=C1Cl XWVFYJPQFMTKCQ-UHFFFAOYSA-N 0.000 description 3
- 108010029945 ABT-122 Proteins 0.000 description 3
- 108010093667 ALX-0061 Proteins 0.000 description 3
- 108010067717 AT-1001 Proteins 0.000 description 3
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 239000005489 Bromoxynil Substances 0.000 description 3
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 3
- WGEWYYPHYMGJNT-HLHYUOOASA-N CC(C)C[C@@H](NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(=O)N)C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N1)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](N)CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)C(=O)O Chemical compound CC(C)C[C@@H](NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(=O)N)C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N1)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](N)CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)C(=O)O WGEWYYPHYMGJNT-HLHYUOOASA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 108010018888 Choline kinase Proteins 0.000 description 3
- 102100031065 Choline kinase alpha Human genes 0.000 description 3
- 241000193163 Clostridioides difficile Species 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- MWHHJYUHCZWSLS-UHFFFAOYSA-N FC=1C=C(C=CC1C1=C2CNC(C2=C(C=C1)C=1NC(=CN1)C)=O)NC(=O)NC1=C(C=C(C=C1F)F)F Chemical compound FC=1C=C(C=CC1C1=C2CNC(C2=C(C=C1)C=1NC(=CN1)C)=O)NC(=O)NC1=C(C=C(C=C1F)F)F MWHHJYUHCZWSLS-UHFFFAOYSA-N 0.000 description 3
- 108090001047 Fibroblast growth factor 10 Proteins 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 102100023416 G-protein coupled receptor 15 Human genes 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- ANMATWQYLIFGOK-UHFFFAOYSA-N Iguratimod Chemical compound CS(=O)(=O)NC1=CC=2OC=C(NC=O)C(=O)C=2C=C1OC1=CC=CC=C1 ANMATWQYLIFGOK-UHFFFAOYSA-N 0.000 description 3
- 102000002227 Interferon Type I Human genes 0.000 description 3
- 108010014726 Interferon Type I Proteins 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- 108090001007 Interleukin-8 Proteins 0.000 description 3
- 102000004890 Interleukin-8 Human genes 0.000 description 3
- 208000016604 Lyme disease Diseases 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical class OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 101800002641 Neuregulin-4 Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 102000004257 Potassium Channel Human genes 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 3
- 102100022658 Pro-neuregulin-4, membrane-bound isoform Human genes 0.000 description 3
- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 description 3
- 108010025832 RANK Ligand Proteins 0.000 description 3
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 108010016672 Syk Kinase Proteins 0.000 description 3
- 102000000551 Syk Kinase Human genes 0.000 description 3
- 101710179381 T-cell differentiation antigen CD6 Proteins 0.000 description 3
- 102100025131 T-cell differentiation antigen CD6 Human genes 0.000 description 3
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 3
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 102100024568 Tumor necrosis factor ligand superfamily member 11 Human genes 0.000 description 3
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 description 3
- NYGCNONRVCGHAT-UFIKZEAMSA-N acetic acid;2-[[(2s)-1-[(2s)-5-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]acetic acid Chemical compound CC(O)=O.NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O NYGCNONRVCGHAT-UFIKZEAMSA-N 0.000 description 3
- 229950011466 alicaforsen Drugs 0.000 description 3
- 229950004817 amiselimod Drugs 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000000074 antisense oligonucleotide Substances 0.000 description 3
- 238000012230 antisense oligonucleotides Methods 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 229960004168 balsalazide Drugs 0.000 description 3
- 229950002483 bardoxolone Drugs 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229950002853 bimekizumab Drugs 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 229960002874 briakinumab Drugs 0.000 description 3
- 229960003735 brodalumab Drugs 0.000 description 3
- 229960004436 budesonide Drugs 0.000 description 3
- 229940046731 calcineurin inhibitors Drugs 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 3
- 108010017271 denileukin diftitox Proteins 0.000 description 3
- 229960002923 denileukin diftitox Drugs 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000003363 dihydroorotate dehydrogenase inhibitor Substances 0.000 description 3
- 108010022410 dolcanatide Proteins 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 3
- 229960004945 etoricoxib Drugs 0.000 description 3
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000003176 fibrotic effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 3
- 229960000308 fosfomycin Drugs 0.000 description 3
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 3
- 108020001507 fusion proteins Proteins 0.000 description 3
- 102000037865 fusion proteins Human genes 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 229950003909 iguratimod Drugs 0.000 description 3
- 229960004769 imidazole salicylate Drugs 0.000 description 3
- 239000005414 inactive ingredient Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 229950009700 laflunimus Drugs 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Inorganic materials [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 3
- 229960000994 lumiracoxib Drugs 0.000 description 3
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 0.000 description 3
- 229940124302 mTOR inhibitor Drugs 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 3
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 3
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 3
- IVAQJHSXBVHUQT-ZVHZXABRSA-N methyl (e)-3-(3,5-dimethoxyphenyl)-2-[4-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]phenyl]prop-2-enoate Chemical compound C=1C=C(OC=2C=CC(CC3C(NC(=O)S3)=O)=CC=2)C=CC=1/C(C(=O)OC)=C\C1=CC(OC)=CC(OC)=C1 IVAQJHSXBVHUQT-ZVHZXABRSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 108010032806 molgramostim Proteins 0.000 description 3
- 229960003063 molgramostim Drugs 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 229960002715 nicotine Drugs 0.000 description 3
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 3
- 229950005751 ocrelizumab Drugs 0.000 description 3
- 229950010006 olokizumab Drugs 0.000 description 3
- 102000039479 opioid growth factor receptor family Human genes 0.000 description 3
- 108091056482 opioid growth factor receptor family Proteins 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 229950010552 pelubiprofen Drugs 0.000 description 3
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 108020001213 potassium channel Proteins 0.000 description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 description 3
- 235000011009 potassium phosphates Nutrition 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- JUOSGGQXEBBCJB-GORDUTHDSA-N rivanicline Chemical compound CNCC\C=C\C1=CC=CN=C1 JUOSGGQXEBBCJB-GORDUTHDSA-N 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 210000000130 stem cell Anatomy 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 3
- 229960002149 valganciclovir Drugs 0.000 description 3
- VJYDOJXJUCJUHL-UHFFFAOYSA-N varespladib methyl Chemical compound CCC1=C(C(=O)C(N)=O)C2=C(OCC(=O)OC)C=CC=C2N1CC1=CC=CC=C1 VJYDOJXJUCJUHL-UHFFFAOYSA-N 0.000 description 3
- 206010047470 viral myocarditis Diseases 0.000 description 3
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 3
- 229960005332 zileuton Drugs 0.000 description 3
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 2
- SFGFYNXPJMOUHK-PKAFTLKUSA-N (2r)-2-[[(2r)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-n-[(2r)-1-[[(2r)-1-[[(2r)-1-[[(2r)-1-[[(2r)-1-[[(2r)-1-[[2-[[(2r)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohe Chemical compound NC(N)=NCCC[C@@H](N)C(=O)N[C@H](CCCC)C(=O)N[C@H](CCCC)C(=O)N[C@H](CCCC)C(=O)N[C@H](CCCN=C(N)N)C(=O)N[C@H](CCCC)C(=O)N[C@H](CCCC)C(=O)N[C@H](CCCC)C(=O)NCC(=O)N[C@@H](C(N)=O)CC1=CC=C(O)C=C1 SFGFYNXPJMOUHK-PKAFTLKUSA-N 0.000 description 2
- YLFZHHDVRSYTKT-NRFANRHFSA-N (2s)-2-[(2,6-difluorobenzoyl)amino]-3-[4-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]phenyl]propanoic acid Chemical compound COC1=CC(COCC)=CC(OC)=C1C(C=C1)=CC=C1C[C@@H](C(O)=O)NC(=O)C1=C(F)C=CC=C1F YLFZHHDVRSYTKT-NRFANRHFSA-N 0.000 description 2
- NSPHQWLKCGGCQR-DLJDZFDSSA-N (2s)-2-[[(1r,4s,7s,10s,13s,16r,21r,27s,34r,37s,40s)-10-(2-amino-2-oxoethyl)-34-[[(2s)-4-carboxy-2-[[(2s)-3-carboxy-2-[[(2s)-2,4-diamino-4-oxobutanoyl]amino]propanoyl]amino]butanoyl]amino]-37-(2-carboxyethyl)-27-[(1r)-1-hydroxyethyl]-4-methyl-40-(2-methylp Chemical compound N1C(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(N)=O)CSSC[C@@H]2NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CSSC[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)[C@H]([C@@H](C)O)NC2=O NSPHQWLKCGGCQR-DLJDZFDSSA-N 0.000 description 2
- QLJYLJGYIDIJPT-VIFPVBQESA-N (2s)-3-(4-aminophenyl)-2-methoxypropanoic acid Chemical compound CO[C@H](C(O)=O)CC1=CC=C(N)C=C1 QLJYLJGYIDIJPT-VIFPVBQESA-N 0.000 description 2
- KSELABKNBIUMGG-YGBAREPYSA-N (2z,3ar,4r,5r,6as)-3,3-difluoro-4-[(e,3r,4r)-3-hydroxy-4-(3-methylphenyl)pent-1-enyl]-2-[4-(2h-tetrazol-5-yl)butylidene]-4,5,6,6a-tetrahydro-3ah-cyclopenta[b]furan-5-ol Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@H]1C1(F)F)/C=C/[C@@H](O)[C@H](C)C=2C=C(C)C=CC=2)\C1=C/CCCC=1N=NNN=1 KSELABKNBIUMGG-YGBAREPYSA-N 0.000 description 2
- DNBCBAXDWNDRNO-FOSCPWQOSA-N (3aS,6aR)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxamide Chemical compound COC1=NSC(NC(=O)N2C[C@H]3CC(C[C@H]3C2)N(C)C=2C=3C=CNC=3N=CN=2)=N1 DNBCBAXDWNDRNO-FOSCPWQOSA-N 0.000 description 2
- PYDDRGVUBLLKNK-CMPAXRDWSA-N (3e)-3-[[4-[(z)-3-[4-[(2-methylimidazo[4,5-c]pyridin-1-yl)methyl]piperidin-1-yl]-3-oxo-1-phenylprop-1-enyl]phenyl]hydrazinylidene]-6-oxocyclohexa-1,4-diene-1-carboxylic acid Chemical compound CC1=NC2=CN=CC=C2N1CC(CC1)CCN1C(=O)\C=C(C=1C=CC(N\N=C/2C=C(C(=O)C=C\2)C(O)=O)=CC=1)\C1=CC=CC=C1 PYDDRGVUBLLKNK-CMPAXRDWSA-N 0.000 description 2
- WZTIQQBMSJTRBR-WYKNNRPVSA-N (4S)-5-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-oxo-4-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]pentanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCC(=O)N1 WZTIQQBMSJTRBR-WYKNNRPVSA-N 0.000 description 2
- DOAUQKRTILFGHV-PDCMDPCFSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-6-amino-1-[[(2S,3S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]acetyl]amino]-5-oxopentanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)Cc1c[nH]cn1)[C@@H](C)O)[C@@H](C)O)[C@@H](C)CC)[C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O DOAUQKRTILFGHV-PDCMDPCFSA-N 0.000 description 2
- AKTXOQVMWSFEBQ-LCYFTJDESA-N (5z)-2-amino-5-[(3,5-ditert-butyl-4-hydroxyphenyl)methylidene]-1,3-thiazol-4-one Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(\C=C/2C(N=C(N)S\2)=O)=C1 AKTXOQVMWSFEBQ-LCYFTJDESA-N 0.000 description 2
- ZRYMMWAJAFUANM-INIZCTEOSA-N (7s)-3-fluoro-4-[3-(8-fluoro-1-methyl-2,4-dioxoquinazolin-3-yl)-2-methylphenyl]-7-(2-hydroxypropan-2-yl)-6,7,8,9-tetrahydro-5h-carbazole-1-carboxamide Chemical compound C1[C@@H](C(C)(C)O)CCC2=C1NC1=C2C(C2=C(C(=CC=C2)N2C(C3=CC=CC(F)=C3N(C)C2=O)=O)C)=C(F)C=C1C(N)=O ZRYMMWAJAFUANM-INIZCTEOSA-N 0.000 description 2
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- YQYFEGTYCUQBEI-UHFFFAOYSA-N 1-(2-chloro-3-fluorophenyl)-3-(4-chloro-2-hydroxy-3-piperazin-1-ylsulfonylphenyl)urea Chemical compound C1=CC(Cl)=C(S(=O)(=O)N2CCNCC2)C(O)=C1NC(=O)NC1=CC=CC(F)=C1Cl YQYFEGTYCUQBEI-UHFFFAOYSA-N 0.000 description 2
- ZIMLRKWQDLVPEK-UHFFFAOYSA-N 1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone Chemical compound C1=C(Cl)C(OC)=CC(N2CCN(CC2)C(=O)CN2C3=NC=CC=C3C(C=3NC=CN=3)=N2)=C1 ZIMLRKWQDLVPEK-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 102100024682 14-3-3 protein eta Human genes 0.000 description 2
- 101710188276 14-3-3 protein eta Proteins 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- MUFJHYRCIHHATF-UHFFFAOYSA-N 2-(3-phenyl-4,5-dihydro-1,2-oxazol-5-yl)acetic acid Chemical compound O1C(CC(=O)O)CC(C=2C=CC=CC=2)=N1 MUFJHYRCIHHATF-UHFFFAOYSA-N 0.000 description 2
- ADQZGIYHFQQPRB-UHFFFAOYSA-N 2-(4-fluorophenyl)-4-methoxy-3-pyridin-4-yl-1h-pyrrolo[2,3-b]pyridin-6-amine Chemical compound C1=2C(OC)=CC(N)=NC=2NC(C=2C=CC(F)=CC=2)=C1C1=CC=NC=C1 ADQZGIYHFQQPRB-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- MVGWUTBTXDYMND-QGZVFWFLSA-N 2-[(3r)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid Chemical compound C([C@@H]1CC(=O)O)CC(C2=C3)=C1NC2=CC=C3OCC(C=C1C(F)(F)F)=CC=C1C1CCCC1 MVGWUTBTXDYMND-QGZVFWFLSA-N 0.000 description 2
- OMPATGZMNFWVOH-UHFFFAOYSA-N 2-[2,6-difluoro-4-(3-methoxyphenyl)anilino]pyridine-3-carboxylic acid Chemical compound COC1=CC=CC(C=2C=C(F)C(NC=3C(=CC=CN=3)C(O)=O)=C(F)C=2)=C1 OMPATGZMNFWVOH-UHFFFAOYSA-N 0.000 description 2
- TYCOFFBAZNSQOJ-UHFFFAOYSA-N 2-[4-(3-fluorophenyl)phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC(F)=C1 TYCOFFBAZNSQOJ-UHFFFAOYSA-N 0.000 description 2
- TXGKRVFSSHPBAJ-JKSUJKDBSA-N 2-[[(1r,2s)-2-aminocyclohexyl]amino]-4-[3-(triazol-2-yl)anilino]pyrimidine-5-carboxamide Chemical compound N[C@H]1CCCC[C@H]1NC1=NC=C(C(N)=O)C(NC=2C=C(C=CC=2)N2N=CC=N2)=N1 TXGKRVFSSHPBAJ-JKSUJKDBSA-N 0.000 description 2
- MYIFLDFUXIHOCJ-UHFFFAOYSA-N 2-amino-2-[2-[2-chloro-4-(3-phenylmethoxyphenyl)sulfanylphenyl]ethyl]propane-1,3-diol;hydrochloride Chemical compound Cl.C1=C(Cl)C(CCC(CO)(CO)N)=CC=C1SC1=CC=CC(OCC=2C=CC=CC=2)=C1 MYIFLDFUXIHOCJ-UHFFFAOYSA-N 0.000 description 2
- XFKYKTBPRBZDFG-UHFFFAOYSA-N 2-aminoacetonitrile;hydrochloride Chemical compound Cl.NCC#N XFKYKTBPRBZDFG-UHFFFAOYSA-N 0.000 description 2
- XSFPZBUIBYMVEA-CELUQASASA-N 2-benzamidoacetic acid;ethyl (2s)-2-amino-3-[4-[2-amino-6-[(1r)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]phenyl]propanoate Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1.C1=CC(C[C@H](N)C(=O)OCC)=CC=C1C1=CC(O[C@H](C=2C(=CC(Cl)=CC=2)N2N=C(C)C=C2)C(F)(F)F)=NC(N)=N1 XSFPZBUIBYMVEA-CELUQASASA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- CQOQDQWUFQDJMK-SSTWWWIQSA-N 2-methoxy-17beta-estradiol Chemical compound C([C@@H]12)C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CCC1=C2C=C(OC)C(O)=C1 CQOQDQWUFQDJMK-SSTWWWIQSA-N 0.000 description 2
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- NLALOHVNOVPDGN-UHFFFAOYSA-N 3,3-diethoxy-2-formylpropanenitrile;potassium Chemical compound [K].CCOC(OCC)C(C=O)C#N NLALOHVNOVPDGN-UHFFFAOYSA-N 0.000 description 2
- XZYXCQXTKOYHGK-UHFFFAOYSA-N 3-(2-hydroxy-1-methylindol-3-yl)indol-2-one Chemical compound Cn1c(O)c(C2=c3ccccc3=NC2=O)c2ccccc12 XZYXCQXTKOYHGK-UHFFFAOYSA-N 0.000 description 2
- FWXVGKSWZJEPQI-UHFFFAOYSA-N 3-[[4-[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]naphthalen-1-yl]oxypyrimidin-2-yl]amino]-5-ethynyl-n-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]benzamide Chemical compound C#CC1=CC(C(=O)NCCOCCOCCOC)=CC(NC=2N=C(OC=3C4=CC=CC=C4C(NC(=O)NC=4C(=C(NS(C)(=O)=O)C=C(C=4)C(C)(C)C)OC)=CC=3)C=CN=2)=C1 FWXVGKSWZJEPQI-UHFFFAOYSA-N 0.000 description 2
- TYNLGDBUJLVSMA-UHFFFAOYSA-N 4,5-diacetyloxy-9,10-dioxo-2-anthracenecarboxylic acid Chemical compound O=C1C2=CC(C(O)=O)=CC(OC(C)=O)=C2C(=O)C2=C1C=CC=C2OC(=O)C TYNLGDBUJLVSMA-UHFFFAOYSA-N 0.000 description 2
- BGLPECHZZQDNCD-UHFFFAOYSA-N 4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide Chemical compound C1CN(S(=O)(=O)CC)CCN1C(C=C1)=CC=C1NC1=NC=C(C(N)=O)C(NC2CC2)=N1 BGLPECHZZQDNCD-UHFFFAOYSA-N 0.000 description 2
- CADWTPLFEZSAHM-UHFFFAOYSA-N 4-[1-[[6-[[4-(trifluoromethyl)phenyl]methyl]-6-azaspiro[2.5]octane-7-carbonyl]amino]cyclopropyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1(NC(=O)C2N(CCC3(CC3)C2)CC=2C=CC(=CC=2)C(F)(F)F)CC1 CADWTPLFEZSAHM-UHFFFAOYSA-N 0.000 description 2
- YBFGSJUVEOYPIS-OALUTQOASA-N 4-[8-[4-[(1s,4s)-2-propan-2-yl-2,5-diazabicyclo[2.2.1]heptan-5-yl]anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]furan-2-carboxamide Chemical compound C([C@]1(N(C[C@]2([H])C1)C(C)C)[H])N2C(C=C1)=CC=C1NC(C1=NC=NN11)=NC=C1C1=COC(C(N)=O)=C1 YBFGSJUVEOYPIS-OALUTQOASA-N 0.000 description 2
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 2
- HIMUHMBGRATXMK-LBPRGKRZSA-N 5-[1-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C=C)CC[C@@H]1OC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 HIMUHMBGRATXMK-LBPRGKRZSA-N 0.000 description 2
- XDBHURGONHZNJF-UHFFFAOYSA-N 6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4-yl]pyridine-2-carboxylic acid Chemical compound C1=C(OCC)C(OCC)=CC=C1C1=NC(C=2N=C(C=CC=2)C(O)=O)=CS1 XDBHURGONHZNJF-UHFFFAOYSA-N 0.000 description 2
- SEJLPXCPMNSRAM-GOSISDBHSA-N 6-amino-9-[(3r)-1-but-2-ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one Chemical compound C1N(C(=O)C#CC)CC[C@H]1N1C(=O)N(C=2C=CC(OC=3C=CC=CC=3)=CC=2)C2=C(N)N=CN=C21 SEJLPXCPMNSRAM-GOSISDBHSA-N 0.000 description 2
- ZTUJNJAKTLHBEX-UHFFFAOYSA-N 6-cyclopropyl-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]-6-oxopyridin-3-yl]phenyl]isoquinolin-1-one Chemical compound C1CN(C)CCN1C(C=N1)=CC=C1NC1=CC(C=2C(=C(C=CC=2)N2C(C3=C(F)C=C(C=C3C=C2)C2CC2)=O)CO)=CN(C)C1=O ZTUJNJAKTLHBEX-UHFFFAOYSA-N 0.000 description 2
- NJIAKNWTIVDSDA-FQEVSTJZSA-N 7-[4-(1-methylsulfonylpiperidin-4-yl)phenyl]-n-[[(2s)-morpholin-2-yl]methyl]pyrido[3,4-b]pyrazin-5-amine Chemical compound C1CN(S(=O)(=O)C)CCC1C1=CC=C(C=2N=C(NC[C@H]3OCCNC3)C3=NC=CN=C3C=2)C=C1 NJIAKNWTIVDSDA-FQEVSTJZSA-N 0.000 description 2
- MHFGDXMUCVQVNR-UHFFFAOYSA-N 7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile Chemical compound BrC1=CC=C2N1N=CC(=C2)C#N MHFGDXMUCVQVNR-UHFFFAOYSA-N 0.000 description 2
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 description 2
- WQDDSULPVSBTBO-UHFFFAOYSA-N 8-methylnonyl 2-amino-5-hydroxybenzoate Chemical compound CC(C)CCCCCCCOC(=O)C1=CC(O)=CC=C1N WQDDSULPVSBTBO-UHFFFAOYSA-N 0.000 description 2
- IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 2
- 108010049290 ADP Ribose Transferases Proteins 0.000 description 2
- 102000009062 ADP Ribose Transferases Human genes 0.000 description 2
- PWJFNRJRHXWEPT-UHFFFAOYSA-N ADP ribose Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OCC(O)C(O)C(O)C=O)C(O)C1O PWJFNRJRHXWEPT-UHFFFAOYSA-N 0.000 description 2
- 108010005042 AMG-220 Proteins 0.000 description 2
- 108010009522 AMG623 peptibody Proteins 0.000 description 2
- 102000015936 AP-1 transcription factor Human genes 0.000 description 2
- 108050004195 AP-1 transcription factor Proteins 0.000 description 2
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 description 2
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 description 2
- 229940121683 Acetylcholine receptor antagonist Drugs 0.000 description 2
- 108010052946 Activin Receptors Proteins 0.000 description 2
- 102000018918 Activin Receptors Human genes 0.000 description 2
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 108010049777 Ankyrins Proteins 0.000 description 2
- 102000008102 Ankyrins Human genes 0.000 description 2
- 108010056301 Apolipoprotein C-III Proteins 0.000 description 2
- 102100030970 Apolipoprotein C-III Human genes 0.000 description 2
- 102100022718 Atypical chemokine receptor 2 Human genes 0.000 description 2
- 108010028006 B-Cell Activating Factor Proteins 0.000 description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 2
- 101710117995 B-lymphocyte antigen CD19 Proteins 0.000 description 2
- 108010018763 Biotin carboxylase Proteins 0.000 description 2
- 108091005575 Bromodomain-containing proteins Proteins 0.000 description 2
- 102000001805 Bromodomains Human genes 0.000 description 2
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 description 2
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 description 2
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 2
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 2
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 description 2
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 description 2
- 108010074051 C-Reactive Protein Proteins 0.000 description 2
- 102100036166 C-X-C chemokine receptor type 1 Human genes 0.000 description 2
- 102100028989 C-X-C chemokine receptor type 2 Human genes 0.000 description 2
- 102100032752 C-reactive protein Human genes 0.000 description 2
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 2
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 2
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 2
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 2
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 2
- 102100031171 CCN family member 1 Human genes 0.000 description 2
- 101710137355 CCN family member 1 Proteins 0.000 description 2
- 101150019010 CCR3 gene Proteins 0.000 description 2
- 108010065524 CD52 Antigen Proteins 0.000 description 2
- 229940124297 CDK 4/6 inhibitor Drugs 0.000 description 2
- 101150063947 CHST15 gene Proteins 0.000 description 2
- 102100024155 Cadherin-11 Human genes 0.000 description 2
- 101000947501 Camptotheca acuminata (S)-8-oxocitronellyl enol synthase CYC1 Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 229940122820 Cannabinoid receptor antagonist Drugs 0.000 description 2
- 102000016362 Catenins Human genes 0.000 description 2
- 108010067316 Catenins Proteins 0.000 description 2
- 108090000625 Cathepsin K Proteins 0.000 description 2
- 102000004171 Cathepsin K Human genes 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 241001543077 Chromis alpha Species 0.000 description 2
- 241000193171 Clostridium butyricum Species 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 102100031506 Complement C5 Human genes 0.000 description 2
- 108010028773 Complement C5 Proteins 0.000 description 2
- 102400000739 Corticotropin Human genes 0.000 description 2
- 101800000414 Corticotropin Proteins 0.000 description 2
- 241000702141 Corynephage beta Species 0.000 description 2
- 101710105094 Cyclic AMP-responsive element-binding protein Proteins 0.000 description 2
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 2
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 2
- 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 2
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 2
- 108010025461 Cyclin-Dependent Kinase 9 Proteins 0.000 description 2
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 2
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 2
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 2
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 description 2
- 101710106276 Cyclin-dependent kinase 7 Proteins 0.000 description 2
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 2
- 102100033270 Cyclin-dependent kinase inhibitor 1 Human genes 0.000 description 2
- 101710157567 Cyclin-dependent kinase inhibitor 1 Proteins 0.000 description 2
- 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- 229940127399 DNA Polymerase Inhibitors Drugs 0.000 description 2
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 2
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 108010077448 Diamine N-acetyltransferase Proteins 0.000 description 2
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102100023266 Dual specificity mitogen-activated protein kinase kinase 2 Human genes 0.000 description 2
- 101710146529 Dual specificity mitogen-activated protein kinase kinase 2 Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 description 2
- 102100031334 Elongation factor 2 Human genes 0.000 description 2
- 108010092408 Eosinophil Peroxidase Proteins 0.000 description 2
- 102100028471 Eosinophil peroxidase Human genes 0.000 description 2
- 102100023688 Eotaxin Human genes 0.000 description 2
- 101710139422 Eotaxin Proteins 0.000 description 2
- 101800003838 Epidermal growth factor Proteins 0.000 description 2
- 108010075944 Erythropoietin Receptors Proteins 0.000 description 2
- 102100036509 Erythropoietin receptor Human genes 0.000 description 2
- 108010041356 Estrogen Receptor beta Proteins 0.000 description 2
- 102100029951 Estrogen receptor beta Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010071289 Factor XIII Proteins 0.000 description 2
- 102100028412 Fibroblast growth factor 10 Human genes 0.000 description 2
- 229940121703 Free fatty acid receptor 2 antagonist Drugs 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229940118503 G protein-coupled receptor 84 antagonist Drugs 0.000 description 2
- 101710108136 G-protein coupled receptor 15 Proteins 0.000 description 2
- 102000004300 GABA-A Receptors Human genes 0.000 description 2
- 108090000839 GABA-A Receptors Proteins 0.000 description 2
- 102000004610 GATA3 Transcription Factor Human genes 0.000 description 2
- 108010003338 GATA3 Transcription Factor Proteins 0.000 description 2
- 229940125633 GPCR agonist Drugs 0.000 description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 206010017964 Gastrointestinal infection Diseases 0.000 description 2
- 108010072051 Glatiramer Acetate Proteins 0.000 description 2
- 102400000326 Glucagon-like peptide 2 Human genes 0.000 description 2
- 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 2
- 102000053187 Glucuronidase Human genes 0.000 description 2
- 108010060309 Glucuronidase Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102000009465 Growth Factor Receptors Human genes 0.000 description 2
- 108010009202 Growth Factor Receptors Proteins 0.000 description 2
- 108010078321 Guanylate Cyclase Proteins 0.000 description 2
- 102000014469 Guanylate cyclase Human genes 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 2
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 2
- 229940119240 Histamine H4 receptor antagonist Drugs 0.000 description 2
- 108090000246 Histone acetyltransferases Proteins 0.000 description 2
- 102000003893 Histone acetyltransferases Human genes 0.000 description 2
- 101000678892 Homo sapiens Atypical chemokine receptor 2 Proteins 0.000 description 2
- 101000716070 Homo sapiens C-C chemokine receptor type 9 Proteins 0.000 description 2
- 101000947174 Homo sapiens C-X-C chemokine receptor type 1 Proteins 0.000 description 2
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 description 2
- 101000878602 Homo sapiens Immunoglobulin alpha Fc receptor Proteins 0.000 description 2
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 description 2
- 101000994375 Homo sapiens Integrin alpha-4 Proteins 0.000 description 2
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 description 2
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 2
- 101100236405 Homo sapiens MAP3K2 gene Proteins 0.000 description 2
- 101000884271 Homo sapiens Signal transducer CD24 Proteins 0.000 description 2
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 2
- 101000830603 Homo sapiens Tumor necrosis factor ligand superfamily member 11 Proteins 0.000 description 2
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 2
- 102000016878 Hypoxia-Inducible Factor 1 Human genes 0.000 description 2
- 108010028501 Hypoxia-Inducible Factor 1 Proteins 0.000 description 2
- 239000003458 I kappa b kinase inhibitor Substances 0.000 description 2
- 101150050263 ICAM1 gene Proteins 0.000 description 2
- 101150030057 IFNB gene Proteins 0.000 description 2
- 229940124753 IL-2 agonist Drugs 0.000 description 2
- 101150085950 IL10 gene Proteins 0.000 description 2
- 108091054729 IRF family Proteins 0.000 description 2
- 102100038005 Immunoglobulin alpha Fc receptor Human genes 0.000 description 2
- 102100021854 Inhibitor of nuclear factor kappa-B kinase subunit beta Human genes 0.000 description 2
- 101710205525 Inhibitor of nuclear factor kappa-B kinase subunit beta Proteins 0.000 description 2
- 102100025323 Integrin alpha-1 Human genes 0.000 description 2
- 102100025305 Integrin alpha-2 Human genes 0.000 description 2
- 102100022341 Integrin alpha-E Human genes 0.000 description 2
- 101710122982 Integrin alpha-E Proteins 0.000 description 2
- 108010041341 Integrin alpha1 Proteins 0.000 description 2
- 102100025304 Integrin beta-1 Human genes 0.000 description 2
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 2
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 2
- 102000016854 Interferon Regulatory Factors Human genes 0.000 description 2
- 108050006617 Interleukin-1 receptor Proteins 0.000 description 2
- 102000003814 Interleukin-10 Human genes 0.000 description 2
- 108090000174 Interleukin-10 Proteins 0.000 description 2
- 102000004554 Interleukin-17 Receptors Human genes 0.000 description 2
- 108010017525 Interleukin-17 Receptors Proteins 0.000 description 2
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 2
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- 102100021592 Interleukin-7 Human genes 0.000 description 2
- 108010002586 Interleukin-7 Proteins 0.000 description 2
- 108010018951 Interleukin-8B Receptors Proteins 0.000 description 2
- 101150009057 JAK2 gene Proteins 0.000 description 2
- 101150069380 JAK3 gene Proteins 0.000 description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 2
- YFIZRWPXUYFCSN-UHFFFAOYSA-N LY293111 Chemical compound C1=CC=C(OC=2C(=CC=CC=2)C(O)=O)C(CCC)=C1OCCCOC(C(=C1)CC)=CC(O)=C1C1=CC=C(F)C=C1 YFIZRWPXUYFCSN-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 108090001090 Lectins Proteins 0.000 description 2
- 102000004856 Lectins Human genes 0.000 description 2
- 102000003680 Leukotriene B4 receptors Human genes 0.000 description 2
- 108090000093 Leukotriene B4 receptors Proteins 0.000 description 2
- 102000003820 Lipoxygenases Human genes 0.000 description 2
- 108090000128 Lipoxygenases Proteins 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 102000002576 MAP Kinase Kinase 1 Human genes 0.000 description 2
- 108010068342 MAP Kinase Kinase 1 Proteins 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 102100028396 MAP kinase-activated protein kinase 5 Human genes 0.000 description 2
- 108010041164 MAP-kinase-activated kinase 5 Proteins 0.000 description 2
- 101150022772 MAP3K2 gene Proteins 0.000 description 2
- 101150053046 MYD88 gene Proteins 0.000 description 2
- 241000282567 Macaca fascicularis Species 0.000 description 2
- 241000282560 Macaca mulatta Species 0.000 description 2
- 102100025354 Macrophage mannose receptor 1 Human genes 0.000 description 2
- 101710124692 Macrophage mannose receptor 1 Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 2
- 108010008364 Melanocortins Proteins 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 102100030335 Midkine Human genes 0.000 description 2
- 108010092801 Midkine Proteins 0.000 description 2
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 2
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 2
- 101710095845 Monocyte differentiation antigen CD14 Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 102100030608 Mothers against decapentaplegic homolog 7 Human genes 0.000 description 2
- 101001065566 Mus musculus Lymphocyte antigen 6A-2/6E-1 Proteins 0.000 description 2
- 101100268066 Mus musculus Zap70 gene Proteins 0.000 description 2
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 description 2
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 description 2
- 102100024134 Myeloid differentiation primary response protein MyD88 Human genes 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 102100031455 NAD-dependent protein deacetylase sirtuin-1 Human genes 0.000 description 2
- 101150086808 NAMPT gene Proteins 0.000 description 2
- 108091008877 NK cell receptors Proteins 0.000 description 2
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 2
- 102100021462 Natural killer cells antigen CD94 Human genes 0.000 description 2
- 206010051606 Necrotising colitis Diseases 0.000 description 2
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 2
- 101150041793 Nfe2l2 gene Proteins 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 description 2
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 description 2
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 2
- 102100034925 P-selectin glycoprotein ligand 1 Human genes 0.000 description 2
- 108010054395 P-selectin ligand protein Proteins 0.000 description 2
- 239000012661 PARP inhibitor Substances 0.000 description 2
- 108091008010 PERKs Proteins 0.000 description 2
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 2
- 108010077519 Peptide Elongation Factor 2 Proteins 0.000 description 2
- 101710111747 Peptidyl-prolyl cis-trans isomerase FKBP12 Proteins 0.000 description 2
- 102100029251 Phagocytosis-stimulating peptide Human genes 0.000 description 2
- 101710177686 Phagocytosis-stimulating peptide Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229940124090 Platelet-derived growth factor (PDGF) receptor antagonist Drugs 0.000 description 2
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 229940127473 Prostaglandin Receptor Agonists Drugs 0.000 description 2
- 229940122144 Prostaglandin receptor antagonist Drugs 0.000 description 2
- 102000048176 Prostaglandin-D synthases Human genes 0.000 description 2
- 108030003866 Prostaglandin-D synthases Proteins 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical class CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 101000912235 Rebecca salina Acyl-lipid (7-3)-desaturase Proteins 0.000 description 2
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 description 2
- 102100033909 Retinoic acid receptor beta Human genes 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- 108010084054 SBI-087 Proteins 0.000 description 2
- 101700026522 SMAD7 Proteins 0.000 description 2
- 101000877236 Siganus canaliculatus Acyl-CoA Delta-4 desaturase Proteins 0.000 description 2
- 102100038081 Signal transducer CD24 Human genes 0.000 description 2
- 108010041191 Sirtuin 1 Proteins 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 108010052164 Sodium Channels Proteins 0.000 description 2
- 102000018674 Sodium Channels Human genes 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 229940127322 Sodium-Glucose Transporter 2 Inhibitors Drugs 0.000 description 2
- 229940127504 Somatostatin Receptor Agonists Drugs 0.000 description 2
- 102100039024 Sphingosine kinase 1 Human genes 0.000 description 2
- 102100027662 Sphingosine kinase 2 Human genes 0.000 description 2
- 101710156532 Sphingosine kinase 2 Proteins 0.000 description 2
- 102100030684 Sphingosine-1-phosphate phosphatase 1 Human genes 0.000 description 2
- 101710168942 Sphingosine-1-phosphate phosphatase 1 Proteins 0.000 description 2
- 102100037346 Substance-P receptor Human genes 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 2
- 108700002718 TACI receptor-IgG Fc fragment fusion Proteins 0.000 description 2
- 229940126123 TAK-020 Drugs 0.000 description 2
- 101150033527 TNF gene Proteins 0.000 description 2
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 2
- 102000007000 Tenascin Human genes 0.000 description 2
- 108010008125 Tenascin Proteins 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 150000004940 Tofacitinib derivatives Chemical class 0.000 description 2
- 108010031154 Transcription Factor RelA Proteins 0.000 description 2
- 102100032727 Transcription factor RelB Human genes 0.000 description 2
- 108090000952 Transcription factor RelB Proteins 0.000 description 2
- 102100035100 Transcription factor p65 Human genes 0.000 description 2
- 102000004338 Transferrin Human genes 0.000 description 2
- 108090000901 Transferrin Proteins 0.000 description 2
- 102000007641 Trefoil Factors Human genes 0.000 description 2
- 108010007389 Trefoil Factors Proteins 0.000 description 2
- 101710138398 Tryptophan 5-hydroxylase Proteins 0.000 description 2
- 102100036922 Tumor necrosis factor ligand superfamily member 13B Human genes 0.000 description 2
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 2
- 102100038183 Tyrosine-protein kinase SYK Human genes 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 108010073925 Vascular Endothelial Growth Factor B Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 102100038217 Vascular endothelial growth factor B Human genes 0.000 description 2
- 229950008347 abrilumab Drugs 0.000 description 2
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 description 2
- FHEAIOHRHQGZPC-KIWGSFCNSA-N acetic acid;(2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 FHEAIOHRHQGZPC-KIWGSFCNSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 229960004308 acetylcysteine Drugs 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000002404 acyltransferase inhibitor Substances 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 239000002593 adenosine A3 receptor agonist Substances 0.000 description 2
- 239000002487 adenosine deaminase inhibitor Substances 0.000 description 2
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 description 2
- 239000000674 adrenergic antagonist Substances 0.000 description 2
- 101150045355 akt1 gene Proteins 0.000 description 2
- 208000002353 alcoholic hepatitis Diseases 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 2
- 229950002889 apilimod Drugs 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 108010038239 aspartyl-alanyl-diketopiperazine Proteins 0.000 description 2
- 229950009925 atacicept Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- IPOKCKJONYRRHP-FMQUCBEESA-N balsalazide Chemical compound C1=CC(C(=O)NCCC(=O)O)=CC=C1\N=N\C1=CC=C(O)C(C(O)=O)=C1 IPOKCKJONYRRHP-FMQUCBEESA-N 0.000 description 2
- 229950000971 baricitinib Drugs 0.000 description 2
- XUZMWHLSFXCVMG-UHFFFAOYSA-N baricitinib Chemical compound C1N(S(=O)(=O)CC)CC1(CC#N)N1N=CC(C=2C=3C=CNC=3N=CN=2)=C1 XUZMWHLSFXCVMG-UHFFFAOYSA-N 0.000 description 2
- 229960004669 basiliximab Drugs 0.000 description 2
- 229960005347 belatacept Drugs 0.000 description 2
- ABSXPNGWJFAPRT-UHFFFAOYSA-N benzenesulfonic acid;n-[3-[[5-fluoro-2-[4-(2-methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound OS(=O)(=O)C1=CC=CC=C1.C1=CC(OCCOC)=CC=C1NC1=NC=C(F)C(NC=2C=C(NC(=O)C=C)C=CC=2)=N1 ABSXPNGWJFAPRT-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229950010015 bertilimumab Drugs 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 229950004201 blisibimod Drugs 0.000 description 2
- 101150048834 braF gene Proteins 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 239000006189 buccal tablet Substances 0.000 description 2
- 229940046011 buccal tablet Drugs 0.000 description 2
- 229960005084 calcitriol Drugs 0.000 description 2
- 235000020964 calcitriol Nutrition 0.000 description 2
- 239000011612 calcitriol Substances 0.000 description 2
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 2
- 229960005069 calcium Drugs 0.000 description 2
- 229960001838 canakinumab Drugs 0.000 description 2
- 239000003520 cannabinoid receptor affecting agent Substances 0.000 description 2
- 239000003536 cannabinoid receptor antagonist Substances 0.000 description 2
- 229940041011 carbapenems Drugs 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 2
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 229960001684 catridecacog Drugs 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 229950006295 cerdulatinib Drugs 0.000 description 2
- RNZOILMUIJSTSY-UHFFFAOYSA-N chembl16733 Chemical compound S1C(OCC)=NN=C1C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 RNZOILMUIJSTSY-UHFFFAOYSA-N 0.000 description 2
- NNXDIGHYPZHXTR-ONEGZZNKSA-N chembl2035185 Chemical compound C=1C=C(C=2)NC(N=3)=NC=CC=3C(O3)=CC=C3COC\C=C\COCC=2C=1OCCN1CCCC1 NNXDIGHYPZHXTR-ONEGZZNKSA-N 0.000 description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 108010088797 cibinetide Proteins 0.000 description 2
- 229950001629 cibinetide Drugs 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 2
- 229960000258 corticotropin Drugs 0.000 description 2
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 2
- 239000003099 cyclic gmp dependent protein kinase inhibitor Substances 0.000 description 2
- AFDPFLDWOXXHQM-NRFANRHFSA-N cyclopentyl (2s)-2-cyclohexyl-2-[[6-[3-(hydroxyamino)-3-oxopropyl]pyridin-3-yl]methylamino]acetate Chemical compound C1=NC(CCC(=O)NO)=CC=C1CN[C@H](C(=O)OC1CCCC1)C1CCCCC1 AFDPFLDWOXXHQM-NRFANRHFSA-N 0.000 description 2
- 229960002806 daclizumab Drugs 0.000 description 2
- 229950000393 darbufelone Drugs 0.000 description 2
- 229950004849 dersalazine Drugs 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 229960004590 diacerein Drugs 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- 229960001193 diclofenac sodium Drugs 0.000 description 2
- XSDVOEIEBUGRQX-RBUKOAKNSA-N dihydroceramide Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC=O XSDVOEIEBUGRQX-RBUKOAKNSA-N 0.000 description 2
- 108020001096 dihydrofolate reductase Proteins 0.000 description 2
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 2
- 229960004419 dimethyl fumarate Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229950008818 dolcanatide Drugs 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 230000036267 drug metabolism Effects 0.000 description 2
- 229950004949 duvelisib Drugs 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 229950006357 elubrixin Drugs 0.000 description 2
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 2
- 210000003979 eosinophil Anatomy 0.000 description 2
- 229940116977 epidermal growth factor Drugs 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 229960005093 esomeprazole strontium Drugs 0.000 description 2
- 229950001288 etalocib Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 229940012444 factor xiii Drugs 0.000 description 2
- 108010072257 fibroblast activation protein alpha Proteins 0.000 description 2
- 101150015947 fimH gene Proteins 0.000 description 2
- 229950005849 firategrast Drugs 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 229950001284 fluprofen Drugs 0.000 description 2
- 239000004052 folic acid antagonist Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 102000034356 gene-regulatory proteins Human genes 0.000 description 2
- 108091006104 gene-regulatory proteins Proteins 0.000 description 2
- 229930182494 ginsenoside Natural products 0.000 description 2
- 229960003776 glatiramer acetate Drugs 0.000 description 2
- TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 2
- 239000003635 glucocorticoid antagonist Substances 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 125000004404 heteroalkyl group Chemical group 0.000 description 2
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 2
- 239000003396 histamine H4 receptor antagonist Substances 0.000 description 2
- 102000055277 human IL2 Human genes 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229950011428 indatuximab ravtansine Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 229940076144 interleukin-10 Drugs 0.000 description 2
- 229940028885 interleukin-4 Drugs 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 230000000155 isotopic effect Effects 0.000 description 2
- 229950003818 itolizumab Drugs 0.000 description 2
- 229940126397 ivarmacitinib Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- GKWPCEFFIHSJOE-UHFFFAOYSA-N laquinimod Chemical compound OC=1C2=C(Cl)C=CC=C2N(C)C(=O)C=1C(=O)N(CC)C1=CC=CC=C1 GKWPCEFFIHSJOE-UHFFFAOYSA-N 0.000 description 2
- 229960004577 laquinimod Drugs 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000002523 lectin Substances 0.000 description 2
- 229960004942 lenalidomide Drugs 0.000 description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 2
- 150000002617 leukotrienes Chemical class 0.000 description 2
- 101150004907 litaf gene Proteins 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229950007254 mavrilimumab Drugs 0.000 description 2
- 101150094281 mcl1 gene Proteins 0.000 description 2
- 239000002865 melanocortin Substances 0.000 description 2
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 229950001907 monalizumab Drugs 0.000 description 2
- ABASMUXUCSQFKC-PKEKLUKKSA-N mongersen Chemical compound CC1=CN([C@H]2C[C@H](OP(=S)(O)OC[C@H]3O[C@H](C[C@@H]3OP(=S)(O)OC[C@H]4O[C@H](C[C@@H]4OP(=S)(O)OC[C@H]5O[C@H](C[C@@H]5OP(=S)(O)OC[C@H]6O[C@H](C[C@@H]6OP(=S)(O)OC[C@H]7O[C@H](C[C@@H]7O)N8C=CC(=NC8=O)N)n9cnc%10C(=O)NC(=Nc9%10)N)n%11cnc%12c(N)ncnc%11%12)N%13C=CC(=NC%13=O)N)n%14cnc%15C(=O)NC(=Nc%14%15)N)[C@@H](COP(=S)(O)O[C@H]%16C[C@@H](O[C@@H]%16COP(=S)(O)O[C@H]%17C[C@@H](O[C@@H]%17COP(=S)(O)O[C@H]%18C[C@@H](O[C@@H]%18COP(=S)(O)O[C@H]%19C[C@@H](O[C@@H]%19COP(=S)(O)O[C@H]%20C[C@@H](O[C@@H]%20COP(=S)(O)O[C@H]%21C[C@@H](O[C@@H]%21COP(=S)(O)O[C@H]%22C[C@@H](O[C@@H]%22COP(=S)(O)O[C@H]%23C[C@@H](O[C@@H]%23COP(=S)(O)O[C@H]%24C[C@@H](O[C@@H]%24COP(=S)(O)O[C@H]%25C[C@@H](O[C@@H]%25COP(=S)(O)O[C@H]%26C[C@@H](O[C@@H]%26COP(=S)(O)O[C@H]%27C[C@@H](O[C@@H]%27COP(=S)(O)O[C@H]%28C[C@@H](O[C@@H]%28COP(=S)(O)O[C@H]%29C[C@@H](O[C@@H]%29COP(=S)(O)O[C@H]%30C[C@@H](O[C@@H]%30CO)n%31cnc%32C(=O)NC(=Nc%31%32)N)N%33C=C(C)C(=O)NC%33=O)N%34C=C(C)C(=NC%34=O)N)n%35cnc%36C(=O)NC(=Nc%35%36)N)N%37C=CC(=NC%37=O)N)N%38C=CC(=NC%38=O)N)N%39C=CC(=NC%39=O)N)N%40C=CC(=NC%40=O)N)N%41C=C(C)C(=O)NC%41=O)N%42C=C(C)C(=O)NC%42=O)N%43C=CC(=NC%43=O)N)N%44C=C(C)C(=O)NC%44=O)N%45C=CC(=NC%45=O)N)N%46C=CC(=NC%46=O)N)N%47C=CC(=NC%47=O)N)O2)C(=O)N=C1N ABASMUXUCSQFKC-PKEKLUKKSA-N 0.000 description 2
- 229950002917 mongersen Drugs 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- PWDYHMBTPGXCSN-VCBMUGGBSA-N n,n'-bis[3,5-bis[(e)-n-(diaminomethylideneamino)-c-methylcarbonimidoyl]phenyl]decanediamide Chemical compound NC(N)=N/N=C(\C)C1=CC(C(=N/N=C(N)N)/C)=CC(NC(=O)CCCCCCCCC(=O)NC=2C=C(C=C(C=2)C(\C)=N\N=C(N)N)C(\C)=N\N=C(N)N)=C1 PWDYHMBTPGXCSN-VCBMUGGBSA-N 0.000 description 2
- HSKAZIJJKRAJAV-KOEQRZSOSA-N n-[(e)-(3-methylphenyl)methylideneamino]-6-morpholin-4-yl-2-(2-pyridin-2-ylethoxy)pyrimidin-4-amine Chemical compound CC1=CC=CC(\C=N\NC=2N=C(OCCC=3N=CC=CC=3)N=C(C=2)N2CCOCC2)=C1 HSKAZIJJKRAJAV-KOEQRZSOSA-N 0.000 description 2
- SVGRIJCSKWXOPA-UHFFFAOYSA-N n-[2,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide Chemical compound OC1=CC=C(Br)C=C1C(=O)NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F SVGRIJCSKWXOPA-UHFFFAOYSA-N 0.000 description 2
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 2
- 229960004270 nabumetone Drugs 0.000 description 2
- AKFJWRDCWYYTIG-ZDUSSCGKSA-N naproxcinod Chemical compound C1=C([C@H](C)C(=O)OCCCCO[N+]([O-])=O)C=CC2=CC(OC)=CC=C21 AKFJWRDCWYYTIG-ZDUSSCGKSA-N 0.000 description 2
- 229960003759 naproxcinod Drugs 0.000 description 2
- 208000004995 necrotizing enterocolitis Diseases 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 229960001698 nicotine polacrilex Drugs 0.000 description 2
- 229960002480 nitazoxanide Drugs 0.000 description 2
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 2
- 229960001180 norfloxacin Drugs 0.000 description 2
- 229960002450 ofatumumab Drugs 0.000 description 2
- QQBDLJCYGRGAKP-FOCLMDBBSA-N olsalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=C(C(O)=CC=2)C(O)=O)=C1 QQBDLJCYGRGAKP-FOCLMDBBSA-N 0.000 description 2
- 229960004110 olsalazine Drugs 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 108010000953 osteoblast cadherin Proteins 0.000 description 2
- 229950008141 ozanimod Drugs 0.000 description 2
- 229950004327 ozoralizumab Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- XEBWQGVWTUSTLN-UHFFFAOYSA-M phenylmercury acetate Chemical compound CC(=O)O[Hg]C1=CC=CC=C1 XEBWQGVWTUSTLN-UHFFFAOYSA-M 0.000 description 2
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- XESLSYPFOYZAPG-UHFFFAOYSA-N piperidin-1-ium-2-one;chloride Chemical compound Cl.O=C1CCCCN1 XESLSYPFOYZAPG-UHFFFAOYSA-N 0.000 description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 2
- 229960002702 piroxicam Drugs 0.000 description 2
- 108010018859 plecanatide Proteins 0.000 description 2
- 229950008515 plecanatide Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 108060006632 protein arginine deiminase Proteins 0.000 description 2
- 102000001235 protein arginine deiminase Human genes 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- 239000003227 purinergic agonist Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 102000003702 retinoic acid receptors Human genes 0.000 description 2
- 108090000064 retinoic acid receptors Proteins 0.000 description 2
- 108091008726 retinoic acid receptors α Proteins 0.000 description 2
- 108091008761 retinoic acid receptors β Proteins 0.000 description 2
- 229960001886 rilonacept Drugs 0.000 description 2
- 108010046141 rilonacept Proteins 0.000 description 2
- 229950007943 risankizumab Drugs 0.000 description 2
- 229960000215 ruxolitinib Drugs 0.000 description 2
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 2
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229950006348 sarilumab Drugs 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000002412 selectin antagonist Substances 0.000 description 2
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 2
- 229950000055 seliciclib Drugs 0.000 description 2
- 229950011005 semapimod Drugs 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 229950006094 sirukumab Drugs 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 2
- 229950002089 spebrutinib Drugs 0.000 description 2
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 2
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 2
- 108010035597 sphingosine kinase Proteins 0.000 description 2
- 108010066791 sphingosine-1-phosphate phosphatase Proteins 0.000 description 2
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 2
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 2
- 239000012089 stop solution Substances 0.000 description 2
- NCGHIAKEJNQSMS-QLGOZJDFSA-N strontium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide;tetrahydrate Chemical compound O.O.O.O.[Sr+2].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C NCGHIAKEJNQSMS-QLGOZJDFSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000004808 supercritical fluid chromatography Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- 229950005628 tarenflurbil Drugs 0.000 description 2
- 108010073046 teduglutide Proteins 0.000 description 2
- CILIXQOJUNDIDU-ASQIGDHWSA-N teduglutide Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 CILIXQOJUNDIDU-ASQIGDHWSA-N 0.000 description 2
- 229960002444 teduglutide Drugs 0.000 description 2
- 229950011306 telotristat etiprate Drugs 0.000 description 2
- 229960000235 temsirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 2
- 229960003676 tenidap Drugs 0.000 description 2
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 108091008743 testicular receptors 4 Proteins 0.000 description 2
- 229950002896 tetomilast Drugs 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 229960003433 thalidomide Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 208000037816 tissue injury Diseases 0.000 description 2
- 229940044655 toll-like receptor 9 agonist Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000012581 transferrin Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 239000002750 tryptase inhibitor Substances 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- 102000009310 vitamin D receptors Human genes 0.000 description 2
- 108050000156 vitamin D receptors Proteins 0.000 description 2
- YKPUWZUDDOIDPM-VURMDHGXSA-N zucapsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C/C(C)C)=CC=C1O YKPUWZUDDOIDPM-VURMDHGXSA-N 0.000 description 2
- 229960002860 zucapsaicin Drugs 0.000 description 2
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 description 1
- 229930014124 (-)-epigallocatechin gallate Natural products 0.000 description 1
- UZNXSBPBWFLVDK-NKWVEPMBSA-N (1r,3s)-3-(6-aminopurin-9-yl)cyclopentan-1-ol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](O)C1 UZNXSBPBWFLVDK-NKWVEPMBSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- FIAINKIUSZGVGX-HSHFZTNMSA-N (2r)-2-aminopropanamide;hydrochloride Chemical compound Cl.C[C@@H](N)C(N)=O FIAINKIUSZGVGX-HSHFZTNMSA-N 0.000 description 1
- WGPIHVKMTHWKHL-BIGPACBVSA-K (2r)-5-[[(2s)-2-amino-3-[[(2s)-3-carboxylato-1-[[(1r)-1-carboxylato-2-sulfanylethyl]amino]-1-oxopropan-2-yl]amino]-3-oxopropyl]amino]-5-oxo-2-[[4-[(4-oxo-1h-pteridin-6-yl)methylamino]benzoyl]amino]pentanoate;oxotechnetium-99(3+) Chemical compound [99Tc+3]=O.C1=CC(C(=O)N[C@H](CCC(=O)NC[C@H](N)C(=O)N[C@@H](CC([O-])=O)C(=O)N[C@@H](CS)C([O-])=O)C([O-])=O)=CC=C1NCC1=CN=C(NC=NC2=O)C2=N1 WGPIHVKMTHWKHL-BIGPACBVSA-K 0.000 description 1
- JUPPCXIRHYEIQN-PGMHMLKASA-N (3R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride Chemical compound Cl.CC(C)(O)[C@H](F)CN JUPPCXIRHYEIQN-PGMHMLKASA-N 0.000 description 1
- QNFKDKWENVIYDB-SCSAIBSYSA-N (3r)-4-amino-3-fluoro-2-methylbutan-2-ol Chemical compound CC(C)(O)[C@H](F)CN QNFKDKWENVIYDB-SCSAIBSYSA-N 0.000 description 1
- ZGFJFBOLVLFLLN-MOLVWPNASA-N (4s)-4-(4-chlorophenyl)-1-[(3e)-3-[9-(2-hydroxypropan-2-yl)-5h-[1]benzoxepino[3,4-b]pyridin-11-ylidene]propyl]-3,3-dimethylpiperidin-4-ol Chemical compound C1([C@]2(CCN(CC2(C)C)CC\C=C2/C3=CC=CN=C3COC3=CC=C(C=C32)C(C)(O)C)O)=CC=C(Cl)C=C1 ZGFJFBOLVLFLLN-MOLVWPNASA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- VSWBSWWIRNCQIJ-GJZGRUSLSA-N (R,R)-asenapine Chemical compound O1C2=CC=CC=C2[C@@H]2CN(C)C[C@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-GJZGRUSLSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical class OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- QACMXJJLQXUOPQ-UHFFFAOYSA-N 1,2-dichloroethane;3-(ethyliminomethylideneamino)-n,n-dimethylpropan-1-amine Chemical compound ClCCCl.CCN=C=NCCCN(C)C QACMXJJLQXUOPQ-UHFFFAOYSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- NLMDJJTUQPXZFG-UHFFFAOYSA-N 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane Chemical compound C1COCCOCCNCCOCCOCCN1 NLMDJJTUQPXZFG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZHXUEUKVDMWSKV-UHFFFAOYSA-N 1-(3,5-ditert-butyl-4-hydroxyphenyl)hex-5-yn-1-one Chemical compound CC(C)(C)C1=CC(C(=O)CCCC#C)=CC(C(C)(C)C)=C1O ZHXUEUKVDMWSKV-UHFFFAOYSA-N 0.000 description 1
- DAEKZKUAFVMFKP-UHFFFAOYSA-N 1-(7-tert-butyl-3,3-dimethyl-2h-1-benzofuran-5-yl)-4-cyclopropylbutan-1-one Chemical compound C=1C(C(CO2)(C)C)=C2C(C(C)(C)C)=CC=1C(=O)CCCC1CC1 DAEKZKUAFVMFKP-UHFFFAOYSA-N 0.000 description 1
- YPUCYLJVVMYCHR-KSZLIROESA-N 1-[(1R,9R,10R)-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2,4,6-trien-6-yl]ethanone Chemical compound C(C)(=O)C1=CC=CC=2[C@@]34CCCC[C@H]3[C@@H](CC1=2)NCC4 YPUCYLJVVMYCHR-KSZLIROESA-N 0.000 description 1
- GTDPZONCGOCXOD-JPYJTQIMSA-N 1-[(2r)-1-[(4s)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl]-3-methyl-1-oxobutan-2-yl]-3-(2-hydroxy-2-methylpropyl)urea Chemical compound CC1(C)CN(C(=O)[C@H](NC(=O)NCC(C)(C)O)C(C)C)CC[C@]1(O)C1=CC=C(Cl)C=C1 GTDPZONCGOCXOD-JPYJTQIMSA-N 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- YSYIWCNPSZNNKW-UHFFFAOYSA-N 11-nitroso-10h-indeno[1,2-b]quinoxaline Chemical compound C1=CC=C[C]2N[C]3C(N=O)=C(C=CC=C4)C4=C3N=C21 YSYIWCNPSZNNKW-UHFFFAOYSA-N 0.000 description 1
- ZQFNDBISEYQVRR-LOSJGSFVSA-N 2,2-difluoro-N-[(1R,2S)-3-methyl-1-[1-(1-methyl-6-oxopyridin-3-yl)indazol-5-yl]oxy-1-phenylbutan-2-yl]propanamide Chemical compound FC(C(=O)N[C@H]([C@@H](C1=CC=CC=C1)OC=1C=C2C=NN(C2=CC=1)C1=CN(C(C=C1)=O)C)C(C)C)(C)F ZQFNDBISEYQVRR-LOSJGSFVSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- WEEMDRWIKYCTQM-UHFFFAOYSA-N 2,6-dimethoxybenzenecarbothioamide Chemical compound COC1=CC=CC(OC)=C1C(N)=S WEEMDRWIKYCTQM-UHFFFAOYSA-N 0.000 description 1
- BIZSVVIRPJXFOI-UHFFFAOYSA-M 2,6-ditert-butyl-4-(2-sulfanylidene-3h-1,3,4-thiadiazol-5-yl)phenolate;2-hydroxyethyl(trimethyl)azanium Chemical compound C[N+](C)(C)CCO.CC(C)(C)C1=C([O-])C(C(C)(C)C)=CC(C=2SC(=S)NN=2)=C1 BIZSVVIRPJXFOI-UHFFFAOYSA-M 0.000 description 1
- MFSJSVNVUDQHLV-UHFFFAOYSA-N 2-(3-benzoylphenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1.OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFSJSVNVUDQHLV-UHFFFAOYSA-N 0.000 description 1
- GJFVAEMLAFFGDZ-UHFFFAOYSA-N 2-(4-fluorophenyl)-3-pyridin-4-yl-6,7-dihydro-5h-pyrrolo[1,2-a]imidazole Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=CN=CC=2)N2CCCC2=N1 GJFVAEMLAFFGDZ-UHFFFAOYSA-N 0.000 description 1
- PDNNUMNEXITLCZ-UHFFFAOYSA-N 2-(9-chloro-2,3-dimethylindolo[3,2-b]quinoxalin-6-yl)-n-[2-(dimethylamino)ethyl]acetamide Chemical compound CC1=C(C)C=C2N=C3N(CC(=O)NCCN(C)C)C4=CC=C(Cl)C=C4C3=NC2=C1 PDNNUMNEXITLCZ-UHFFFAOYSA-N 0.000 description 1
- XMGJGSKRRWXOIF-UHFFFAOYSA-N 2-(azepan-1-yl)ethyl 2-cyclohexyl-2-thiophen-3-ylacetate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1CCCCC1C(C1=CSC=C1)C(=O)OCCN1CCCCCC1 XMGJGSKRRWXOIF-UHFFFAOYSA-N 0.000 description 1
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 1
- KTBSXLIQKWEBRB-UHFFFAOYSA-N 2-[1-[1-[3-fluoro-2-(trifluoromethyl)pyridine-4-carbonyl]piperidin-4-yl]-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile Chemical compound C1=CN=C(C(F)(F)F)C(F)=C1C(=O)N1CCC(N2CC(CC#N)(C2)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CC1 KTBSXLIQKWEBRB-UHFFFAOYSA-N 0.000 description 1
- FGBGXESDYFKUFX-UHFFFAOYSA-N 2-[2,6-ditert-butyl-4-[2-(3,5-ditert-butyl-4-hydroxyphenyl)sulfanylpropan-2-ylsulfanyl]phenoxy]acetic acid Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(SC(C)(C)SC=2C=C(C(OCC(O)=O)=C(C=2)C(C)(C)C)C(C)(C)C)=C1 FGBGXESDYFKUFX-UHFFFAOYSA-N 0.000 description 1
- PQZDYFRDRHRZGF-UHFFFAOYSA-N 2-[3,5-dimethyl-4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,7-dimethoxy-1h-quinazolin-4-one Chemical compound C=1C(OC)=CC(OC)=C(C(N2)=O)C=1N=C2C(C=C1C)=CC(C)=C1OCCN1CCCC1 PQZDYFRDRHRZGF-UHFFFAOYSA-N 0.000 description 1
- KDRNOBUWMVLVFH-UHFFFAOYSA-N 2-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)prop-2-enamide Chemical compound CC(=C)C(=O)NC1CC(C)(C)NC(C)(C)C1 KDRNOBUWMVLVFH-UHFFFAOYSA-N 0.000 description 1
- JGBUBSOKFSVXKS-LBPRGKRZSA-N 2-methylsulfonylethyl (2s)-2-(6-methoxynaphthalen-2-yl)propanoate Chemical compound C1=C([C@H](C)C(=O)OCCS(C)(=O)=O)C=CC2=CC(OC)=CC=C21 JGBUBSOKFSVXKS-LBPRGKRZSA-N 0.000 description 1
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 1
- WBOXEOCWOCJQNK-UHFFFAOYSA-N 3,3-diethoxypropanenitrile Chemical compound CCOC(CC#N)OCC WBOXEOCWOCJQNK-UHFFFAOYSA-N 0.000 description 1
- VGUSQKZDZHAAEE-UHFFFAOYSA-N 3-[5-amino-4-(3-cyanobenzoyl)pyrazol-1-yl]-n-cyclopropyl-4-methylbenzamide Chemical compound CC1=CC=C(C(=O)NC2CC2)C=C1N(C=1N)N=CC=1C(=O)C1=CC=CC(C#N)=C1 VGUSQKZDZHAAEE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- GWYIZOFIYNAMAC-UHFFFAOYSA-N 4,6-dichloro-2-methylpyridine-3-carboxylic acid Chemical compound CC1=NC(Cl)=CC(Cl)=C1C(O)=O GWYIZOFIYNAMAC-UHFFFAOYSA-N 0.000 description 1
- PGIFNMLEHONLJH-UHFFFAOYSA-N 4-[2-(2,7-dichloro-9h-fluoren-9-yl)ethoxycarbonylamino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC(=O)OCCC1C2=CC(Cl)=CC=C2C2=CC=C(Cl)C=C21 PGIFNMLEHONLJH-UHFFFAOYSA-N 0.000 description 1
- FIKVYIRIUOFLLR-UHFFFAOYSA-N 4-[4-(2,4-difluorophenyl)phenyl]-2-methyl-4-oxobutanoic acid Chemical compound C1=CC(C(=O)CC(C)C(O)=O)=CC=C1C1=CC=C(F)C=C1F FIKVYIRIUOFLLR-UHFFFAOYSA-N 0.000 description 1
- GDTQLZHHDRRBEB-UHFFFAOYSA-N 4-[5-(cyclopropylcarbamoyl)-2-methylanilino]-5-methyl-n-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide Chemical compound C12=C(C)C(C(=O)NCCC)=CN2N=CN=C1NC(C(=CC=1)C)=CC=1C(=O)NC1CC1 GDTQLZHHDRRBEB-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- LAMQVIQMVKWXOC-UHFFFAOYSA-N 4-methyl-n-[2-[3-(morpholin-4-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]-2-pyridin-3-yl-1,3-thiazole-5-carboxamide Chemical compound CC=1N=C(C=2C=NC=CC=2)SC=1C(=O)NC1=CC=CC=C1C(N=C1SC=2)=CN1C=2CN1CCOCC1 LAMQVIQMVKWXOC-UHFFFAOYSA-N 0.000 description 1
- JRWROCIMSDXGOZ-UHFFFAOYSA-N 4-tert-butyl-n-[4-chloro-2-(1-oxidopyridin-1-ium-4-carbonyl)phenyl]benzenesulfonamide Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1C(=O)C1=CC=[N+]([O-])C=C1 JRWROCIMSDXGOZ-UHFFFAOYSA-N 0.000 description 1
- 229940124125 5 Lipoxygenase inhibitor Drugs 0.000 description 1
- IFGWYHGYNVGVRB-UHFFFAOYSA-N 5-(2,4-difluorophenoxy)-n-[2-(dimethylamino)ethyl]-1-(2-methylpropyl)indazole-6-carboxamide Chemical compound CN(C)CCNC(=O)C=1C=C2N(CC(C)C)N=CC2=CC=1OC1=CC=C(F)C=C1F IFGWYHGYNVGVRB-UHFFFAOYSA-N 0.000 description 1
- FCRFVPZAXGJLPW-UHFFFAOYSA-N 5-(4,6-dimethyl-1h-benzimidazol-2-yl)-4-methyl-n-[3-(1-methylpiperidin-4-yl)propyl]pyrimidin-2-amine Chemical compound C1CN(C)CCC1CCCNC(N=C1C)=NC=C1C1=NC2=C(C)C=C(C)C=C2N1 FCRFVPZAXGJLPW-UHFFFAOYSA-N 0.000 description 1
- JOPSSWGWLCLPPF-RUDMXATFSA-N 5-[2-(2-carboxyethyl)-3-[(e)-6-(4-methoxyphenyl)hex-5-enoxy]phenoxy]pentanoic acid Chemical compound C1=CC(OC)=CC=C1\C=C\CCCCOC1=CC=CC(OCCCCC(O)=O)=C1CCC(O)=O JOPSSWGWLCLPPF-RUDMXATFSA-N 0.000 description 1
- FNRNBCNUWGWVFO-UHFFFAOYSA-N 5-[[4-(carboxymethyl)phenyl]diazenyl]-2-hydroxybenzoic acid Chemical compound C1=CC(CC(=O)O)=CC=C1N=NC1=CC=C(O)C(C(O)=O)=C1 FNRNBCNUWGWVFO-UHFFFAOYSA-N 0.000 description 1
- GUBJNPWVIUFSTR-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CN(C(=O)CN(C)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 GUBJNPWVIUFSTR-UHFFFAOYSA-N 0.000 description 1
- OKRSVUYYCJPECG-LFGMFVMYSA-N 5α-hydroxytriptolide Chemical compound O=C1OCC([C@]2(O)C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 OKRSVUYYCJPECG-LFGMFVMYSA-N 0.000 description 1
- MJZJYWCQPMNPRM-UHFFFAOYSA-N 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine Chemical compound CC1(C)N=C(N)N=C(N)N1OCCCOC1=CC(Cl)=C(Cl)C=C1Cl MJZJYWCQPMNPRM-UHFFFAOYSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- XSMSNFMDVXXHGJ-UHFFFAOYSA-N 6-(1h-indazol-6-yl)-n-(4-morpholin-4-ylphenyl)imidazo[1,2-a]pyrazin-8-amine Chemical compound C1COCCN1C(C=C1)=CC=C1NC1=NC(C=2C=C3NN=CC3=CC=2)=CN2C1=NC=C2 XSMSNFMDVXXHGJ-UHFFFAOYSA-N 0.000 description 1
- YOELZIQOLWZLQC-UHFFFAOYSA-N 6-(4-fluorophenyl)-5-pyridin-4-yl-2,3-dihydroimidazo[2,1-b]thiazole Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=CN=CC=2)N2CCSC2=N1 YOELZIQOLWZLQC-UHFFFAOYSA-N 0.000 description 1
- KKYABQBFGDZVNQ-UHFFFAOYSA-N 6-[5-[(cyclopropylamino)-oxomethyl]-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)-3-pyridinecarboxamide Chemical compound CC1=C(F)C=C(C(=O)NC2CC2)C=C1C1=CC=C(C(=O)NCC(C)(C)C)C=N1 KKYABQBFGDZVNQ-UHFFFAOYSA-N 0.000 description 1
- SLZBEPLWGGRZAY-UHFFFAOYSA-N 6-[[3-fluoro-5-(4-methoxyoxan-4-yl)phenoxy]methyl]-1-methylquinolin-2-one Chemical compound C=1C(F)=CC(OCC=2C=C3C=CC(=O)N(C)C3=CC=2)=CC=1C1(OC)CCOCC1 SLZBEPLWGGRZAY-UHFFFAOYSA-N 0.000 description 1
- KQVQQSLYBUVFRU-UHFFFAOYSA-N 6-chloro-4-(methylamino)pyridine-3-carboxylic acid Chemical compound CNC1=CC(Cl)=NC=C1C(O)=O KQVQQSLYBUVFRU-UHFFFAOYSA-N 0.000 description 1
- NSMOZFXKTHCPTQ-UHFFFAOYSA-N 6-fluoro-n-[(5-fluoro-2-methoxypyridin-3-yl)methyl]-5-[(5-methyl-1h-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyridin-2-amine Chemical compound COC1=NC=C(F)C=C1CNC(N=C1F)=CC=C1CC1=CNC2=NC=C(C)C=C12 NSMOZFXKTHCPTQ-UHFFFAOYSA-N 0.000 description 1
- ZXXHOPNSTZKWRI-UHFFFAOYSA-N 7-[2-[4-[3-(trifluoromethyl)phenyl]-3,6-dihydro-2h-pyridin-1-yl]ethyl]isoquinoline Chemical compound FC(F)(F)C1=CC=CC(C=2CCN(CCC=3C=C4C=NC=CC4=CC=3)CC=2)=C1 ZXXHOPNSTZKWRI-UHFFFAOYSA-N 0.000 description 1
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- SRNWOUGRCWSEMX-TYASJMOZSA-N ADP-D-ribose Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1OC(O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-TYASJMOZSA-N 0.000 description 1
- SRNWOUGRCWSEMX-KEOHHSTQSA-N ADP-beta-D-ribose Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-KEOHHSTQSA-N 0.000 description 1
- 229940121819 ATPase inhibitor Drugs 0.000 description 1
- MROJXXOCABQVEF-UHFFFAOYSA-N Actarit Chemical compound CC(=O)NC1=CC=C(CC(O)=O)C=C1 MROJXXOCABQVEF-UHFFFAOYSA-N 0.000 description 1
- 229940122216 Adenosine A3 receptor agonist Drugs 0.000 description 1
- 229940080778 Adenosine deaminase inhibitor Drugs 0.000 description 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- FVVDKUPCWXUVNP-UHFFFAOYSA-M Aminosalicylate sodium anhydrous Chemical compound [Na+].NC1=CC=C(C([O-])=O)C(O)=C1 FVVDKUPCWXUVNP-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000000412 Annexin Human genes 0.000 description 1
- 108050008874 Annexin Proteins 0.000 description 1
- 102100027203 B-cell antigen receptor complex-associated protein beta chain Human genes 0.000 description 1
- 108091007065 BIRCs Proteins 0.000 description 1
- 229940124291 BTK inhibitor Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102100026437 Branched-chain-amino-acid aminotransferase, cytosolic Human genes 0.000 description 1
- 101710142286 Branched-chain-amino-acid transaminase 1 Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- QRSLLJXPHSUGHX-GOSISDBHSA-N C(#N)C1=CC=2N(N=C1)C(=CC=2)C1=NC=C(C(=O)NC[C@H](C(C)(C)O)F)C(=C1)NC Chemical compound C(#N)C1=CC=2N(N=C1)C(=CC=2)C1=NC=C(C(=O)NC[C@H](C(C)(C)O)F)C(=C1)NC QRSLLJXPHSUGHX-GOSISDBHSA-N 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 101150012716 CDK1 gene Proteins 0.000 description 1
- 229940122739 Calcineurin inhibitor Drugs 0.000 description 1
- 102100024123 Calcineurin-binding protein cabin-1 Human genes 0.000 description 1
- 101710192106 Calcineurin-binding protein cabin-1 Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 208000010445 Chilblains Diseases 0.000 description 1
- 241001517241 Chromis delta Species 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- UNPLRYRWJLTVAE-UHFFFAOYSA-N Cloperastine hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)OCCN1CCCCC1 UNPLRYRWJLTVAE-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000014997 Crohn colitis Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102100026398 Cyclic AMP-responsive element-binding protein 3 Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000003849 Cytochrome P450 Human genes 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- RPYWXZCFYPVCNQ-RVDMUPIBSA-N DMXB-A Chemical compound COC1=CC(OC)=CC=C1\C=C/1C(C=2C=NC=CC=2)=NCCC\1 RPYWXZCFYPVCNQ-RVDMUPIBSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 description 1
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 102100037024 E3 ubiquitin-protein ligase XIAP Human genes 0.000 description 1
- 101710136259 E3 ubiquitin-protein ligase XIAP Proteins 0.000 description 1
- IONAQTGMWFXHIX-UHFFFAOYSA-N E3040 Chemical compound CC1=C(O)C(C)=C2SC(NC)=NC2=C1CC1=CC=CN=C1 IONAQTGMWFXHIX-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 206010014486 Elevated triglycerides Diseases 0.000 description 1
- YRSSFEUQNAXQMX-UHFFFAOYSA-N Esonarimod Chemical compound CC(=O)SCC(C(O)=O)CC(=O)C1=CC=C(C)C=C1 YRSSFEUQNAXQMX-UHFFFAOYSA-N 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 102000004864 Fibroblast growth factor 10 Human genes 0.000 description 1
- 102000010449 Folate receptor beta Human genes 0.000 description 1
- 108050001930 Folate receptor beta Proteins 0.000 description 1
- 102000016970 Follistatin Human genes 0.000 description 1
- 108010014612 Follistatin Proteins 0.000 description 1
- 229940123570 Fyn tyrosine kinase inhibitor Drugs 0.000 description 1
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- 229940123127 Glucocorticoid agonist Drugs 0.000 description 1
- 229940123037 Glucocorticoid antagonist Drugs 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 108010093013 HLA-DR1 Antigen Proteins 0.000 description 1
- 102100025255 Haptoglobin Human genes 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 108010023925 Histone Deacetylase 6 Proteins 0.000 description 1
- 102100022893 Histone acetyltransferase KAT5 Human genes 0.000 description 1
- 101710116149 Histone acetyltransferase KAT5 Proteins 0.000 description 1
- 102100022537 Histone deacetylase 6 Human genes 0.000 description 1
- 229940122617 Histone deacetylase 6 inhibitor Drugs 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000806242 Homo sapiens 17-beta-hydroxysteroid dehydrogenase type 1 Proteins 0.000 description 1
- 101001045223 Homo sapiens 17-beta-hydroxysteroid dehydrogenase type 2 Proteins 0.000 description 1
- 101000924488 Homo sapiens Atrial natriuretic peptide receptor 3 Proteins 0.000 description 1
- 101000914491 Homo sapiens B-cell antigen receptor complex-associated protein beta chain Proteins 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 101000855520 Homo sapiens Cyclic AMP-responsive element-binding protein 3 Proteins 0.000 description 1
- 101000829794 Homo sapiens G-protein coupled receptor 15 Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101001011442 Homo sapiens Interferon regulatory factor 5 Proteins 0.000 description 1
- 101001032342 Homo sapiens Interferon regulatory factor 7 Proteins 0.000 description 1
- 101001076407 Homo sapiens Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 101000852483 Homo sapiens Interleukin-1 receptor-associated kinase 1 Proteins 0.000 description 1
- 101000740112 Homo sapiens Membrane-associated transporter protein Proteins 0.000 description 1
- 101001018196 Homo sapiens Mitogen-activated protein kinase kinase kinase 5 Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 101150101999 IL6 gene Proteins 0.000 description 1
- 108091058560 IL8 Proteins 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 229940123965 Immunoglobulin inhibitor Drugs 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 102100030131 Interferon regulatory factor 5 Human genes 0.000 description 1
- 102100038070 Interferon regulatory factor 7 Human genes 0.000 description 1
- 229940119178 Interleukin 1 receptor antagonist Drugs 0.000 description 1
- 108010072621 Interleukin-1 Receptor-Associated Kinases Proteins 0.000 description 1
- 102000006940 Interleukin-1 Receptor-Associated Kinases Human genes 0.000 description 1
- 102000045959 Interleukin-1 Receptor-Like 1 Human genes 0.000 description 1
- 108700003107 Interleukin-1 Receptor-Like 1 Proteins 0.000 description 1
- 102000019223 Interleukin-1 receptor Human genes 0.000 description 1
- 101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 description 1
- 102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 description 1
- 102000013264 Interleukin-23 Human genes 0.000 description 1
- 102000010782 Interleukin-7 Receptors Human genes 0.000 description 1
- 108010038498 Interleukin-7 Receptors Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 101150051809 KCNH2 gene Proteins 0.000 description 1
- 239000012839 Krebs-Henseleit buffer Substances 0.000 description 1
- 108010092694 L-Selectin Proteins 0.000 description 1
- 102100033467 L-selectin Human genes 0.000 description 1
- 229940122145 LYN tyrosine kinase inhibitor Drugs 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 108010031336 MIV-247 Proteins 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 101150010110 Map3k8 gene Proteins 0.000 description 1
- 102100037258 Membrane-associated transporter protein Human genes 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 108020005196 Mitochondrial DNA Proteins 0.000 description 1
- 102100033127 Mitogen-activated protein kinase kinase kinase 5 Human genes 0.000 description 1
- 102100026907 Mitogen-activated protein kinase kinase kinase 8 Human genes 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- ZKGNPQKYVKXMGJ-UHFFFAOYSA-N N,N-dimethylacetamide Chemical compound CN(C)C(C)=O.CN(C)C(C)=O ZKGNPQKYVKXMGJ-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- GUUWHOSUKOCRHG-UHFFFAOYSA-N NAV2729 Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(N1)=CC(=O)N2C1=C(C=1C=CC(Cl)=CC=1)C(CC=1C=CC=CC=1)=N2 GUUWHOSUKOCRHG-UHFFFAOYSA-N 0.000 description 1
- UNHZLHSLZZWMNP-LLVKDONJSA-N NC(=O)c1ccc([C@@H]2CCCN(C2)C(=O)C=C)c2cc[nH]c12 Chemical compound NC(=O)c1ccc([C@@H]2CCCN(C2)C(=O)C=C)c2cc[nH]c12 UNHZLHSLZZWMNP-LLVKDONJSA-N 0.000 description 1
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 description 1
- 102000002452 NPR3 Human genes 0.000 description 1
- 101100165729 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) stk-1 gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- UFAHZIUFPNSHSL-MRVPVSSYSA-N O-propanoyl-L-carnitine Chemical compound CCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C UFAHZIUFPNSHSL-MRVPVSSYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 108010027220 PEGylated soluble tumor necrosis factor receptor I Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 108010043958 Peptoids Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 108010039230 Protein Kinase C-delta Proteins 0.000 description 1
- 108010078137 Protein Kinase C-epsilon Proteins 0.000 description 1
- 108010015499 Protein Kinase C-theta Proteins 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 101710092489 Protein kinase 2 Proteins 0.000 description 1
- 102100037340 Protein kinase C delta type Human genes 0.000 description 1
- 102100037339 Protein kinase C epsilon type Human genes 0.000 description 1
- 102100021556 Protein kinase C eta type Human genes 0.000 description 1
- 102100021566 Protein kinase C theta type Human genes 0.000 description 1
- 102000007131 Proto-Oncogene Proteins c-fyn Human genes 0.000 description 1
- 108010072960 Proto-Oncogene Proteins c-fyn Proteins 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- ALLWOAVDORUJLA-UHFFFAOYSA-N Rebamipida Chemical compound C=1C(=O)NC2=CC=CC=C2C=1CC(C(=O)O)NC(=O)C1=CC=C(Cl)C=C1 ALLWOAVDORUJLA-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 1
- 101710088493 Rho-associated protein kinase 2 Proteins 0.000 description 1
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 102000005473 Secretory Phospholipases A2 Human genes 0.000 description 1
- 108010031873 Secretory Phospholipases A2 Proteins 0.000 description 1
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 108700042805 TRU-015 Proteins 0.000 description 1
- 101710172152 TSC22 domain family protein 3 Proteins 0.000 description 1
- 102100035260 TSC22 domain family protein 3 Human genes 0.000 description 1
- 108010010057 TYK2 Kinase Proteins 0.000 description 1
- 102000015774 TYK2 Kinase Human genes 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 241001061127 Thione Species 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 229940122954 Transcription factor inhibitor Drugs 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 1
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000029265 Type 1 interferonopathy Diseases 0.000 description 1
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 102100040729 Zinc finger protein 383 Human genes 0.000 description 1
- BPMMYKAHRIEVDH-VOQZNFBZSA-N [(1r,3s)-1-amino-3-[(6r)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl]cyclopentyl]methanol Chemical compound C([C@H](CC1=CC=2)CCCCCC)CC1=CC=2[C@H]1CC[C@](N)(CO)C1 BPMMYKAHRIEVDH-VOQZNFBZSA-N 0.000 description 1
- IXYNFLOLUBKHQU-FZCWJHTDSA-N [(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[(2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [(2R,3S,5R)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]-5-(6-aminopurin-9-yl)oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]-5-(6-aminopurin-9-yl)oxolan-3-yl] hydrogen phosphate Chemical compound Cc1cn([C@H]2C[C@H](OP(O)(=O)OC[C@H]3O[C@H](C[C@@H]3OP(O)(=O)OC[C@H]3O[C@H](C[C@@H]3OP(O)(=O)OC[C@H]3O[C@H](C[C@@H]3OP(O)(=O)OC[C@H]3O[C@H](C[C@@H]3OP(O)(=S)OC[C@H]3O[C@H](C[C@@H]3OP(O)(=S)OC[C@H]3O[C@H](C[C@@H]3OP(O)(=S)OC[C@H]3O[C@H](C[C@@H]3O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)[C@@H](COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=S)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=S)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)O2)c(=O)[nH]c1=O IXYNFLOLUBKHQU-FZCWJHTDSA-N 0.000 description 1
- BVXLAHSJXXSWFF-KEKPKEOLSA-N [(2r,4as,10ar)-4a-benzyl-7-[(2-methylpyridin-3-yl)carbamoyl]-2-(trifluoromethyl)-1,3,4,9,10,10a-hexahydrophenanthren-2-yl] dihydrogen phosphate Chemical compound CC1=NC=CC=C1NC(=O)C1=CC=C2[C@]3(CC=4C=CC=CC=4)CC[C@@](C(F)(F)F)(OP(O)(O)=O)C[C@H]3CCC2=C1 BVXLAHSJXXSWFF-KEKPKEOLSA-N 0.000 description 1
- XQYASZNUFDVMFH-CQSZACIVSA-N [5-chloro-2-[2-[(2r)-4-[(4-fluorophenyl)methyl]-2-methylpiperazin-1-yl]-2-oxoethoxy]phenyl]urea Chemical compound C([C@H](N(CC1)C(=O)COC=2C(=CC(Cl)=CC=2)NC(N)=O)C)N1CC1=CC=C(F)C=C1 XQYASZNUFDVMFH-CQSZACIVSA-N 0.000 description 1
- XAYQDTPEOFCYIG-UHFFFAOYSA-N [[4-[5-(cyclopropylcarbamoyl)-2-methylanilino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carbonyl]-propylcarbamoyl]oxymethyl 2-(4-phosphonooxyphenyl)acetate Chemical compound C=1N2N=CN=C(NC=3C(=CC=C(C=3)C(=O)NC3CC3)C)C2=C(C)C=1C(=O)N(CCC)C(=O)OCOC(=O)CC1=CC=C(OP(O)(O)=O)C=C1 XAYQDTPEOFCYIG-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- VOVIALXJUBGFJZ-AMTWPJRWSA-N ac1l1y6y Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3O[C@H](CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-AMTWPJRWSA-N 0.000 description 1
- WDENQIQQYWYTPO-IBGZPJMESA-N acalabrutinib Chemical compound CC#CC(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C(=O)NC=2N=CC=CC=2)=C2N1C=CN=C2N WDENQIQQYWYTPO-IBGZPJMESA-N 0.000 description 1
- 229950009821 acalabrutinib Drugs 0.000 description 1
- XOYXESIZZFUVRD-UVSAJTFZSA-M acemannan Chemical compound CC(=O)O[C@@H]1[C@H](O)[C@@H](OC)O[C@H](CO)[C@H]1O[C@@H]1[C@@H](O)[C@@H](OC(C)=O)[C@H](O[C@@H]2[C@H]([C@@H](OC(C)=O)[C@H](O[C@@H]3[C@H]([C@@H](O)[C@H](O[C@@H]4[C@H]([C@@H](OC(C)=O)[C@H](O[C@@H]5[C@H]([C@@H](OC(C)=O)[C@H](O[C@@H]6[C@H]([C@@H](OC(C)=O)[C@H](O[C@@H]7[C@H]([C@@H](OC(C)=O)[C@H](OC)[C@@H](CO)O7)O)[C@@H](CO)O6)O)[C@H](O5)C([O-])=O)O)[C@@H](CO)O4)O)[C@@H](CO)O3)NC(C)=O)[C@@H](CO)O2)O)[C@@H](CO)O1 XOYXESIZZFUVRD-UVSAJTFZSA-M 0.000 description 1
- 229960005327 acemannan Drugs 0.000 description 1
- LPQVLIUFLWUMHG-UHFFFAOYSA-N acetyl 2-aminoacetate Chemical compound CC(=O)OC(=O)CN LPQVLIUFLWUMHG-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 229950003218 actarit Drugs 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229960002648 alanylglutamine Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- SOGAXMICEFXMKE-UHFFFAOYSA-N alpha-Methyl-n-butyl acrylate Natural products CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Chemical class OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- 210000003423 ankle Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 229960005245 asenapine Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- XDCNKOBSQURQOZ-MVIJUDHYSA-L balsalazide disodium Chemical compound O.O.[Na+].[Na+].C1=C(C([O-])=O)C(O)=CC=C1\N=N\C1=CC=C(C(=O)NCCC([O-])=O)C=C1 XDCNKOBSQURQOZ-MVIJUDHYSA-L 0.000 description 1
- 229960003270 belimumab Drugs 0.000 description 1
- PQRLQZNKDQQMBC-LSYPWIJNSA-M benzenesulfonate;1-[(3s)-3-(3,4-dichlorophenyl)-3-[2-(4-phenyl-1-azoniabicyclo[2.2.2]octan-1-yl)ethyl]piperidin-1-yl]-2-(3-propan-2-yloxyphenyl)ethanone Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1.CC(C)OC1=CC=CC(CC(=O)N2C[C@](CC[N+]34CCC(CC3)(CC4)C=3C=CC=CC=3)(CCC2)C=2C=C(Cl)C(Cl)=CC=2)=C1 PQRLQZNKDQQMBC-LSYPWIJNSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- FCPVYOBCFFNJFS-LQDWTQKMSA-M benzylpenicillin sodium Chemical group [Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 FCPVYOBCFFNJFS-LQDWTQKMSA-M 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- ACWZRVQXLIRSDF-UHFFFAOYSA-N binimetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1F ACWZRVQXLIRSDF-UHFFFAOYSA-N 0.000 description 1
- 229950003054 binimetinib Drugs 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229950005901 briobacept Drugs 0.000 description 1
- 229960003655 bromfenac Drugs 0.000 description 1
- ZBPLOVFIXSTCRZ-UHFFFAOYSA-N bromfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 ZBPLOVFIXSTCRZ-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical class O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229950008094 camobucol Drugs 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 206010008129 cerebral palsy Diseases 0.000 description 1
- 229940125400 channel inhibitor Drugs 0.000 description 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 229950002334 clenoliximab Drugs 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229950001404 cobitolimod Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000008120 corn starch Substances 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
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000002739 cryptand Substances 0.000 description 1
- 229940121384 cxc chemokine receptor type 4 (cxcr4) antagonist Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 229950005026 dapirolizumab pegol Drugs 0.000 description 1
- 108010048522 dapirolizumab pegol Proteins 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- UFIVEPVSAGBUSI-UHFFFAOYSA-N dihydroorotic acid Chemical compound OC(=O)C1CC(=O)NC(=O)N1 UFIVEPVSAGBUSI-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- DDVFLVSIVNKSLB-UHFFFAOYSA-J dioxido-oxo-(phosphonatomethyl)-$l^{5}-phosphane;technetium(4+) Chemical compound [Tc+4].[O-]P([O-])(=O)CP([O-])([O-])=O DDVFLVSIVNKSLB-UHFFFAOYSA-J 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- MVCOAUNKQVWQHZ-UHFFFAOYSA-N doramapimod Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCCN3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 MVCOAUNKQVWQHZ-UHFFFAOYSA-N 0.000 description 1
- 229950005521 doramapimod Drugs 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 229940112141 dry powder inhaler Drugs 0.000 description 1
- 229960002224 eculizumab Drugs 0.000 description 1
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 1
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 208000037902 enteropathy Diseases 0.000 description 1
- 229950004136 entospletinib Drugs 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 229950004843 esonarimod Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229950004356 foralumab Drugs 0.000 description 1
- 229950002546 fosdagrocorat Drugs 0.000 description 1
- 229950005309 fostamatinib Drugs 0.000 description 1
- GKDRMWXFWHEQQT-UHFFFAOYSA-N fostamatinib Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C(NC=3N=C4N(COP(O)(O)=O)C(=O)C(C)(C)OC4=CC=3)C(F)=CN=2)=C1 GKDRMWXFWHEQQT-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 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
- 229960002518 gentamicin Drugs 0.000 description 1
- 229950003717 gevokizumab Drugs 0.000 description 1
- 229940089161 ginsenoside Drugs 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 229950010864 guselkumab Drugs 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 102000044389 human CD22 Human genes 0.000 description 1
- 102000046824 human IL1RN Human genes 0.000 description 1
- 102000057041 human TNF Human genes 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000004093 hydrolase inhibitor Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000008938 immune dysregulation Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 102000014909 interleukin-1 receptor activity proteins Human genes 0.000 description 1
- 108040006732 interleukin-1 receptor activity proteins Proteins 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000005445 isotope effect Effects 0.000 description 1
- 229950001890 itacitinib Drugs 0.000 description 1
- 229960005435 ixekizumab Drugs 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 229950007278 lenercept Drugs 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 229950003265 losmapimod Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Chemical class 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- ZEASAUSJELNJFI-UHFFFAOYSA-N methyl 6-bromo-4-chloropyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(Br)C=C1Cl ZEASAUSJELNJFI-UHFFFAOYSA-N 0.000 description 1
- MCMCCUAPYAUWBV-UHFFFAOYSA-N methyl 6-chloro-4-(methylamino)pyridine-3-carboxylate Chemical compound CNC1=CC(Cl)=NC=C1C(=O)OC MCMCCUAPYAUWBV-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- QOSMEMHKXNNIGG-SSEXGKCCSA-N n-[1-[(3r)-3-(3,5-difluorophenyl)-3-(1-methylsulfonylpiperidin-4-yl)propyl]piperidin-4-yl]-n-ethyl-2-(4-methylsulfonylphenyl)acetamide Chemical compound C1([C@@H](CCN2CCC(CC2)N(CC)C(=O)CC=2C=CC(=CC=2)S(C)(=O)=O)C=2C=C(F)C=C(F)C=2)CCN(S(C)(=O)=O)CC1 QOSMEMHKXNNIGG-SSEXGKCCSA-N 0.000 description 1
- CDOOFZZILLRUQH-GDLZYMKVSA-N n-[3-[6-[4-[(2r)-1,4-dimethyl-3-oxopiperazin-2-yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide Chemical compound CN1CCN(C)C(=O)[C@H]1C(C=C1)=CC=C1NC1=NC(C=2C(=C(NC(=O)C=3SC=4CCCCC=4C=3)C=CC=2)C)=CN(C)C1=O CDOOFZZILLRUQH-GDLZYMKVSA-N 0.000 description 1
- MPYACSQFXVMWNO-UHFFFAOYSA-N n-[5-[4-(3,3-dimethylazetidine-1-carbonyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide Chemical compound C1C(C)(C)CN1C(=O)C1=CC=C(C=2N3N=C(NC(=O)C4CC4)N=C3C=CC=2)C=C1 MPYACSQFXVMWNO-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229950007708 namilumab Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229940069817 neflamapimod Drugs 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000003227 neuromodulating effect Effects 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229950011147 nolpitantium besilate Drugs 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 229950009090 ocaratuzumab Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229950010444 onercept Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229950000867 pegsunercept Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 102000014187 peptide receptors Human genes 0.000 description 1
- 108010011903 peptide receptors Proteins 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 210000003668 pericyte Anatomy 0.000 description 1
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Chemical group 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229950008092 placulumab Drugs 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 230000036278 prepulse Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 108010027883 protein kinase C eta Proteins 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- PJESVVYWPFAJCS-UHFFFAOYSA-N pyridazine-3-carbonitrile Chemical compound N#CC1=CC=CN=N1 PJESVVYWPFAJCS-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- YNZAFFFENDLJQG-UHFFFAOYSA-N pyrrol-1-amine Chemical compound NN1C=CC=C1 YNZAFFFENDLJQG-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229950006043 rabeximod Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 229950004535 rebamipide Drugs 0.000 description 1
- 108010003189 recombinant human tumor necrosis factor-binding protein-1 Proteins 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229950004205 repifermin Drugs 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- BTGNGJJLZOIYID-UHFFFAOYSA-N sivelestat Chemical compound C1=CC(OC(=O)C(C)(C)C)=CC=C1S(=O)(=O)NC1=CC=CC=C1C(=O)NCC(O)=O BTGNGJJLZOIYID-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229960003339 sodium phosphate Drugs 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- SGAKODIXAHVUKL-LFELFHSZSA-M sodium;(2s,3s)-3-[[(2s)-4-methyl-1-(2-methylpropoxy)pentan-2-yl]carbamoyl]oxirane-2-carboxylate Chemical compound [Na+].CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C([O-])=O SGAKODIXAHVUKL-LFELFHSZSA-M 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229950009133 solcitinib Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229960002385 streptomycin sulfate Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940066769 systemic antihistamines substituted alkylamines Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 229950010265 tabalumab Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229950003441 tebufelone Drugs 0.000 description 1
- 229960005186 technetium (99mtc) etarfolatide Drugs 0.000 description 1
- 108010083425 technetium Tc 99m RP128 Proteins 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- XYKWNRUXCOIMFZ-UHFFFAOYSA-N tepoxalin Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(CCC(=O)N(C)O)=N1 XYKWNRUXCOIMFZ-UHFFFAOYSA-N 0.000 description 1
- 229950009638 tepoxalin Drugs 0.000 description 1
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 229950005515 tildrakizumab Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 230000003614 tolerogenic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229950001802 toralizumab Drugs 0.000 description 1
- 229950001641 toreforant Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229950000835 tralokinumab Drugs 0.000 description 1
- 239000007930 transdermal spray Substances 0.000 description 1
- 239000003558 transferase inhibitor Substances 0.000 description 1
- 229950010086 tregalizumab Drugs 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000005259 triarylamine group Chemical group 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000003211 trypan blue cell staining Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 1
- 210000003954 umbilical cord Anatomy 0.000 description 1
- 229960003824 ustekinumab Drugs 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229950000815 veltuzumab Drugs 0.000 description 1
- 229950007805 vercirnon Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 229950004393 visilizumab Drugs 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229950009002 zanolimumab Drugs 0.000 description 1
- 108010027843 zonulin Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
式(I)的化合物、其药学上可接受的盐、其氘代类似物、其组合物以及使用其化合物治疗疾病的方法,其中所述可变取代基在本文中公开。
Description
技术领域
本公开涉及新的化合物,其为激酶IRAK4的抑制剂。本公开还涉及制备所述化合物的方法以及包括该化合物的药物组合物。
背景技术
白介素-1受体相关激酶4(IRAK4)是一种丝氨酸-苏氨酸激酶,充当白介素-1/Toll样受体(IL-1/TLR)信号级联反应中的介质。更具体地说,IRAK4参与衔接蛋白髓样分化初次应答基因88(MyD88)信号级联的活化,并被认为在炎症和纤维化障碍中起作用,如类风湿性关节炎(RA)、炎症性肠病(IBD)、痛风、莱姆病(Lyme disease)、关节炎、牛皮癣、盆腔炎、全身性红斑狼疮(SLE)、干燥综合征(Sjogren’s syndrome)、病毒性心肌炎、急性和慢性组织损伤、非酒精性脂肪性肝炎(NASH)、酒精性肝炎和肾脏疾病(包括慢性肾脏疾病和糖尿病性肾脏疾病)。另外,IRAK4在某些癌症中起作用,并且被认为在与包括艰难梭状芽胞杆菌(C.difficile.)在内的胃肠道感染有关的炎症中起作用。通过IL-1R/TLR信号传导导致MyD88活化,从而补充IRAK4和IRAK1形成信号传导复合物。然后,该复合物与一系列激酶、转接蛋白和连接酶相互作用,最终导致被活化的B细胞的核因子κ轻链增强子(NF-κB)、活化蛋白1(AP1)、环状AMP-应答元件-结合蛋白(CREB)和干扰素调节因子(IRF)(包括IRF5和IRF7)的活化,从而诱导促炎性细胞因子和I型干扰素的产生。
因此,IRAK4抑制剂可用于治疗炎症和纤维化障碍,如类风湿性关节炎(RA)、炎症性肠病(IBD)、痛风、莱姆病(Lyme disease)、关节炎、牛皮癣、盆腔炎、全身性红斑狼疮(SLE)、干燥综合征(Sjogren’s syndrome)、包括艰难梭状芽胞杆菌(C.difficile.)在内的胃肠道感染相关的炎症、病毒性心肌炎、急性和慢性组织损伤、非酒精性脂肪性肝炎(NASH)、酒精性肝炎和肾脏疾病(包括慢性肾脏疾病和糖尿病性肾脏疾病)。(Joosten,L.A.B等人,TOLL-LIKE RECEPTORS AND CHRONIC INFLAMMATION IN RHEUMATIC DISEASES:NEW DEVELOPMENTS,Nat.Rev.Rheumatol.,346|2016年6月12;344-357 2016年5月12日在线发表)(Valaperti,A.et al.,INNATE IMMUNE INTERLEUKIN-1RECEPTOR-ASSOCIATEDKINASE 4EXACERBATES VIRAL MYOCARDITIS BY REDUCING CCR5+CD11b+MONOCYTEMIGRATION AND IMPAIRING INTERFERON PRODUCTION,Circulation,128|2013年9月14;1542-1554),以及I型干扰素病,例如Aicardi-Goutières综合征、家族性冻疮样狼疮和伴随大脑脑蛋白营养不良的视网膜血管病变(Lee-Kirsch等人,TYPE I INTERFERONOPATHIES—AN EXPANDING DISEASE SPECTRUM OF IMMUNODYSREGULATION,Semin.Immunopathol.(2015)37:349–357),(Leaf,I.A.等人,PERICYTE MYD88 AND IRAK4 CONTROLINFLAMMATORY AND FIBROTIC RESPONSES TO TISSUE INJURY,The Journal of ClinicalInvestigation,127|2017年1月1日;321-334),(Seki,E.等人,TLR4 ENHANCES TGF-βSIGNALING AND HEPATIC FIBROSIS,Nature Medicine,13|2007年11月11日;1324-1332),(Garcia-Martinez,I.等人,HEPATOCYTE MITOCHONDRIAL DNA DRIVES NONALCHOLICSTEATOHEPATITIS BY ACTIVATION OF TLR9,The Journal of Clinical Investigation,126|2016年3月3日;859-864)。
此外,某些癌症(包括淋巴瘤)可能在MYD88衔接蛋白中含有一个或多个突变,其导致可促进肿瘤细胞存活的组成性信号传导级联反应。(Kelly等人,IRAK4 inhibitor forautoimmunity and lymphoma,J.Exp.Med.2015,第212卷,第13期,2189–2201)
因此,IRAK4的抑制剂可用于治疗包括淋巴瘤的癌症。
当前没有审批通过的IRAK4抑制药物。因此,提供一种具有适于作为药剂施用于哺乳动物,特别是人类的特性的IRAK4抑制化合物是有用的。选择药学上的化合物的考虑因素是多方面的。经常会分析化合物的特征,包括靶标效价、药代动力学、pKa、溶解度、稳定性(例如,代谢稳定性)和脱靶倾向(包括潜在的心脏毒性),以及潜在的药物-药物相互作用。
抑制人类ether-à-gogo相关基因(hERG)编码的心脏离子通道会导致心律不齐,其是药物发现和开发中的主要问题。自动化的电生理膜片钳可在药物开发早期评估hERG通道效应以辅助药物化学程序,并且已成为制药公司的常规方法。Early identification ofhERG liability in drug discovery programs by automated patch clamp,FrontPharmaco.(2014年9月2日);5:203。
WO2016210034、WO2016210036、WO2015150995、WO2016127024和WO2016210037记载了据称可用作IRAK4抑制剂的化合物。
发明内容
本文提供了用作IRAK4抑制剂的化合物和药物组合物。本公开的一些化合物可以与至少一种药学上可接受的赋形剂一起用于药物组合物中,用于治疗需要其的受试者。还发现本公开的化合物抑制促炎性细胞因子TNFα、IL-6、IL-1β、IL8、IL12、IL-23和I型干扰素IFNα和IFNβ的产生,所有这些都是炎症和免疫反应的介质。本公开还提供了组合物,包括药物组合物、包括所述化合物的试剂盒,以及使用和制备所述化合物的方法。
在本公开的一个实施方案中,提供了式(I)的化合物或其药学上可接受的盐或结构异构体:
其中:
R1选自H、氘或C1-4烷基,且所述C1-4烷基任选地被一个或多个卤素取代;
R2选自H、氘或C1-4烷基,且所述烷基任选地被一个或多个卤素取代;或
R1和R2,与它们所连接的碳原子一起形成C3-C6环烷基;以及
R3为C0-4烷基-CN。
在一个实施方案中,R2为H。
在一个实施方案中,R1为甲基。
在一个实施方案中,R3为–CN。
在另一个实施方案中,提供了式II的化合物或其药学上可接受的盐或结构异构体:
其中:
R1选自H、氘或C1-4烷基,且所述C1-4烷基具有一个或多个任选地被氘替代的氢原子。
R2选自H、氘或C1-4烷基,且所述C1-4烷基具有一个或多个任选地被氘替代的氢原子;以及
R3为C0-4烷基-CN。
在式(II)的一个实施方案中,R2为H。
在另一个实施方案中,R2为氘。
在式(II)的一个实施方案中,R1为甲基。
在式(II)的一个实施方案中,R1为甲基,且一个或多个与所述甲基相连的氢原子被氘替代。
在一个实施方案中,R3为–CN。
在另一个实施方案中,提供了式(III)的化合物或其药学上可接受的盐或氘代类似物:
其中:
R1为H、氘或甲基,所述甲基具有一个或多个任选地被氘替代的氢原子。
在一个实施方案中,提供了具有以下结构的化合物或其药学上可接受的盐:
在一个实施方案中,提供了药物组合物,其包括本文的化合物或其药学上可接受的盐,以及药学上可接受的载体。
本公开的另一个实施方案提供了一种药物组合物,其包括本公开的化合物以及药学上可接受的载体,以及任选地稀释剂。
本公开的另一个实施方案提供了在有需要的患者中治疗与炎症相关的疾病或障碍的方法,该方法包括向所述患者施用本公开的化合物或其药物组合物。
发明详述
定义
以下描述阐述了示例性方法、参数等。然而,应当认识到,这样的描述并非旨在限制本公开的范围,而是作为示例性实施方案的描述而提供。
不在两个字母或符号之间的短横线(“-”)用于表示取代基的连接点。例如,-C(O)NH2通过碳原子连接。为了方便起见,在化学基团的前端或末端加一个短横线;化学基团可以用或不用一个或多个短横线来表示,而不会失去它们的普通含义。通过结构中的线绘制的波浪线表示基团的连接点。除非化学或结构要求,否则化学基团的书写或命名顺序不会指示或暗含任何方向性。
前缀“Cu-v”表示以下基团具有从u至v个碳原子。例如,“C1-6烷基”表示该烷基具有1至6个碳原子。C0表示不存在碳,或者换句话说,表示与下一个取代基的键。
本文中对“约”值或参数的提及包括(并描述)针对该值或参数本身的实施方案。在一些实施方案中,术语“约”包括指示量±10%。在其他实施方案中,术语“约”包括指示量±5%。在某些其他实施方案中,术语“约”包括指示量±1%。同样,术语“约X”包括对“X”的描述。另外,除非上下文另外明确指出,单数形式的“一个”和“该”包括复数形式。因此,例如,提及“化合物”包括多种这样的化合物,并且提及“测定”包括提及本领域技术人员已知的一个或多个测定及其等同形式。
“烷基”是指直链或支链的饱和烃链。如本文所用,烷基具有1至20个碳原子(即,C1-20烷基)、1至8个碳原子(即,C1-8烷基)、1至6个碳原子(即,C1-6烷基))或1-4个碳原子(即C1-4烷基)。烷基的实例包括甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基和3-甲基戊基。当具有特定碳原子数的烷基残基以化学名称命名或由分子式标识时,可涵盖具有该碳原子数的所有位置异构体;因此,例如,“丁基”包括正丁基(即,-(CH2)3CH3))、仲丁基(即,-CH(CH3)CH2CH3)、异丁基(即,-CH2CH(CH3)2)和叔丁基(即,-C(CH3)3);“丙基”包括正丙基(即,-(CH2)2CH3)和异丙基(即-CH(CH3)2)。
“氰基”是指基团-CN。
“卤代”是指–F、-Cl、-Br、-I。
可以使用某些常用的替代化学名称。例如,二价基团,例如二价“烷基”基团,二价“芳基”基团等,也可以分别称为“亚烷基”基团或“亚芳基”基团。同样,除非另有明确说明,否则在本文中基团的组合作为一个部分提及时,例如芳基烷基,最后提到的基团包括通过该原子与分子的其余部分相连的原子。
术语“任选的”或“任选地”是指随后描述的事件或情况可能发生或可能不发生,并且该描述包括所述事件或情况发生的情况以及事件或情况没有发生的情况。同样,术语“任选地被取代”是指指定原子或基团上的任何一个或多个氢原子可以被或可以不被氢以外的部分取代。“任选取代的”可以是零到最大数的可能取代,并且每次出现都是独立的。当使用术语“取代的”时,则需要在所示取代基的可取代氢原子上进行该取代。任选取代可以与(必需)取代相同或不同。
当部分被“任选地取代”时,并提及通用术语,例如任何“烷基”、“烯基”、“炔基”、“卤代烷基”、“环烷基”、“芳基”或“杂芳基”时,那么该通用术语可以指任何具体叙述的在先术语,例如(C1-3烷基)、(C4-6烷基)、-O(C1-4烷基)、(C3-10环烷基)、O-(C3-10环烷基)等。例如,“任何芳基”包括“芳基”以及芳基的实例,例如苯基或萘基等。同样,术语“任何杂环基”包括杂环基,例如氧杂环丁烷基、四氢吡喃基、吗啉基、哌啶基等。以相同的方式,术语“任何杂芳基”包括杂芳基,例如吡啶、哒嗪、噻唑、噻二唑、喹啉等。
一些化合物以互变异构体形式存在。互变异构体彼此平衡。例如,含酰胺的化合物可以与亚氨酸互变异构体平衡存在。不管显示哪种互变异构体,并且无论互变异构体之间的平衡性质如何,本领域普通技术人员都将所述化合物理解为既包括酰胺互变异构体,又包括亚氨酸互变异构体。因此,含酰胺的化合物应理解为包括其亚氨酸互变异构体。同样,含酰亚氨酸的化合物应理解为包括其酰胺互变异构体。
本文给出的任何式或结构也意图代表化合物的未标记形式以及同位素标记形式。同位素标记的化合物具有本文给出的结构式所描述的结构,不同之处在于一个或多个原子被具有选定原子质量或质量数的原子取代。可掺入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如但不限于2H(氘,D)、3H(氚)、11C、13C、14C、15N、18F、15O、18O、31P、32P、35S、36Cl和125I。本公开的各种同位素标记的化合物包括例如其中掺入有放射性同位素如3H、13C和14C的那些。此类同位素标记的化合物可用于代谢研究、反应动力学研究、检测或成像技术,例如正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT),包括药物或基质组织分布测定或用于患者的放射性治疗中。
本公开还包括式I化合物的“氘代类似物”,其中连接至碳原子的1至n个氢被氘替代,其中n是分子中的氢数。此类化合物对代谢表现出增加的抗性,因此当给药于哺乳动物,特别是人时,可用于增加任何式I化合物的半衰期。参见,例如,Foster,“DeuteriumIsotope Effects in Studies of Drug Metabolism”,Trends Pharmacol.Sci.5(12):524-527(1984)。这样的化合物通过本领域公知的方法合成,例如通过使用其中一个或多个氢已被氘替代的原料。
本公开的氘标记或取代的治疗化合物可具有与分布、代谢和排泄(ADME)有关的改善的DMPK(药物代谢和药代动力学)性质。由于具有更高的代谢稳定性,例如,体内半衰期延长,剂量要求降低和/或治疗指数提高,用重同位素(例如氘)取代可能会提供某些治疗优势。18F标记的化合物可用于PET或SPECT研究。本公开的同位素标记的化合物及其前药通常可以通过用下述容易获得的同位素标记的试剂代替非同位素标记的试剂,进行以下方案或实施例和制备中公开的方法来制备。应当理解,在这种情况下,氘被认为是式I化合物中的取代基。
这种重同位素,特别是氘的浓度可以由同位素富集因子定义。在本公开的化合物中,未特别指定为特定同位素的任何原子意在表示该原子的任何稳定同位素。除非另有说明,否则当将位置具体指定为“H”或“氢”时,该位置应理解为以其自然丰度同位素组成具有氢。因此,在本公开的化合物中,任何特别指定为氘(D)的原子均意在表示氘。
在许多情况下,由于存在氨基和/或羧基或与其类似的基团,本发明的化合物能够形成酸和/或碱式盐。
本文还提供所述化合物的药学上可接受的盐、水合物、溶剂化物、互变异构形式、多晶型物和前药。“药学上可接受的”或“生理上可接受的”是指化合物、盐、组合物、剂型和其他材料,其可用于制备适合于兽或人药学用途的药物组合物。
给定化合物的术语“药学上可接受的盐”是指保留给定化合物的生物学效力和性质并且在生物学上或其他方面不是不期望的盐。“药学上可接受的盐”或“生理上可接受的盐”包括例如与无机酸的盐和与有机酸的盐。另外,如果以酸加成盐获得本文所述的化合物,则可以通过碱化该酸式盐的溶液来获得游离碱。相反,如果产物是游离碱,则可以按照常规的从碱化合物制备酸加成盐的方法,通过将游离碱溶解在合适的有机溶剂中并用酸处理该溶液,来制备加成盐,特别是药学上可接受的加成盐。本领域技术人员将认识到可以用于制备无毒的药学上可接受的加成盐的各种合成方法。药学上可接受的酸加成盐可以由无机酸和有机酸制备。衍生自无机酸的盐包括盐酸、氢溴酸、硫酸、硝酸、磷酸等的盐。衍生自有机酸的盐包括乙酸、丙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等的盐。同样,药学上可接受的碱加成盐可以由无机和有机碱制备。仅作为示例,盐衍生自无机碱的包括钠,钾,锂,铵,钙和镁盐。衍生自有机碱的盐包括但不限于伯、仲和叔胺的盐,例如烷基胺(即,NH2(烷基))、二烷基胺(即,HN(烷基)2)、三烷基胺(即,N(烷基)3)、取代的烷基胺(即,NH2(取代的烷基))、二(取代的烷基)胺(即,HN(取代的烷基)2)、三(取代的烷基)胺(即,N(取代的烷基)3)、烯基胺(即,NH2(烯基))、二烯基胺(即,HN(烯基)2)、三烯基胺(即,N(烯基)3)、取代的烯基胺(即,NH2(取代的烯基))、二(取代的烯基)胺(即,HN(取代的烯基)2)、三(取代的)烯基胺(即,N(取代的烯基)3)、单-、二-或三-环烷基胺(即,NH2(环烷基)、HN(环烷基)2、N(环烷基)3)、单-,二-或三-芳基胺(即NH2(芳基)、HN(芳基)2、N(芳基)3)或混合胺等的盐。仅作为举例,合适的胺的具体实例包括,例如异丙胺、三甲胺、二乙胺、三(异丙基)胺、三(正丙基)胺、乙醇胺、2-二甲基氨基乙醇、哌嗪、哌啶、吗啉、N-乙基哌啶等。
术语“取代的”是指指定原子或基团上的一个或多个氢原子被氢以外的一个或多个取代基取代,只要不超过指定原子的正常化合价。所述一个或多个取代基包括但不限于,烷基、烯基、炔基、烷氧基、酰基、氨基、酰胺基、脒基、芳基、叠氮基、氨基甲酰基、羧基、羧基酯、氰基、胍基、卤素、卤代烷基、卤代烷氧基、杂烷基、杂芳基、杂环基、羟基、肼基、亚氨基、氧代、硝基、烷基亚磺酰基、磺酸、烷基磺酰基、硫氰酸酯、硫醇、硫酮或它们的组合。聚合物或类似的不确定结构是通过定义无限地附加有其他取代基的取代基而得到的(例如,具有取代烷基的取代芳基本身被取代的芳基基团取代,该取代基本身又被取代的杂烷基取代,等等),不包括在此处。除非另有说明,否则本文所述化合物中连续取代的最大数目为三个。例如,取代的芳基被两个其他取代的芳基的连续取代限于((取代的芳基)取代的芳基)取代的芳基。类似地,上述定义无意包括不允许的取代方式(例如,被5个氟取代的甲基或具有两个相邻氧环原子的杂芳基)。这种不允许的取代方式是技术人员众所周知的。当用于修饰化学基团时,术语“取代的”可以描述本文定义的其他化学基团。除非另有说明,否则当基团描述为任选取代时,该基团的任何取代基本身都是未取代的。例如,在一些实施方案中,术语“取代的烷基”是指具有一个或多个取代基的烷基,所述取代基包括羟基、卤素、烷氧基、环烷基、杂环基、芳基和杂芳基。在其他实施方案中,所述一个或多个取代基可以进一步被各自取代的卤素、烷基、卤代烷基、羟基、烷氧基、环烷基、杂环基、芳基或杂芳基取代。在其他实施方案中,所述取代基可以进一步被各自未被取代的卤素、烷基、卤代烷基、烷氧基、羟基、环烷基、杂环基、芳基或杂芳基取代。本领域技术人员将认识到,本文中的取代基以及通式的化合物的其它部分应以提供一种足够稳定,可以被配制成可接受的稳定的药物组合物的药学上有用的化合物为目的来进行选择。具有这种稳定性的化合物被认为落入本发明的范围内。本领域技术人员应理解,上述定义和取代基的任何组合均不应导致不可操作的物质或化合物。
如本文所用,“药学上可接受的载体”或“药学上可接受的赋形剂”包括任何和所有溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等。这种介质和试剂用于药物活性物质的用途是本领域众所周知的。除非任何常规介质或试剂与活性成分不相容,否则将考虑将其用于治疗组合物中。补充活性成分也可以掺入组合物中。
通过溶剂和化合物的相互作用形成了“溶剂化物”。本文还提供了所述化合物的盐的溶剂化物。本文还提供了所述化合物的水合物。
组合
通过施用本公开的IRAK4抑制剂治疗的患者经常表现出受益于其他治疗剂治疗的疾病或病症。这些疾病或病症可以具有炎性性质,或者可以与癌症、代谢障碍、胃肠道障碍等有关。因此,本公开的一个方面是治疗炎症相关疾病或病症、或代谢障碍、胃肠道障碍或癌症等的方法,其包括将本公开化合物与一种或多种可用于治疗这些病的化合物组合施用于需要其的受试者,特别是人类受试者。
在一些实施方案中,将本公开的化合物与另外的一种或多种活性成分共同配制。在一些实施方案中,另一活性成分以分开的剂型在大约相同的时间施用。在一些实施方案中,所述其他活性成分是顺序施用的,并且相对于本公开的化合物可以在不同的时间施用。
用于炎性疾病和病症的组合
例如,本公开的化合物可以与以下一种或多种组合:5-脂氧合酶抑制剂、乙酰胆碱酯酶抑制剂、乙酰辅酶A羧化酶(ACC)抑制剂、ACTH受体激动剂、活化素受体拮抗剂、酰基转移酶抑制剂、肾上腺皮质激素配体、AKT1基因抑制剂、碱性磷酸酶调节剂、碱性磷酸酶刺激剂、雄激素受体激动剂、载脂蛋白C3拮抗剂、ASK1激酶抑制剂、杀菌通透性蛋白刺激剂、β肾上腺素受体拮抗剂、β-葡萄糖醛酸苷酶抑制剂、B淋巴细胞抗原CD20抑制剂、缓激肽受体调节剂、BTK激酶抑制剂、钙调神经磷酸酶抑制剂、钙通道抑制剂、大麻素CB1受体调节剂、大麻素CB2受体调节剂、大麻素受体拮抗剂、大麻素受体调节剂、半胱天冬酶抑制剂、组织蛋白酶S抑制剂、CCN蛋白刺激剂、CCR3趋化因子拮抗剂、CCR5趋化因子拮抗剂、CCR9趋化因子拮抗剂、CD3调节剂、CD40配体抑制剂、CD40配体受体拮抗剂、CD49b拮抗剂、CD49d拮抗剂、CD89激动剂、细胞粘附分子抑制剂、趋化因子CXC配体抑制剂、CHST15基因抑制剂、胶原调节剂、CSF-1激动剂、CSF-1拮抗剂、CXC10趋化因子配体抑制剂、CXCR2趋化因子拮抗剂、环状GMP磷酸二酯酶抑制剂、环氧合酶2抑制剂、环氧合酶抑制剂、环氧合酶刺激剂、细胞色素P450 3A4抑制剂、细胞毒性T淋巴细胞蛋白-4刺激剂、二氢神经酰胺δ4去饱和酶抑制剂、二氢乳清酸脱氢酶抑制剂、DNA聚合酶抑制剂、DPP-4抑制剂、EGFR家族酪氨酸激酶受体调节剂、嗜酸性粒细胞过氧化酶抑制剂、嗜酸性粒细胞趋化因子配体抑制剂、EP4前列腺素受体激动剂、表皮生长因子激动剂、表皮生长因子配体、雌激素受体β激动剂、因子XIII激动剂、FGF-10配体、FGF2受体激动剂、趋化因子分形素配体(Fractalkine ligand)抑制剂、游离脂肪酸受体2拮抗剂、FXR激动剂、GATA 3转录因子抑制剂、胰高血糖素样肽1激动剂、胰高血糖素样肽2激动剂、糖皮质激素激动剂、GM-CSF受体激动剂、G蛋白偶联受体84拮抗剂、鸟苷酸环化酶受体激动剂、组胺H2受体拮抗剂、组蛋白乙酰转移酶抑制剂、组蛋白脱乙酰酶抑制剂、HLA II类抗原调节剂、水解酶抑制剂、HSD17β13抑制剂、ICAM1基因抑制剂、ICAM-1抑制剂、IL1基因抑制剂、IL-10激动剂、IL10基因刺激剂、IL-11激动剂、IL-12拮抗剂、IL12基因抑制剂、IL-13拮抗剂、IL-17拮抗剂、IL-2拮抗剂、IL-2受体α亚基抑制剂、IL-21拮抗剂、IL-23拮抗剂、IL-6拮抗剂、IL6基因抑制剂、IL-6受体调节剂、IL-7拮抗剂、IL-8拮抗剂、免疫球蛋白G1激动剂、免疫球蛋白G2调节剂、肌苷单磷酸脱氢酶抑制剂、胰岛素增敏剂、整合素α-4/β-1拮抗剂、整合素α-4/β-7拮抗剂、整合素α-E拮抗剂、整合素拮抗剂、整合素β-7拮抗剂、干扰素β配体、白介素17E配体抑制剂、白介素配体抑制剂、白介素受体17A拮抗剂、白介素受体17B拮抗剂、白介素-1β配体、白介素-1β配体调节剂、白介素-6配体抑制剂、JAK酪氨酸激酶抑制剂、Jak1酪氨酸激酶抑制剂、JAK2基因抑制剂、Jak3酪氨酸激酶抑制剂、Jun N末端激酶抑制剂、LanC样蛋白2调节剂、白三烯BLT受体拮抗剂、脂氧合酶调节剂、L-选择素拮抗剂、MAdCAM抑制剂、基质金属蛋白酶抑制剂、基质金属蛋白酶调节剂、黑皮质素激动剂、膜铜胺氧化酶抑制剂、金属蛋白酶-2抑制剂、金属蛋白酶-9抑制剂、MIP 3α配体抑制剂、线粒体10kDa热休克蛋白刺激剂、单核细胞分化抗原CD14抑制剂、mTOR抑制剂、粘蛋白刺激剂、NAD-依赖性脱乙酰酶sirtuin-1刺激剂、利钠肽受体C激动剂、神经调节蛋白4配体、烟碱乙酰胆碱受体激动剂、烟碱ACh受体α4亚基调节剂、烟碱ACh受体α7亚基刺激剂、烟碱ACh受体β2亚基调节剂、NK1受体拮抗剂、NKG2 D活化NK受体拮抗剂、核因子κB抑制剂、阿片类生长因子受体激动剂、阿片类受体拮抗剂、阿片类受体δ拮抗剂、氧化还原酶抑制剂、P2X7嘌呤受体激动剂、p38MAP激酶抑制剂、PARP抑制剂、PDE 4抑制剂、PDGF受体激动剂、吞噬作用刺激肽调节剂、磷酸MurNAc五肽转移酶抑制剂、磷脂酶A2抑制剂、血小板活化因子受体拮抗剂、钾通道抑制剂、PPARα激动剂、PPARδ激动剂、PPARγ激动剂、蛋白CYR61刺激剂、蛋白fimH抑制剂、蛋白激酶Cα抑制剂、蛋白激酶Cβ抑制剂、蛋白激酶Cδ抑制剂、蛋白激酶Cε抑制剂、蛋白激酶Cη抑制剂、蛋白激酶Cθ抑制剂、蛋白激酶G抑制剂、蛋白激酶抑制剂、P-选择素糖蛋白配体-1抑制剂、PurH嘌呤生物合成蛋白抑制剂、维甲酸受体α激动剂、维甲酸受体β激动剂、维甲酸受体激动剂、RNA聚合酶抑制剂、SMAD-7抑制剂、钠通道抑制剂、生长抑素受体激动剂、鞘氨醇1磷酸磷酸酶1刺激剂、鞘氨醇1磷酸磷酸酶调节剂、鞘氨醇激酶1抑制剂、鞘氨醇激酶2抑制剂、鞘氨醇-1-磷酸酯受体-1激动剂、鞘氨醇-1-磷酸酯受体-1拮抗剂、鞘氨醇-1-磷酸酯受体-1调节剂、鞘氨醇-1-磷酸酯受体-5调节剂、STAT3基因抑制剂、STAT-3抑制剂、STAT-4抑制剂、干细胞抗原-1抑制剂、超氧化物歧化酶调节剂、超氧化物歧化酶刺激剂、SYK激酶抑制剂、T细胞表面糖蛋白CD28抑制剂、TGFβ1配体抑制剂、胸腺九肽(Thymulin)激动剂、THR-β激动剂、TLR-2拮抗剂、TLR-4拮抗剂、TLR-9激动剂、TNFα配体抑制剂、TNFα配体调节剂、TNF拮抗剂、TPL2激酶抑制剂、三叶因子调节剂、类胰蛋白酶抑制剂、色氨酸5-羟化酶抑制剂、肿瘤坏死因子14配体调节剂、TYK2激酶抑制剂、I型TNF受体拮抗剂、II型TNF受体调节剂、非特定生长因子受体调节剂、香草精类VR1激动剂、维生素D3受体激动剂、连蛋白(Zonulin)抑制剂、阿巴西普(abatacept);乙酰吗喃(acemannan);阿达木单抗(adalimumab);DCCT-10;阿普斯特(apremilast);AST-120;巴柳氮(balsalazide);巴柳氮钠;basiliximab;二丙酸倍氯米松(beclomethasone dipropionate);布地奈德(budesonide);D-9421;布地奈德MMX;卡曲得考(catridecacog);聚乙二醇化妥珠单抗(certolizumab pegol);丁酸梭菌(Clostridiumbutyricum);依那西普(etanercept);芬戈莫德(fingolimod);醋酸格拉替雷(glatirameracetate);戈利木单抗(golimumab);英夫利西单抗(infliximab);英夫利西单抗(infliximab)生物类似药;英夫利西单抗(infliximab)后续生物制剂;干扰素β-1a;来那度胺(lenalidomide);美沙拉秦(mesalazine);GED-0001;AJG-501;醋酸metenkefalin联合醋酸tridecactide、霉酚酸酯(mycophenolate mofetil);纳曲酮(naltrexone);那他珠单抗(natalizumab);硝唑尼特(nitazoxanide);奥沙拉秦(olsalazine);奥普瑞白介素(oprelvekin);丙酰基-L-肉碱(propionyl-L-carnitine);重组干扰素β-1a;remestemcel-L;利福昔明(rifaximin);利妥昔单抗(rituximab);罗哌卡因(ropivacaine);罗格列酮(rosiglitazone);沙格司亭(sargramostim);苏金单抗(secukinumab);SPD-480;他克莫司(tacrolimus);他米巴罗汀(tamibarotene);替度鲁肽(teduglutide);沙利度胺(thalidomide);托珠单抗(tocilizumab);RO-4877533;托法替尼(tofacitinib);CP-690550;猪鞭虫卵(Trichuris suis ova);ASP-1002;优特克单抗(ustekinumab);缬更昔洛韦(valganciclovir);维多珠单抗(vedolizumab);齐留通(zileuton);抗CD3显像剂(抗体片段,癌症/自身免疫性疾病)、ImaginAb;AVX-470;环孢素(ciclosporin);CXCR1/2配体mAb(免疫学)、Eli Lilly;FFP-102;GSK-3050002;INN-108;IR-777;SGM-1019;peg-伊洛白介素(peg-ilodecakin);PF-06480605;PF-06651600;SER-287;Syn-1002;Thetanix;耐受性树突状细胞治疗剂TOP-1288;VBY-036;VBY-129;946414-98-8;BMS-936557;99mTc-膜联蛋白V-128;ABC-294640;阿昔单抗(abrilumab);Alequel;AMG-139;amiselimod;APD-334;ASP-3291;二丙酸倍氯米松(beclomethasone dipropionate);柏替木单抗(bertilimumab);环孢素(ciclosporin);clazakizumab;DLX-105;dolcanatide;E-6011;ETX-201;FFP-104;filgotinib;foralumab;GED-0507-34-Levo;givinostat;GLPG-0974;GLPG-1205;iberogast N(溃疡性结肠炎),Bayer;BAY98-7410;INV-103;JNJ-40346527;K(D)PT;KAG-308;KHK-4083;KRP-203;larazotide acetate;CB-01-05-MMX;LY-3074828;美沙拉嗪(mesalamine)联合N-乙酰半胱氨酸;midismase;molgramostim后续生物制剂联合磷霉素联合碳青霉烯、Reponex;多能成体祖细胞治疗剂(局部缺血/脑性瘫痪)、Athersys/Healios;NN-8828;奥洛珠单抗(olokizumab);OvaSave;P-28-GST;PDA-002;PF-4236921;PF-547659;泼尼松龙(prednisolone);PUR-0110;QBECO;RBX-2660;改变用途的纳曲酮(naltrexone);JKB-122;SB-012;sotrastaurin;STNM-01;TAK-114;tetomilast;Debio-0512;TRK-170;TRX-318;伐他珠单抗(vatelizumab);VB-201;ZP-1848;珠卡赛辛(zucapsaicin);ABT-494;alicaforsen;Ampion;BI-655066;briakinumab;大麻二酚(cannabidiol);carotegastmethyl;cobitolimod;地塞米松磷酸钠(dexamethasone sodium phosphate);elafibranor;依托珠单抗(etrolizumab);GS-5745;HMPL-004;LP-02;美沙拉秦(mesalazine);metronidazole mongersen;奥珠单抗(ocrelizumab);ozanimod;peficitinib;RHB-104;利福昔明(rifaximin);替拉珠单抗(tildrakizumab);tralokinumab;布罗达单抗(brodalumab);拉喹莫德(laquinimod);plecanatide;telotristat etiprate;英夫利西单抗(infliximab)生物类似药、Samsung Bioepis;AZD-058;以及利福布汀(利福布丁(rifabutin))联合克拉霉素(克拉霉素(clarithromycin))以及进一步联合氯法齐明(氯法齐明(clofazimine))。
同样,下面的化合物类别和化合物的非详尽列表可以与本公开的化合物组合:5-脂氧合酶抑制剂,例如齐留通(zileuton)、etalocibm FPL-64170、E-3040和BU-4601A;乙酰胆碱酯酶抑制剂,例如BL-7040;ACTH受体激动剂,例如醋酸metenkefalin联合醋酸tridecactidee和FAR-404;活化素受体拮抗剂,例如follistatin;酰基转移酶抑制剂,例如AZD-0585;肾上腺皮质激素配体,例如醋酸metenkefalin联合醋酸tridecactidee和FAR-404;AKT1基因抑制剂,例如vidofludimus;碱性磷酸酶调节剂,例如重组人碱性磷酸酶(口服,溃疡性结肠炎),AM-Pharma;碱性磷酸酶刺激剂,例如牛碱性磷酸酶;雄激素受体激动剂,例如PB-005;载脂蛋白C3拮抗剂,例如AZD-0585;杀菌通透性蛋白刺激剂,例如opebacan;β肾上腺素受体拮抗剂,例如NM-001;β-葡萄糖醛酸苷酶抑制剂,例如KD-018;B淋巴细胞抗原CD20抑制剂,例如奥珠单抗(ocrelizumab)、利妥昔单抗(rituximab);缓激肽受体调节剂,例如givinostat;钙调神经磷酸酶抑制剂,例如他克莫司(tacrolimus)、环孢素(ciclosporin);钙通道抑制剂,例如clotrimazole;大麻素CB1受体调节剂,例如GWP42003-P、大麻二酚(cannabidiol);大麻素CB2受体调节剂,例如GWP42003-P、大麻二酚(cannabidiol);大麻素受体拮抗剂,例如芬戈莫德(fingolimod);大麻素受体调节剂,例如GWP42003-P、大麻二酚(cannabidiol);组织蛋白酶S抑制剂,例如VBY-129、VBY-036;CCN蛋白刺激剂,例如CSA-13;CCR3趋化因子拮抗剂,例如柏替木单抗(bertilimumab);CCR5趋化因子拮抗剂,例如HGS-1025;CCR9趋化因子拮抗剂,例如MLN-3126、vercirnon、CCX-025;CD3调节剂,例如维西珠单抗(visilizumab);CD40配体抑制剂,例如FFP-104;CD40配体受体拮抗剂,例如FFP-104、FFP-102、托拉珠单抗(toralizumab);CD49b拮抗剂,例如伐他珠单抗(vatelizumab);CD49d拮抗剂,例如ELND-004;CD89激动剂,例如HF-1020;细胞粘附分子抑制剂,例如那他珠单抗(natalizumab)、alicaforsen(静脉)、ASP-2002、ISIS-2302;趋化因子CXC配体抑制剂,例如CXCR1/2配体mAb(免疫学)、Eli Lilly;CHST15基因抑制剂,例如STNM-01;胶原调节剂,例如脂肪衍生的干细胞治疗剂(Celution系统)、Cytori、DCCT-10;CSF-1激动剂,例如沙格司亭(sargramostim)、molgramostim后续生物制剂联合磷霉素联合碳青霉烯(肠内,克罗恩氏病(Crohn’s disease))、Reponex;CSF-1拮抗剂,例如JNJ-40346527;CXC10趋化因子配体抑制剂,例如946414-98-8、BMS-936557;CXCR2趋化因子拮抗剂,例如elubrixin;环状GMP磷酸二酯酶抑制剂,例如CEL-031;环氧合酶2抑制剂,例如P-54;环氧合酶抑制剂,例如美沙拉秦(mesalazine)、4-氨基水杨酸钠、AJG-501、AGI-022;环氧合酶刺激剂,例如尼古丁口含锭(nicotine polacrilex);细胞色素P450 3A4抑制剂,例如KD-018;细胞毒性T淋巴细胞蛋白-4刺激剂,例如阿巴西普(abatacept);二氢神经酰胺δ4去饱和酶抑制剂,例如ABC-294640;二氢乳清酸脱氢酶抑制剂,例如vidofludimus;DNA聚合酶抑制剂,例如缬更昔洛韦(valganciclovir);EGFR家族酪氨酸激酶受体调节剂,例如神经调节蛋白4(克罗恩氏病(Crohn’s disease)/溃疡性结肠炎/坏死性小肠结肠炎)、Avexegen疗法/洛杉矶儿童医院(Children’s Hospital of Los Angeles);嗜酸性粒细胞过氧化酶抑制剂,例如AWEPOPD-01、AWEPO-003;趋化因子配体抑制剂,例如柏替木单抗(bertilimumab);EP4前列腺素受体激动剂,例如KAG-308;表皮生长因子激动剂,例如肝素-EGF-样因子,Scios Nova;表皮生长因子配体,例如Hebervis;雌激素受体β激动剂,例如prinaberel;因子XIII激动剂,例如卡曲得考(catridecacog);FGF-10配体,例如repifermin;FGF2受体激动剂,例如F2A;趋化因子分形素配体(Fractalkine ligand)抑制剂,例如E-6011;游离脂肪酸受体2拮抗剂,例如GLPG-0974;GATA 3转录因子抑制剂,例如SB-012;胰高血糖素样肽2激动剂,例如替度鲁肽(teduglutide)、ZP-1848、NB-1002;糖皮质激素激动剂,例如布地奈德(budesonide)、二丙酸倍氯米松(beclomethasonedipropionate)、地塞米松磷酸钠(dexamethasone sodium phosphate)、AJG-511、DOR-201、D-9421-C;GM-CSF受体激动剂,例如沙格司亭(sargramostim)、molgramostim后续生物制剂联合磷霉素联合碳青霉烯(肠内,克罗恩氏病(Crohn’s disease))、Reponex;G蛋白偶联受体84拮抗剂,例如GLPG-1205;鸟苷酸环化酶受体激动剂,例如dolcanatide、SP-333;组胺H2受体拮抗剂,例如铋、Medeva;组蛋白乙酰转移酶抑制剂,例如TIP60抑制剂(溃疡性结肠炎/炎症性肠病/自体免疫疾病)(University of Pennsylvania);组蛋白脱乙酰酶抑制剂,例如givinostat;HLA II类抗原调节剂,例如HLA II类蛋白调节剂(克罗恩氏病)、NexteraAS;水解酶抑制剂,例如SC-56938;ICAM1基因抑制剂,例如alicaforsen;ICAM-1抑制剂,例如alicaforsen(静脉)、ISIS-2302;IL1基因抑制剂,例如PLR-14;IL-10激动剂,例如peg-伊洛白介素(peg-ilodecakin)、AM-0010;IL10基因刺激剂,例如基因治疗剂(IL-10),帝国理工学院;IL-11激动剂,例如奥普瑞白介素(oprelvekin)、YM-294;IL-12拮抗剂,例如优特克单抗(ustekinumab)、briakinumab、apilimod;IL12基因抑制剂,例如RDP-58;IL-13拮抗剂,例如曲妥单抗(tralokinumab)、anrukinzumab;IL-17拮抗剂,例如苏金单抗(secukinumab)、vidofludimus;IL-2拮抗剂,例如daclizumab;IL-2受体α亚基抑制剂,例如basiliximab、daclizumab、BSX-003、Ro-34-7375;IL-21拮抗剂,例如NN-8828、ATR-107;IL-23拮抗剂,例如替拉珠单抗(tildrakizumab)、优特克单抗(ustekinumab)、BI-655066、AMG-139、briakinumab、LY-3074828、apilimod;IL-6拮抗剂,例如托珠单抗(tocilizumab)、clazakizumab、奥洛珠单抗(olokizumab)、HMPL-004、AMG-220、FM-101;IL6基因抑制剂,例如YSIL6-T-PS;IL-6受体调节剂,例如托珠单抗(tocilizumab);IL-7拮抗剂,例如白介素-7受体调节剂(溃疡性结肠炎/T细胞急性淋巴细胞白血病),Effimune;IL-8拮抗剂,例如elubrixin、clotrimazole;免疫球蛋白G1激动剂,例如HF-1020;免疫球蛋白G2调节剂,例如PF-547659;肌苷单磷酸脱氢酶抑制剂,例如霉酚酸酯(mycophenolate mofetil);胰岛素增敏剂,例如elafibranor、罗格列酮(rosiglitazone)、HE-3286、EGS-21;整合素α-4/β-1拮抗剂,例如那他珠单抗(natalizumab)、TRK-170、firategrast;整合素α-4/β-7拮抗剂,例如依托珠单抗(etrolizumab)、维多珠单抗(vedolizumab)、阿昔单抗(abrilumab)、carotegastmethyl、TRK-170、firategrast;整合素α-E拮抗剂,例如依托珠单抗(etrolizumab);整合素拮抗剂,例如伐他珠单抗(vatelizumab)、ASP-2002;整合素β-7拮抗剂,例如依托珠单抗(etrolizumab);干扰素β配体,例如干扰素β-1a、重组干扰素β-1a,Serono;白介素17E配体抑制剂,例如抗IL-17BR人源化抗体(肺纤维化/哮喘/溃疡性结肠炎),医学研究理事会技术;白介素配体抑制剂,例如HE-3286;白介素受体17A拮抗剂,例如布罗达单抗(brodalumab);白介素受体17B拮抗剂,例如抗IL-17BR人源化抗体(肺纤维化/哮喘/溃疡性结肠炎),医学研究理事会技术;白介素-1β配体,例如K(D)PT、PUR-0110、HMPL-004;白介素-1β配体调节剂,例如PUR-0110、HMPL-004;白介素-6配体抑制剂,例如PF-4236921;JAK酪氨酸激酶抑制剂,例如托法替尼(tofacitinib)、peficitinib;Jak1酪氨酸激酶抑制剂,例如ABT-494、托法替尼(tofacitinib)、filgotinib、peficitinib、GLPG-0555、solcitinib;JAK2基因抑制剂,例如vidofludimus;Jak3酪氨酸激酶抑制剂,例如托法替尼(tofacitinib)、peficitinib;Jun N末端激酶抑制剂,例如塞马莫德(semapimod);LanC样蛋白2调节剂,例如BT-11;白三烯BLT受体拮抗剂,例如ONO-4057、etalocib、SC-53228、SC-52798;脂氧合酶调节剂,例如美沙拉秦(mesalazine);L-选择素拮抗剂,例如BNP-001;MAdCAM抑制剂,例如维多珠单抗(vedolizumab)、PF-547659;基质金属蛋白酶抑制剂,例如D-5410;基质金属蛋白酶调节剂,例如D-5410;黑皮质素激动剂,例如ASP-3291;膜铜胺氧化酶抑制剂,例如维帕莫单抗(vepalimomab);金属蛋白酶-2抑制剂,例如KD-018、RWJ-68354;金属蛋白酶-9抑制剂,例如GS-5745;MIP 3α配体抑制剂,例如GSK-3050002;线粒体10kDa热休克蛋白刺激剂,例如INV-103;单核细胞分化抗原CD14抑制剂,例如CD14抗炎剂,Cornell;mTOR抑制剂,例如P-2281;粘蛋白刺激剂,例如rebamipide;NAD-依赖性脱乙酰酶sirtuin-1刺激剂,例如SRT-2104;钠肽受体C激动剂,例如plecanatide;神经调节蛋白4配体,例如神经调节蛋白4(克罗恩氏病(Crohn’s disease)/溃疡性结肠炎/坏死性小肠结肠炎),Avexegen疗法/洛杉矶儿童医院(Children’s Hospital of Los Angeles);烟碱乙酰胆碱受体激动剂,例如TC-2403、尼古丁口含锭(nicotine polacrilex)、尼古丁;烟碱ACh受体α4亚基调节剂,例如TC-2403;烟碱ACh受体α7亚基刺激剂,例如GTS-21;烟碱ACh受体β2亚基调节剂,例如TC-2403;NK1受体拮抗剂,例如KD-018、苯磺诺匹坦铵(nolpitantiumbesilate);NKG2D活化NK受体拮抗剂,例如NNC-0142-002;核因子κB抑制剂,例如KD-018、cobitolimod、CSA-13、HE-3286、HMPL-004、Avrina、美沙拉嗪(mesalamine)联合N-乙酰半胱氨酸、P-54;阿片类生长因子受体激动剂,例如醋酸metenkefalin联合醋酸tridecactidee、FAR-404;阿片类受体拮抗剂,例如纳曲酮(naltrexone)、IRT-103;阿片类受体δ拮抗剂,例如KD-018;氧化还原酶抑制剂,例如奥沙拉秦(olsalazine);P2X7嘌呤受体激动剂,例如givinostat;p38 MAP激酶抑制剂,例如RDP-58、多玛莫德(doramapimod)、塞马莫德(semapimod)、RWJ-68354;PARP抑制剂,例如EB-47、INO-1003;PDE 4抑制剂,例如阿普斯特(apremilast)、tetomilast、CC-1088;PDGF受体激动剂,例如奥普瑞白介素(oprelvekin)、YM-294;吞噬作用刺激肽调节剂,例如99mTc-RP-128;磷酸MurNAc五肽转移酶抑制剂,例如SQ-641;磷脂酶A2抑制剂,例如甲基伐瑞拉迪(varespladib methyl);血小板活化因子受体拮抗剂,例如dersalazine sodium;钾通道抑制剂,例如clotrimazole;PPARα激动剂,例如elafibranor(GFT-1007);PPARδ激动剂,例如elafibranor(GFT-1007);PPARγ激动剂,例如罗格列酮(rosiglitazone)、GED-0507-34-Levo、etalocib;蛋白CYR61刺激剂,例如CSA-13;蛋白fimH抑制剂,例如EB-8018;蛋白激酶Cα抑制剂,例如sotrastaurin(AEB-071);蛋白激酶Cβ抑制剂,例如sotrastaurin(AEB-071);蛋白激酶Cδ抑制剂,例如sotrastaurin(AEB-071);蛋白激酶Cε抑制剂,例如sotrastaurin(AEB-071);蛋白激酶Cη抑制剂,例如sotrastaurin(AEB-071);蛋白激酶Cθ抑制剂,例如sotrastaurin(AEB-071);蛋白激酶G抑制剂,例如CEL-031;蛋白激酶抑制剂,例如TOP-1288;P-选择素糖蛋白配体-1抑制剂,例如SEL-K2;PurH嘌呤生物合成蛋白抑制剂,例如霉酚酸酯(mycophenolate mofetil);维甲酸受体α激动剂,例如他米巴罗汀(tamibarotene);维甲酸受体β激动剂,例如他米巴罗汀(tamibarotene);维甲酸受体激动剂,例如他米巴罗汀(tamibarotene);RNA聚合酶抑制剂,例如利福昔明(rifaximin);SMAD-7抑制剂,例如mongersen(GED-0301);钠通道抑制剂,例如罗哌卡因(ropivacaine);生长抑素受体激动剂,例如vapreotide;鞘氨醇1磷酸磷酸酶1刺激剂,例如APD-334;鞘氨醇1磷酸磷酸酶调节剂,例如S1P调节剂(口服,多发性硬化/溃疡性结肠炎/类风湿性关节炎),Akaal Pharma;鞘氨醇激酶1抑制剂,例如ABC-294640;鞘氨醇激酶2抑制剂,例如ABC-294640;鞘氨醇-1-磷酸酯受体-1激动剂,例如ozanimod(RPC-1063)、KRP-203;鞘氨醇-1-磷酸酯受体-1拮抗剂,例如amiselimod(MT-1303);鞘氨醇-1-磷酸酯受体-1调节剂,例如芬戈莫德(fingolimod)(FTY-720)、ozanimod(RPC-1063)、amiselimod(MT-1303);鞘氨醇-1-磷酸酯受体-5调节剂,例如ozanimod;STAT3基因抑制剂,例如vidofludimus;STAT-3抑制剂,例如TAK-114;STAT-4抑制剂,例如STAT-4反义寡核苷酸(克罗恩氏病/结肠炎),NIAID;干细胞抗原-1抑制剂,例如Ampion、DMI-9523;超氧化物歧化酶调节剂,例如midismase、LT-0011;超氧化物歧化酶刺激剂,例如超氧化物歧化酶;T细胞表面糖蛋白CD28抑制剂,例如阿巴西普(abatacept);TGFβ1配体抑制剂,例如mongersen、GED-0301;胸腺九肽(Thymulin)激动剂,例如Syn-1002;TLR-2拮抗剂,例如VB-201;TLR-4拮抗剂,例如JKB-122、VB-201;TLR-9激动剂,例如BL-7040、cobitolimod;TNFα配体抑制剂,例如阿达木单抗(adalimumab)、聚乙二醇化妥珠单抗(certolizumab pegol)、英夫利西单抗(infliximab)生物类似药、英夫利西单抗(infliximab)、戈利木单抗(golimumab)、ISIS-104838、CSA-13、DLX-105、阿达木单抗(adalimumab)生物类似药、dersalazine sodium、Debio-0512、HMPL-004、DLX-105、英夫利西单抗(infliximab)后续生物制剂、AZD-9773、CYT-020-TNFQb、DOM-0200;TNFα配体调节剂,例如PUR-0110、CDP-571;TNF拮抗剂,例如依那西普(etanercept)、聚乙二醇化妥珠单抗(certolizumab pegol)、AVX-470、奥那西普(onercept);三叶因子调节剂,例如AG-012;类胰蛋白酶抑制剂,例如APC-2059;色氨酸5-羟化酶抑制剂,例如telotristat etiprate;肿瘤坏死因子14配体调节剂,例如SAR-252067;I型TNF受体拮抗剂,例如DOM-0100;II型TNF受体调节剂,例如依那西普(etanercept);非特定生长因子受体调节剂,例如AP-005;香草精类VR1激动剂,例如珠卡赛辛(zucapsaicin);维生素D3受体激动剂,例如骨化三醇(calcitriol);以及连蛋白(Zonulin)抑制剂,例如larazotide acetate、AT-1001。
同样,下面的化合物类别和化合物的非详尽列表可以与本公开的化合物组合:14-3-3蛋白η抑制剂、5-脂氧合酶抑制剂、Abl酪氨酸激酶抑制剂、ACTH受体激动剂、腺苷A3受体激动剂、腺苷脱氨酶抑制剂、ADP核糖环化酶-1调节剂、ADP核糖基化因子6抑制剂、肾上腺皮质激素配体、聚蛋白多糖酶-2抑制剂、白蛋白调节剂、AP1转录因子抑制剂、基础免疫球蛋白抑制剂、Bcr蛋白抑制剂、B淋巴细胞抗原CD19抑制剂、B淋巴细胞抗原CD20抑制剂、B淋巴细胞抗原CD20调节剂、B淋巴细胞刺激剂配体抑制剂、缓激肽受体调节剂、BRAF基因抑制剂、支链氨基酸转氨酶1抑制剂、含溴结构域蛋白抑制剂、Btk酪氨酸激酶抑制剂、钙粘素-11拮抗剂、钙调神经磷酸酶抑制剂、钙通道抑制剂、碳酸酐酶抑制剂、组织蛋白酶K抑制剂、组织蛋白酶S抑制剂、CCR1趋化因子拮抗剂、CCR2趋化因子拮抗剂、CCR3基因调节剂、CCR5趋化因子拮抗剂、CD126拮抗剂、CD29调节剂、CD3调节剂、CD39激动剂、CD4激动剂、CD4拮抗剂、CD40配体抑制剂、CD40配体受体拮抗剂、CD40配体受体调节剂、CD52拮抗剂、CD73激动剂、CD79b调节剂、CD80拮抗剂、CD86拮抗剂、CD95拮抗剂、细胞粘附分子抑制剂、胆碱激酶抑制剂、凝聚素刺激剂、补体C5因子抑制剂、补体因子刺激剂、C-反应蛋白抑制剂、CSF-1拮抗剂、CXC10趋化因子配体抑制剂、CXCR4趋化因子拮抗剂、周期素依赖性激酶抑制剂1抑制剂、周期素依赖性激酶-2抑制剂、周期素依赖性激酶-4抑制剂、周期素依赖性激酶-5抑制剂、周期素依赖性激酶-6抑制剂、周期素依赖性激酶-7抑制剂、周期素依赖性激酶-9抑制剂、环氧合酶2抑制剂、环氧合酶2调节剂、环氧合酶抑制剂、胞浆型磷脂酶(Cytosolic phospholipase)A2抑制剂、细胞毒性T淋巴细胞蛋白-4调节剂、细胞毒性T淋巴细胞蛋白-4刺激剂、DHFR抑制剂、二胺乙酰转移酶抑制剂、二氢乳清酸脱氢酶抑制剂、延长因子2抑制剂、嗜酸细胞活化趋化因子(Eotaxin)2配体抑制剂、EP4前列腺素受体拮抗剂、红细胞生成素受体激动剂、Fas配体、FGF-2配体抑制剂、FK506结合蛋白-12调节剂、叶酸拮抗剂、叶酸受体激动剂、叶酸受体β拮抗剂、叶酸受体调节剂、趋化因子分形素配体(Fractalkine ligand)抑制剂、Fyn酪氨酸激酶抑制剂、G蛋白偶联受体15拮抗剂、GABA A受体调节剂、糖皮质激素激动剂、糖皮质激素拮抗剂、糖皮质激素诱导的亮氨酸拉链蛋白刺激剂、GM-CSF配体抑制剂、GM-CSF受体拮抗剂、GM-CSF受体调节剂、生长调节蛋白α配体抑制剂、Hwith Kwith ATP酶抑制剂、组胺H4受体拮抗剂、组蛋白脱乙酰酶抑制剂、组蛋白脱乙酰酶-6抑制剂、HIV-1gp120蛋白抑制剂、HLA II类抗原DQ-2α调节剂、HLA II类抗原抑制剂、HLA II类抗原调节剂、Hsp 70家族抑制剂、缺氧诱发因子-1抑制剂、IFNB基因刺激剂、I-κB激酶β抑制剂、I-κB激酶抑制剂、IL-1拮抗剂、IL-10激动剂、IL-11激动剂、IL-12拮抗剂、IL-15拮抗剂、IL-17拮抗剂、IL-17受体调节剂、IL-2激动剂、IL-2拮抗剂、IL-21拮抗剂、IL-23拮抗剂、IL-3拮抗剂、IL-4激动剂、IL-6拮抗剂、IL-6受体调节剂、免疫球蛋白拮抗剂、免疫球蛋白G1激动剂、免疫球蛋白G1拮抗剂、免疫球蛋白G1调节剂、免疫球蛋白G2拮抗剂、免疫球蛋白G2调节剂、免疫球蛋白γFc受体II调节剂、免疫球蛋白γFc受体IIB拮抗剂、免疫球蛋白κ调节剂、免疫球蛋白M拮抗剂、诱导型一氧化氮合酶抑制剂、肌苷单磷酸脱氢酶抑制剂、胰岛素增敏剂、整合素α-1/β-1拮抗剂、整合素α-4/β-1拮抗剂、整合素拮抗剂、干扰素β配体、干扰素γ配体、白介素17A配体抑制剂、白介素17F配体抑制剂、白介素23A抑制剂、白介素配体、白介素受体17A拮抗剂、白介素-1β配体抑制剂、白介素-10配体、白介素-2配体、白介素-4配体、白介素-6配体抑制剂、Itk酪氨酸激酶抑制剂、JAK酪氨酸激酶抑制剂、Jak1酪氨酸激酶抑制剂、Jak2酪氨酸激酶抑制剂、JAK3基因抑制剂、Jak3酪氨酸激酶抑制剂、Jun N末端激酶抑制剂、KCNA电压门控钾离子通道-3调节剂、Kelch样ECH相关蛋白1调节剂、Kit酪氨酸激酶抑制剂、LanC样蛋白2调节剂、LITAF基因抑制剂、淋巴细胞功能抗原-3受体拮抗剂、Lyn酪氨酸激酶抑制剂、巨噬细胞甘露糖受体1调节剂、MAdCAM抑制剂、MAP激酶调节剂、MAP3K2基因抑制剂、MAPKAPK5抑制剂、基质金属蛋白酶抑制剂、MCL1基因抑制剂、MEK蛋白激酶抑制剂、MEK-1蛋白激酶抑制剂、MEK-2蛋白激酶抑制剂、膜铜胺氧化酶抑制剂、金属蛋白酶-2抑制剂、金属蛋白酶-9抑制剂、肝素结合细胞因子(Midkine)配体抑制剂、线粒体10kDa热休克蛋白刺激剂、mTOR复合物1抑制剂、mTOR抑制剂、NAD ADP核糖基转移酶刺激剂、NAMPT基因抑制剂、NFκB抑制剂刺激剂、NFAT基因抑制剂、NFE2L2基因刺激剂、烟碱乙酰胆碱受体拮抗剂、NK细胞受体调节剂、NKG2 A B活化NK受体拮抗剂、NKG2 D活化NK受体拮抗剂、核红血球2相关因子2刺激剂、核因子κB抑制剂、核因子κB调节剂、核因子κB p105抑制剂、阿片类生长因子受体激动剂、阿片类受体δ拮抗剂、破骨细胞分化因子拮抗剂、破骨细胞分化因子配体抑制剂、氧化还原酶抑制剂、P2X7嘌呤受体激动剂、p38 MAP激酶α抑制剂、p38 MAP激酶抑制剂、PDE 4抑制剂、PDE 5抑制剂、PDGF受体激动剂、PDGF受体拮抗剂、PDGF-B配体抑制剂、PERK基因抑制剂、磷酸肌醇-3激酶δ抑制剂、磷酸肌醇-3激酶γ抑制剂、磷脂酶A2抑制剂、血小板活化因子受体拮抗剂、PPARγ激动剂、程序性细胞死亡蛋白1调节剂、前列腺素D合成酶刺激剂、蛋白精氨酸脱亚胺酶抑制剂、蛋白酪氨酸激酶抑制剂、PurH嘌呤生物合成蛋白抑制剂、Rho相关蛋白激酶2抑制剂、分离酶(Seprase)抑制剂、信号转导蛋白CD24调节剂、信号转导抑制剂、钠葡萄糖转运蛋白-2抑制剂、鞘氨醇1磷酸磷酸酶调节剂、STAT3基因抑制剂、超氧化物歧化酶刺激剂、SYK家族酪氨酸激酶抑制剂、Syk酪氨酸激酶抑制剂、多配体蛋白聚糖-1抑制剂、T细胞受体拮抗剂、T细胞受体调节剂、T细胞表面糖蛋白CD28抑制剂、T细胞表面糖蛋白CD28刺激剂、TAK1结合蛋白调节剂、人踝蛋白调节剂、T-细胞分化抗原CD6抑制剂、T-细胞表面糖蛋白CD8抑制剂、腱生蛋白调节剂、TGFβ激动剂、胸腺九肽(Thymulin)激动剂、TLR-2拮抗剂、TLR-4拮抗剂、TLR-9拮抗剂、TNFα配体抑制剂、TNFα配体调节剂、TNF拮抗剂、TNF基因抑制剂、TNF受体调节剂、TNFSF11基因抑制剂、转录因子p65抑制剂、转录因子RelB抑制剂、运铁蛋白调节剂、肿瘤坏死因子13C受体拮抗剂、肿瘤坏死因子15配体抑制剂、肿瘤坏死因子配体13抑制剂、肿瘤坏死因子配体抑制剂、I型IL-1受体拮抗剂、I型TNF受体拮抗剂、II型TNF受体调节剂、非特定GPCR激动剂、VEGF受体拮抗剂、VEGF-2受体拮抗剂、VEGF-2受体调节剂、VEGF-B配体抑制剂、凋亡蛋白抑制剂的X连锁抑制剂、Zap70酪氨酸激酶抑制剂、99mTc标记的膜联蛋白V-128、阿巴西普(abatacept)、阿巴西普(abatacept)生物类似药、ABBV-257、ABT-122、ABT-494、acalabrutinib、醋氯芬酸(aceclofenac)、阿克他利(actarit)、MS-392、阿达木单抗(adalimumab)、阿达木单抗(adalimumab)生物类似药、阿达木单抗(adalimumab)后续生物制剂、AK-106、ALX-0061、氨基蝶呤、阿那白滞素(anakinra)、阿那白滞素(anakinra)生物类似药、阿那白滞素(anakinra)后续生物制剂、ARG-301、ASLAN-003、ASP-5094、AT-132、AZD-9567、巴瑞克替尼(baricitinib)、BI-655064、bimekizumab、BiP(类风湿性关节炎)、伦敦国王学院、BLHP-006、blisibimod、BMS-986104、BMS-986142、ABBV-105、BTT-1023、康纳单抗(canakinumab)、可特立(Cartistem)、CCX-354、CD24-IgFc、塞来昔布(celecoxib)、cerdulatinib、聚乙二醇化妥珠单抗(certolizumab pegol)、CF-101、CFZ-533、CHR-5154、cibinetide、环孢素(ciclosporin)、clazakizumab、CNTO-6785、促肾上腺皮质激素(Mallinckrodt)、CR-6086、CreaVax-RA、CWG-92、CWG-940、Cx-611、DE-098、地夫可特(deflazacort)、Rheumavax、狄诺塞麦(denosumab)、双醋瑞因(diacerein)、双氯芬酸钠(diclofenac)、E-6011、二十碳五烯酸单甘油酯、依那西普(etanercept)、依那西普(etanercept)生物类似药、依那西普(etanercept)后续生物制剂、依托度酸(etodolac)、依托考昔(etoricoxib)、filgotinib、fosdagrocorat、gerilimzumab、人参皂苷(ginsenoside)C-K、givinostat、山羊多克隆抗体、戈利木单抗(golimumab)、GS-5745、GS-9876、GSK-3196165、HM-71224、HMPL-523、透明质酸钠、IB-RA(可注射,类风湿性关节炎)、(Innobioscience)、IB-RA(口服,类风湿性关节炎)(Innobioscience)、艾拉莫德(iguratimod)、IMD-2560、水杨酸咪唑、英夫利西单抗(infliximab)、英夫利西单抗(infliximab)生物较优药、英夫利西单抗(infliximab)生物类似药、INSIX RA、干扰素γ后续生物制剂、白介素-2(可注射的)、白介素-2后续生物制剂、INV-103、IR-501、itolizumab、JNJ-40346527、Ka Shu Ning、KD-025、酪洛芬(ketoprofen)联合奥美拉唑(omeprazole)、来氟米特(leflunomide)、lenzilumab、LLDT-8、罗美昔布(lumiracoxib)、LY-3090106、马赛替尼(masitinib)、mavrilimumab、MBS-2320、MEDI-5117、美洛昔康(meloxicam)、氨甲蝶呤(methotrexate)、MGD-010、米索前列醇(misoprostol)联合双氯芬酸钠(diclofenac)、MM-A01-01、monalizumab、MORAb-022、MPC-300-IV、MRC-375、纳布美通(nabumetone)、namilumab、萘普生(naproxen)联合埃索美拉唑(esomeprazole)、萘普生(naproxen)联合埃索美拉唑锶、ocaratuzumab、奥法木单抗(ofatumumab)、OHR-118、奥洛珠单抗(olokizumab)、OM-89、每日一次萘普生(naproxen)(口服控释,疼痛)、(Alvogen)、ONO-4059(Oralgam)、ozoralizumab、peficitinib、培比洛芬(pelubiprofen)、PF-06687234、盐酸哌啶酮、吡罗昔康(piroxicam)、泼尼松龙(prednisolone)、强的松(prednisone)、Prosorba、PRT-2607、PRTX-100、PRX-167700、QBSAU、rabeximod、RCT-18、重组人CD22单克隆抗体(静脉输液)(Lonn Ryonn Pharma/SinoMab Bioscience(Shenzhen))、重组人白介素-1受体拮抗剂(类风湿性关节炎)(Shanghai Fudan-Zhangjiang Bio-Pharmaceutical)、重组人白介素-2重组TNF受体2-Fc融合蛋白突变、RG-6125、RhuDex、利福布丁(rifabutin)联合克拉霉素(clarithromycin)联合氯法齐明(clofazimine)、利妥昔单抗(rituximab)、利妥昔单抗(rituximab)生物类似药、利妥昔单抗(rituximab)后续生物制剂、RPI-78、SAN-300、sarilumab、SBI-087、seliciclib、SHR-0302、sirukumab、spebrutinib、SSS-07、KDDF-201110-06、Syn-1002、T-5224、TAB-08、他克莫司(tacrolimus)、TAK-020、TAK-079、tarenflurbil(透皮喷雾剂,皮肤病/类风湿性关节炎)(MIKA Pharma/GALENpharma)、锝Tc99m tilmanocept、亚甲基二膦酸锝[99Tc]、替诺昔康(tenoxicam)、Debio-0512、托珠单抗(tocilizumab)、托法替尼(tofacitinib)、猪鞭虫卵(Trichuris suis ova)、脐带衍生的间充质干细胞(umbilical cord-derived mesenchymal stem cells)(静脉内,RA/肝病)(Alliancells/Zhongyuan Union)、优特克单抗(ustekinumab)、VAY-736、VB-201、WF-10、XmAb-5871、YHB-1411-2;14-3-3蛋白η抑制剂,例如抗-AGX-020mAbs(类风湿性关节炎)、Augurex;5-脂氧合酶抑制剂,例如替诺昔康(tenoxicam)、达布飞龙(darbufelone)、特丁非隆(tebufelone)、利克飞龙(licofelone)、ZD-2138、etalocib、替尼达普(tenidap)、替泊沙林(tepoxalin)、氟罗布芬(flobufen)、SKF-86002、PGV-20229、L-708780、WY-28342、T-0757、T-0799、ZM-216800、L-699333、BU-4601A、SKF-104351、CI-986;Abl酪氨酸激酶抑制剂,例如伊马替尼(imatinib);ACTH受体激动剂,例如FAR-404、醋酸metenkefalin联合醋酸tridecactidee;腺苷A3受体激动剂,例如CF-101;腺苷脱氨酶抑制剂,例如克拉屈滨(cladribine)、喷司他丁(pentostatin)、FR-221647;ADP核糖环化酶-1调节剂,例如indatuximab ravtansine;ADP核糖基化因子6抑制剂,例如NAV-2729;肾上腺皮质激素配体,例如促肾上腺皮质激素(Mallinckrodt)、FAR-404、醋酸metenkefalin联合醋酸tridecactidee;聚蛋白多糖酶-2抑制剂,例如GIBH-R-001-2;白蛋白调节剂,例如ALX-0061、ONS-1210;AP1转录因子抑制剂,例如T-5224、tarenflurbil、SP-10030;基础免疫球蛋白抑制剂,例如ERG-240;Bcr蛋白抑制剂,例如伊马替尼(imatinib);B淋巴细胞抗原CD19抑制剂,例如XmAb-5871、MDX-1342;B淋巴细胞抗原CD20抑制剂,例如奥珠单抗(ocrelizumab)、奥法木单抗(ofatumumab)、利妥昔单抗(rituximab)、利妥昔单抗(rituximab)生物类似药、veltuzumab、利妥昔单抗(rituximab)后续生物制剂、ocaratuzumab、BLX-301、IDEC-102、ABP-798、GP-2013、MK-8808、HLX-01、CT-P10、TL-011、PF-05280586、IBPM-001RX、IBI-301、AME-133v、BCD-020、BT-D004、SAIT-101;B淋巴细胞抗原CD20调节剂,例如利妥昔单抗(rituximab)生物类似药、SBI-087、TRU-015、DXL-625;B淋巴细胞刺激剂配体抑制剂,例如belimumab、RCT-18、blisibimod、tabalumab、阿塞西普(atacicept)、briobacept;缓激肽受体调节剂,例如givinostat;BRAF基因抑制剂,例如比尼替尼(binimetinib);支链氨基酸转氨酶1抑制剂,例如ERG-240;含溴结构域蛋白抑制剂,例如RVX-297、ZEN-003694;Btk酪氨酸激酶抑制剂,例如acalabrutinib、HM-71224、spebrutinib、BTK抑制剂(类风湿性关节炎)、(Humanwell Healthcare/Wuxi AppTech)、BMS-986142、TAK-020、ONO-4059、TAS-5315、ABBV-105、AC-0025、RN-486、CG-026806、GDC-0834;钙粘素-11拮抗剂,例如RG-6125;钙调神经磷酸酶抑制剂,例如HS-378、环孢素(ciclosporin);钙通道抑制剂,例如RP-3128;碳酸酐酶抑制剂,例如polmacoxib;组织蛋白酶K抑制剂,例如CRA-013783、T-5224、AM-3876、VEL-0230、NPI-2019;组织蛋白酶S抑制剂,例如MIV-247、AM-3876、RWJ-445380、NPI-2019;CCR1趋化因子拮抗剂,例如BX-471、BMS-817399、BI-638683、CCX-354、MLN-3701、MLN-3897、CP-481715、PS-375179;CCR2趋化因子拮抗剂,例如MK-0812、AZD-6942;CCR3基因调节剂,例如CM-102;CCR5趋化因子拮抗剂,例如马拉韦罗(maraviroc)、OHR-118、NIBR-6465、AZD-5672、AZD-8566;CD126拮抗剂,例如sarilumab;CD29调节剂,例如PF-06687234;CD3调节剂,例如otelixizumab;CD39激动剂,例如AAV5-CD39/CD73(类风湿性关节炎)、Arthrogen;CD4激动剂,例如马拉韦罗(maraviroc);CD4拮抗剂,例如tregalizumab、zanolimumab、MTRX-1011A、BW-4162W94、EP-1645、clenoliximab;CD40配体抑制剂,例如dapirolizumab pegol;CD40配体受体拮抗剂,例如BI-655064、抗-CD40-XTEN、替奈昔单抗(teneliximab);CD40配体受体调节剂,例如CFZ-533;CD52拮抗剂,例如阿仑单抗(alemtuzumab);CD73激动剂,例如AAV5-CD39/CD73(类风湿性关节炎)、Arthrogen;CD79b调节剂,例如MGD-010;CD80拮抗剂,例如RhuDex、XENP-9523、ASP-2408、阿巴西普(abatacept)生物较优药;CD86拮抗剂,例如ES-210、阿巴西普(abatacept)生物更佳药、ASP-2408、XENP-9523;CD95拮抗剂,例如DE-098、CS-9507;细胞粘附分子抑制剂,例如那他珠单抗(natalizumab)、alicaforsen、NPC-17923、TK-280、PD-144795;胆碱激酶抑制剂,例如胆碱激酶抑制剂(类风湿性关节炎)(UC San Diego);凝聚素刺激剂,例如阿仑单抗(alemtuzumab);补体C5因子抑制剂,例如依库丽单抗(eculizumab)、反义寡核苷酸(类风湿性关节炎)(Leiden University Medical Center);补体因子刺激剂,例如CM-101;C-反应蛋白抑制剂,例如IB-RA(口服,类风湿性关节炎)(Innobioscience)、ISIS-353512;CSF-1拮抗剂,例如马赛替尼(masitinib)、FPA-008、JNJ-27301937、JNJ-40346527、PLX-5622、CT-1578、PD-360324、JNJ-28312141;CXC10趋化因子配体抑制剂,例如946414-98-8、BMS-936557;CXCR4趋化因子拮抗剂,例如普乐沙福(plerixafor);周期素依赖性激酶抑制剂1抑制剂,例如CDK-1/2/5/7/9抑制剂(癌症/肿瘤发生/类风湿性关节炎),BioPatterns;周期素依赖性激酶-2抑制剂,例如seliciclib、BP-14;周期素依赖性激酶-4抑制剂,例如CDK-4/6抑制剂(类风湿性关节炎),Teijin;周期素依赖性激酶-5抑制剂,例如BP-14;周期素依赖性激酶-6抑制剂,例如CDK-4/6抑制剂(类风湿性关节炎),Teijin;周期素依赖性激酶-7抑制剂,例如BP-14、seliciclib;周期素依赖性激酶-9抑制剂,例如BP-14、seliciclib;环氧合酶2抑制剂,例如塞来昔布(celecoxib)、依托考昔(etoricoxib)、polmacoxib、拉氟莫司(laflunimus)、依托度酸(etodolac)、美洛昔康(meloxicam)、IB-RA(可注射的,类风湿性关节炎)(Innobioscience)、IB-RA(口服,类风湿性关节炎)(Innobioscience)、SKLB-023、美洛昔康(meloxicam)、罗美昔布(lumiracoxib);环氧合酶2调节剂,例如DRGT-46;环氧合酶抑制剂,例如醋氯芬酸(aceclofenac)、双氯芬酸钠(diclofenac)、水杨酸咪唑、萘普西诺(naproxcinod)、萘普生依特莫(naproxenetemesil)、米索前列醇(misoprostol)联合双氯芬酸钠(diclofenac)、纳布美通(nabumetone)、萘普生(naproxen)联合埃索美拉唑(esomeprazole)、萘普生(naproxen)联合埃索美拉唑锶、每日一次萘普生(naproxen)(口服控释,疼痛)(Alvogen)、培比洛芬(pelubiprofen)、LY-210073、替诺昔康(tenoxicam)、利克飞龙(licofelone)、NS-398、溴芬酸(bromfenac)、L-746483、LY-255283、替尼达普(tenidap)、替泊沙林(tepoxalin)、氟罗布芬(flobufen)、布洛芬、氟比洛芬(flurbiprofen)、SKF-86002、SC-57666、WY-28342、CI-986、柏莫洛芬(bermoprofen);胞浆型磷脂酶(Cytosolic phospholipase)A2抑制剂,例如AVX-002;细胞毒性T淋巴细胞蛋白-4调节剂,例如贝拉西普(belatacept)、ES-210;细胞毒性T淋巴细胞蛋白-4刺激剂,例如阿巴西普(abatacept)、阿巴西普(abatacept)生物类似药、BMS-188667;DHFR抑制剂,例如氨甲蝶呤(methotrexate)、MPI-2505、MBP-Y003;二胺乙酰转移酶抑制剂,例如重氮氨苯脒乙酰甘氨酸盐;二氢乳清酸脱氢酶抑制剂,例如DHODH抑制剂(类风湿性关节炎/自体免疫疾病)(华东理工大学)、ASLAN-003、拉氟莫司(laflunimus)、来氟米特(leflunomide)、HWA-486、ABR-224050;延长因子2抑制剂,例如denileukin diftitox;嗜酸细胞活化趋化因子(Eotaxin)2配体抑制剂,例如CM-102;EP4前列腺素受体拮抗剂,例如CR-6086;红细胞生成素受体激动剂,例如cibinetide;Fas配体,例如AP-300;FGF-2配体抑制剂,例如RBM-007;FK506结合蛋白-12调节剂,例如西罗莫司脂化物(temsirolimus);叶酸拮抗剂,例如氨甲蝶呤(methotrexate)、MBP-Y003;叶酸受体激动剂,例如叶酸受体调节剂(嵌合蛋白、癌症/类风湿性关节炎),Proda Biotech;叶酸受体调节剂,例如锝(99mTc)etarfolatide;趋化因子分形素配体(Fractalkine ligand)抑制剂,例如E-6011;Fyn酪氨酸激酶抑制剂,例如马赛替尼(masitinib)、拉氟莫司(laflunimus);G蛋白偶联受体15拮抗剂,例如GPR15拮抗剂(类风湿性关节炎/HIV-mediatedenteropathy),Omeros;GABA A受体调节剂,例如拉氟莫司(laflunimus);糖皮质激素激动剂,例如泼尼松龙(prednisolone)、fosdagrocorat;糖皮质激素拮抗剂,例如REC-200;糖皮质激素的亮氨酸拉链蛋白刺激剂,例如ART-G01;GM-CSF配体抑制剂,例如namilumab、MORAb-022、lenzilumab;GM-CSF受体拮抗剂,例如mavrilimumab;GM-CSF受体调节剂,例如GSK-3196165;生长调节蛋白α配体抑制剂,例如T-5224;Hwith Kwith ATP酶抑制剂,例如萘普生(naproxen)联合埃索美拉唑(esomeprazole)、萘普生(naproxen)联合埃索美拉唑锶、酪洛芬(ketoprofen)联合奥美拉唑(omeprazole)、KEO-25001、HC-1004、PN-40020;组胺H4受体拮抗剂,例如toreforant、GD-48;组蛋白脱乙酰酶抑制剂,例如givinostat、CHR-5154;组蛋白脱乙酰酶-6抑制剂,例如CKD-506;HIV-1gp120蛋白抑制剂,例如马拉韦罗(maraviroc);HLA II类抗原DQ-2α调节剂,例如NexVax2;HLA II类抗原抑制剂,例如HLA-DR1/DR4抑制剂(类风湿性关节炎),Provid;HLA II类抗原调节剂,例如ARG-301、重组T-细胞受体配体(类风湿性关节炎),Artielle;Hsp 70家族抑制剂,例如胍立莫司三盐酸盐;缺氧诱发因子-1抑制剂,例如2-甲氧雌二醇;IFNB基因刺激剂,例如ART-102;I-κB激酶β抑制剂,例如IMD-2560、IMD-0560;I-κB激酶抑制剂,例如甲基巴多索隆(bardoxolone methyl);IL-1拮抗剂,例如利纳西普(rilonacept)、IBPB-007-IL、反义寡核苷酸(类风湿性关节炎)(Leiden University Medical Center)、重组人白介素-1受体拮抗剂(类风湿性关节炎)(Shanghai Fudan-Zhangjiang Bio-Pharmaceutical);IL-10激动剂,例如peg-伊洛白介素(peg-ilodecakin);IL-11激动剂,例如奥普瑞白介素(oprelvekin);IL-12拮抗剂,例如优特克单抗(ustekinumab)、briakinumab、ddRNAi治疗剂(类风湿性关节炎)、(Medistem/Benitec);IL-15拮抗剂,例如AMG-714、BNZ-132-2;IL-17拮抗剂,例如ixekizumab、苏金单抗(secukinumab)、KD-025;IL-17受体调节剂,例如CNTO-6785;IL-2激动剂,例如白介素-2后续生物制剂;IL-2拮抗剂,例如IB-RA(可注射的,类风湿性关节炎)(Innobioscience)、IB-RA(口服,类风湿性关节炎)(Innobioscience)、BNZ-132-2;IL-21拮抗剂,例如NN-8828、BNZ-132-2;IL-23拮抗剂,例如优特克单抗(ustekinumab)、briakinumab;IL-3拮抗剂,例如抗-IL-3mAbs(类风湿性关节炎)、University of Regensburg;IL-4激动剂,例如SER-130-AMI;IL-6拮抗剂,例如奥洛珠单抗(olokizumab)、clazakizumab、sirukumab、SA-237、托珠单抗(tocilizumab)、ALX-0061、FB-704A、OP-R003、肽IL-6拮抗剂、MEDI-5117、T-5224、人类化抗-IL-6mAb、托珠单抗(tocilizumab)生物类似药、IL-6中和人抗体、抗-IL6抗体、RN-486、BLX-1002、AMG-220、FM-101、K-832、BLX-1025、esonarimod、TA-383;IL-6受体调节剂,例如托珠单抗(tocilizumab)、托珠单抗(tocilizumab)生物类似药、RO-4877533;免疫球蛋白拮抗剂,例如艾拉莫德(iguratimod);免疫球蛋白G1激动剂,例如康纳单抗(canakinumab)、英夫利西单抗(infliximab)生物较优药、英夫利西单抗(infliximab)生物类似药、BX-2922、STI-002、HF-1020;免疫球蛋白G1拮抗剂,例如YHB-1411-2;免疫球蛋白G1调节剂,例如CFZ-533、lenzilumab;免疫球蛋白G2拮抗剂,例如狄诺塞麦(denosumab);免疫球蛋白G2调节剂,例如PF-547659;免疫球蛋白γFc受体II调节剂,例如MGD-010;免疫球蛋白γFc受体IIB拮抗剂,例如XmAb-5871;免疫球蛋白κ调节剂,例如lenzilumab;免疫球蛋白M拮抗剂,例如IB-RA(可注射的,类风湿性关节炎)(Innobioscience)、IB-RA(口服,类风湿性关节炎)(Innobioscience);诱导型一氧化氮合酶抑制剂,例如SKLB-023;肌苷单磷酸脱氢酶抑制剂,例如霉酚酸酯(mycophenolate mofetil);胰岛素增敏剂,例如罗格列酮(rosiglitazone)、THR-0921、HE-3286、BLX-1002;整合素α-1/β-1拮抗剂,例如SAN-300;整合素α-4/β-1拮抗剂,例如那他珠单抗(natalizumab);整合素拮抗剂,例如PEG-HM-3、CY-9652;干扰素β配体,例如重组干扰素β-1a、TA-383;干扰素γ配体,例如干扰素γ后续生物制剂;白介素17A配体抑制剂,例如ABT-122、bimekizumab、ABBV-257;白介素17F配体抑制剂,例如bimekizumab;白介素23A抑制剂,例如guselkumab;白介素配体,例如IBPB-007-IL;白介素受体17A拮抗剂,例如布罗达单抗(brodalumab);白介素-1β配体抑制剂,例如康纳单抗(canakinumab)、利纳西普(rilonacept)、T-5224、gevokizumab、BLX-1002、LY-2189102、PMI-001、K-832、CDP-484;白介素-10配体,例如PF-06687234;白介素-2配体,例如denileukin diftitox、重组白介素-2、白介素-2后续生物制剂、重组人白介素-2、白介素-2(可注射的);白介素-4配体,例如Tetravil;白介素-6配体抑制剂,例如gerilimzumab、PF-4236921;Itk酪氨酸激酶抑制剂,例如ARN-4079;JAK酪氨酸激酶抑制剂,例如托法替尼(tofacitinib)、SHR-0302、cerdulatinib、peficitinib、氘代托法替尼(tofacitinib)类似物、SD-900、CVXL-0074;Jak1酪氨酸激酶抑制剂,例如ABT-494、巴瑞克替尼(baricitinib)、鲁索替尼(ruxolitinib)、filgotinib、托法替尼(tofacitinib)、itacitinib、peficitinib、NIP-585、CS-944X、YJC-50018、GLPG-0555、MRK-12;Jak2酪氨酸激酶抑制剂,例如巴瑞克替尼(baricitinib)、鲁索替尼(ruxolitinib)、CT-1578;JAK3基因抑制剂,例如GBL-5b;Jak3酪氨酸激酶抑制剂,例如decernotinib、托法替尼(tofacitinib)、peficitinib、AC-0025、CS-944X、DNX-04042、MTF-003、ARN-4079、PS-020613;Jun N末端激酶抑制剂,例如IQ-1S;KCNA电压门控钾离子通道-3调节剂,例如MRAD-P1;Kelch样ECH相关蛋白1调节剂,例如富马酸二甲酯;Kit酪氨酸激酶抑制剂,例如伊马替尼(imatinib)、马赛替尼(masitinib);LanC样蛋白2调节剂,例如BT-11;LITAF基因抑制剂,例如GBL-5b;淋巴细胞功能抗原-3受体拮抗剂,例如阿法赛特(alefacept);Lyn酪氨酸激酶抑制剂,例如马赛替尼(masitinib);巨噬细胞甘露糖受体1调节剂,例如锝Tc 99m tilmanocept;MAdCAM抑制剂,例如PF-547659;MAP激酶调节剂,例如SKLB-023;MAP3K2基因抑制剂,例如GBL-5b;MAPKAPK5抑制剂,例如GLPG-0259;基质金属蛋白酶抑制剂,例如GLPG-0259;MCL1基因抑制剂,例如seliciclib;MEK蛋白激酶抑制剂,例如binimetinib、AD-GL0001;MEK-1蛋白激酶抑制剂,例如binimetinib;MEK-2蛋白激酶抑制剂,例如binimetinib;膜铜胺氧化酶抑制剂,例如BTT-1023、PRX-167700、维帕莫单抗(vepalimomab);金属蛋白酶-2抑制剂,例如ERG-240;金属蛋白酶-9抑制剂,例如GS-5745、ERG-240;肝素结合细胞因子(Midkine)配体抑制剂,例如CAB-102;线粒体10kDa热休克蛋白刺激剂,例如INV-103;mTOR复合物1抑制剂,例如依维莫司(everolimus);mTOR抑制剂,例如依维莫司(everolimus)、西罗莫司脂化物(temsirolimus);NAD ADP核糖基转移酶刺激剂,例如denileukin diftitox;NAMPT基因抑制剂,例如ART-D01;NFκB抑制剂刺激剂,例如狄诺塞麦(denosumab);NFAT基因抑制剂,例如T-5224;NFE2L2基因刺激剂,例如甲基巴多索隆(bardoxolone methyl);烟碱乙酰胆碱受体拮抗剂,例如RPI-78、RPI-MN;NK细胞受体调节剂,例如马赛替尼(masitinib);NKG2 A B活化NK受体拮抗剂,例如monalizumab;NKG2 D活化NK受体拮抗剂,例如NNC-0142-002;核红血球2相关因子2刺激剂,例如富马酸二甲酯;核因子κB抑制剂,例如甲基巴多索隆(bardoxolone methyl)、IB-RA(可注射的,类风湿性关节炎)(Innobioscience)、脱羟甲基环氧奎米霉素(quinomicin)、HE-3286、IMD-0560、MP-42、tarenflurbil、VGX-1027、SKLB-023、SP-650003、MG-132、SIM-916、VGX-350、VGX-300、GIT-027、SP-100030、MLN-1145、NVP-IKK-005;核因子κB调节剂,例如REM-1086;核因子κB p105抑制剂,例如REM-1086;阿片类生长因子受体激动剂,例如醋酸metenkefalin联合醋酸tridecactidee、FAR-404;阿片类受体δ拮抗剂,例如HS-378;破骨细胞分化因子拮抗剂,例如狄诺塞麦(denosumab)、环状拟肽(类风湿性关节炎/骨质疏松)(University of Michigan);破骨细胞分化因子配体抑制剂,例如狄诺塞麦(denosumab);氧化还原酶抑制剂,例如依托度酸(etodolac)、水杨酸咪唑;P2X7嘌呤受体激动剂,例如givinostat;p38 MAP激酶α抑制剂,例如VX-745、BMS-582949前药、BMS-751324;p38 MAP激酶抑制剂,例如BCT-197、losmapimod、ARRY-797;PDE 4抑制剂,例如阿普斯特(apremilast);PDE 5抑制剂,例如PDE5抑制剂(类风湿性关节炎)(University ofRochester);PDGF受体激动剂,例如奥普瑞白介素(oprelvekin);PDGF受体拮抗剂,例如伊马替尼(imatinib)、马赛替尼(masitinib);PDGF-B配体抑制剂,例如SL-1026;PERK基因抑制剂,例如binimetinib;磷酸肌醇-3激酶δ抑制剂,例如duvelisib、RP-6503、CT-732、INK-007、GNE-293;磷酸肌醇-3激酶γ抑制剂,例如duvelisib、RP-6503;磷脂酶A2抑制剂,例如AVX-002、人体分泌磷脂酶A2 IIA型整合素结合抑制肽(类风湿性关节炎/哮喘/阿尔茨海默氏病/癌症)(University of California、Davis)、AK-106、甲基伐瑞拉迪(varespladibmethyl)、Ro-31-4493、BM-162353、Ro-23-9358、YM-26734;血小板活化因子受体拮抗剂,例如盐酸哌啶酮;PPARγ激动剂,例如罗格列酮(rosiglitazone)、THR-0921、罗格列酮(rosiglitazone)XR、etalocib;程序性细胞死亡蛋白1调节剂,例如INSIX RA;前列腺素D合成酶刺激剂,例如HF-0220;蛋白精氨酸脱亚胺酶抑制剂,例如PAD抑制剂(类风湿性关节炎)(Leiden University Medical Center/LURIS);蛋白酪氨酸激酶抑制剂,例如来氟米特(leflunomide);PurH嘌呤生物合成蛋白抑制剂,例如霉酚酸酯(mycophenolate mofetil);Rho相关蛋白激酶2抑制剂,例如KD-025;分离酶(Seprase)抑制剂,例如抗-成纤维细胞活化蛋白(FAP)抗体放射示踪物(类风湿性关节炎)(Hoffmann-La Roche/RadboudUniversity);信号转导蛋白CD24调节剂,例如CD24-IgFc;信号转导抑制剂,例如伊马替尼(imatinib);钠葡萄糖转运蛋白-2抑制剂,例如THR-0921;鞘氨醇1磷酸磷酸酶调节剂,例如S1P调节剂(口服,多发性硬化/溃疡性结肠炎/类风湿性关节炎)(Akaal Pharma);STAT3基因抑制剂,例如甲基巴多索隆(bardoxolone methyl)、vidofludimus;超氧化物歧化酶刺激剂,例如imisopasem锰;SYK家族酪氨酸激酶抑制剂,例如MK-8457;Syk酪氨酸激酶抑制剂,例如fostamatinib、entospletinib、KDDF-201110-06、HMPL-523、cerdulatinib、AB-8779、GS-9876、PRT-2607、CVXL-0074、CG-103065和CG-026806;多配体蛋白聚糖-1抑制剂,例如indatuximab ravtansine;T细胞受体拮抗剂,例如TCR抑制SCHOOL肽(全身/局部,类风湿性关节炎/皮炎/硬皮病)(SignaBlok)、CII修饰肽(类风湿性关节炎)(Peking University);T细胞受体调节剂,例如ARG-301;T细胞表面糖蛋白CD28抑制剂,例如阿巴西普(abatacept)、贝拉西普(belatacept)、阿巴西普(abatacept)生物类似药、RhuDex、BMS-188667;T细胞表面糖蛋白CD28刺激剂,例如TAB-08;TAK1结合蛋白调节剂,例如表没食子儿茶素3-没食子酸酯;人踝蛋白调节剂,例如短型人踝蛋白调节剂(类风湿性关节炎)(KayteeBio);T-细胞分化抗原CD6抑制剂,例如itolizumab;T-细胞表面糖蛋白CD8抑制剂,例如tregalizumab;腱生蛋白调节剂,例如Tetravil;TGFβ激动剂,例如tregalizumab;胸腺九肽(Thymulin)激动剂,例如Syn-1002;TLR-2拮抗剂,例如VB-201、P-13;TLR-4拮抗剂,例如VB-201、P-13;TLR-9拮抗剂,例如P-13;TNFα配体抑制剂,例如阿达木单抗(adalimumab)生物类似药YHB-1411-2、阿达木单抗(adalimumab)、英夫利西单抗(infliximab)、英夫利西单抗(infliximab)生物类似药、重组人类化抗-TNF-α单克隆抗体、聚乙二醇化妥珠单抗(certolizumab pegol)、戈利木单抗(golimumab)、ozoralizumab、AT-132、依那西普(etanercept)生物类似药、ISIS-104838、ISU-202、CT-P17、MB-612、Debio-0512、抗-TNFα人单克隆抗体、英夫利西单抗(infliximab)生物较优药、UB-721、KN-002、DA-3113、BX-2922、R-TPR-015、BOW-050、PF-06410293、CKD-760、CHS-1420、GS-071、ABP-710、STI-002、BOW-015、FKB-327、BAX-2200、HLX-03、BI-695501、CNTO-148、MYL-1401AABP-501、HOT-3010、BAX-2923、SCH-215596、ABT-D2E7、BAT-1406、XPro-1595、Atsttrin、SSS-07、戈利木单抗(golimumab)生物类似药、TA-101、阿达木单抗(adalimumab)后续生物制剂、BLX-1002、ABX-0401、TAQ-588、戈利木单抗(golimumab)生物类似药、TeHL-1、placulumab、PMI-001、tgAAV-TNFR:Fc、K-832、CYT-007-TNFQb、SSR-150106、PassTNF、Verigen、DOM-0200、DOM-0215、AME-527、抗-TNF-αmAb、GENZ-38167、BLX-1028、CYT-020-TNFQb、CC-1080、CC-1069;TNFα配体调节剂,例如MM-A01-01、CDP-571、camobucol;TNF拮抗剂,例如依那西普(etanercept)、聚乙二醇化妥珠单抗(certolizumab pegol)、依那西普(etanercept)后续生物制剂、依那西普(etanercept)生物类似药、DNX-114、TNF拮抗剂联合IL-12拮抗剂(类风湿性关节炎)(University ofOxford)、BN-006、SCB-131、pegsunercept、GBL-5b、ACE-772、奥那西普(onercept)、DE-096、PN-0615、lenercept、ITF-1779、MDL-201112、BAX-2200、SCB-808、DA-3853、HD-203;TNF基因抑制剂,例如GIBH-R-001-2;TNF受体调节剂,例如重组TNF受体2-Fc融合蛋白突变、T-0001、tgAAV-TNFR:Fc;TNFSF11基因抑制剂,例如狄诺塞麦(denosumab);转录因子p65抑制剂,例如REM-1086;转录因子RelB抑制剂,例如REM-1086;运铁蛋白调节剂,例如氨甲蝶呤(methotrexate)、MBP-Y003;肿瘤坏死因子13C受体拮抗剂,例如VAY-736;肿瘤坏死因子15配体抑制剂,例如抗-TL1A抗体(类风湿性关节炎/炎症性肠病)、NIAMS;肿瘤坏死因子配体13抑制剂,例如atacicept;肿瘤坏死因子配体抑制剂,例如ABBV-257、依那西普(etanercept)生物类似药、ABT-122;I型IL-1受体拮抗剂,例如阿那白滞素(anakinra)、阿那白滞素(anakinra)生物类似药、阿那白滞素(anakinra)后续生物制剂、AXXO;I型TNF受体拮抗剂,例如NM-9405;II型TNF受体调节剂,例如依那西普(etanercept)、SCB-131、依那西普(etanercept)生物类似药、依那西普(etanercept)后续生物制剂、BAX-2200、SCB-808、LBEC-0101、DMB-3853、DWP-422、BT-D001、DA-3853;非特定GPCR激动剂,例如NCP-70X;VEGF受体拮抗剂,例如2-甲氧雌二醇和NSC-650853、SL-1026;VEGF-2受体拮抗剂,例如CG-026806;VEGF-2受体调节剂,例如VEGFR2中和抗体(类风湿性关节炎)(University ofRochester);VEGF-B配体抑制剂,例如CSL-346;凋亡蛋白抑制剂的X连锁抑制剂,例如IAP抑制剂(口服)(Pharmascience);以及Zap70酪氨酸激酶抑制剂,例如MK-8457、CT-5332。
代谢性疾病或病症的组合
代谢障碍的例子包括但不限于糖尿病,包括I型和II型糖尿病、代谢综合征、血脂异常、肥胖症、葡萄糖耐受不良,高血压、血清胆固醇升高和甘油三酯升高。用于治疗代谢障碍的治疗剂的实例包括抗高血压剂和降脂剂。用于治疗代谢障碍的另外的治疗剂包括胰岛素、磺酰脲类过氧化物酶体增殖物激活受体γ(PPAR-γ)激动剂,例如噻唑烷二酮例如吡格列酮、双胍类、α-葡萄糖苷酶抑制剂、维生素E和肠促胰岛素模拟物。因此,本发明的一个方面是治疗代谢疾病的方法,其包括将本发明的化合物与一种或多种可用于治疗代谢疾病的化合物组合施用于需要其的受试者,特别是人类受试者。
药物组合物
尽管活性成分可以单独给药,但是可能将它们作为药物制剂(组合物)是更优选的。本发明的兽用和人用制剂均包括至少一种如上所定义的活性成分,以及一种或多种为此可接受的载体,以及任选地其他治疗成分。在与制剂的其他成分相容并且对于接受者生理上无害的意义上,载体必须是“可接受的”。
所述制剂包括适合于前述给药途径的那些。所述制剂可以方便地以单位剂型存在,并且可以通过药学领域公知的任何方法制备。技术和制剂通常可在Remington’sPharmaceutical Sciences(Mack Publishing Co.,Easton,PA)中找到。这样的方法包括使活性成分与构成一种或多种辅助成分的非活性成分(例如载体,药物赋形剂等)结合的步骤。通常,通过将活性成分与液体载体或细分的固体载体或两者一起均匀且紧密地结合在一起,然后(如果需要)将产物成型来制备制剂。
在一些实施方案中,适于口服给药的制剂以离散单位存在,例如各自包括预定量的活性成分的胶囊、扁囊剂或片剂。
在一些实施方案中,所述药物制剂包括本发明的一种或多种化合物以及一种或多种药学上可接受的载体或赋形剂以及任选的其他治疗剂。含有活性成分的药物制剂可以是适合于预期给药方法的任何形式。例如,当用于口服时,可以制备成片剂、口含片、锭剂、水性或油性悬浮液、可分散的粉末或颗粒、乳剂、硬或软胶囊、糖浆或酏剂。可以根据用于制造药物组合物的本领域已知的任何方法来制备用于口服的组合物,并且这种组合物可以包括一种或多种试剂,包括甜味剂、调味剂、着色剂和防腐剂,以提供适口的制剂。包括活性成分与适合于片剂生产的无毒的药学上可接受的赋形剂混合的片剂是可接受的。这些赋形剂可以是例如惰性稀释剂,如碳酸钙或碳酸钠、乳糖、乳糖一水合物、交联羧甲基纤维素钠、聚维酮、磷酸钙或磷酸钠;制粒剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如纤维素、微晶纤维素、淀粉、明胶或阿拉伯胶;润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂可以是未包衣的,也可以通过包括微囊化在内的已知技术进行包衣,以延迟在胃肠道中的崩解和吸收,从而在更长的时间内提供持续的作用。例如,可以使用延时材料,例如单独使用或与蜡一起使用的单硬脂酸甘油酯或二硬脂酸甘油酯。
与非活性成分结合以产生剂型的活性成分的量将根据所治疗的主体和特定的给药方式而变化。例如,在一些实施方案中,用于向人口服的剂型包括约1至1000mg的活性物质,该活性物质与适当和方便量的载体物质(例如,非活性成分或赋形剂物质)一起配制。在一些实施方案中,载体材料占总组合物的约5%至约95%(重量:重量)。在一些实施方案中,本文所述的药物组合物包括约1至800mg、1至600mg、1至400mg、1至200mg、1至100mg或1至50mg的式I化合物或其药学上可接受的盐。在一些实施方案中,本文描述的药物组合物包括不超过约400mg的式I化合物。在一些实施方案中,本文描述的药物组合物包括约100mg的式I化合物或其药学上可接受的盐。
应当理解,除了上述特别提及的成分以外,考虑到所讨论的制剂的类型,本文公开的制剂还可以包括本领域常规的其他试剂,例如适合于口服给药的制剂可以包括调味剂。
本文还提供了包括至少一种如上定义的活性成分以及兽医学载体的兽医学组合物。
兽医学载体是可用于给药所述组合物的材料,并且可以是固体、液体或气体材料,其在兽医学上是惰性的或可接受的并且与活性成分相容。这些兽医用组合物可以口服、肠胃外给药或通过任何其他所需途径给药。
活性成分的有效剂量至少取决于所治疗疾病的性质、毒性、是否需要预防性使用该化合物(低剂量)、递送方法和药物制剂,并且将由临床医生使用常规剂量递增研究确定。
给药途径
一种或多种式I的化合物(在此称为活性成分)或其药学上可接受的盐,通过适合于待治疗病症的任何途径给药。合适的途径包括口服、直肠、鼻、局部(包括颊和舌下)、阴道和肠胃外(包括皮下、肌内、静脉内、皮内、鞘内和硬膜外)等。应当理解,优选的途径可以随着例如接受者的状况而变化。本发明化合物的优点是它们是口服生物可利用的并且可以口服给药。因此,在一个实施方案中,本文所述的药物组合物是口服剂型。在一些实施方案中,本文所述的药物组合物是口服固体剂型。
制剂实施例1
制备含有以下成分的硬明胶胶囊:
量
将上述成分混合并填充到硬明胶胶囊中。
制剂实施例2
片剂配方使用以下成分制备:
量
将这些成分混合并压制成片剂。
制剂实施例3
制备包含以下成分的干粉吸入剂制剂:
成分 重量%
活性成分 5
乳糖 95
将所述活性成分与乳糖混合,然后将所述混合物加入干粉吸入器中。
制剂实施例4
每片含30mg活性成分的片剂的制备如下:
使所述活性成分、淀粉和纤维素通过No.20目U.S.筛网并充分混合。将聚乙烯吡咯烷酮溶液与所得粉末混合,然后使其通过16目U.S.筛网。如此制得的颗粒在50℃至60℃下干燥并通过16目U.S.筛网。然后将事先通过No.30目U.S.筛网的羧甲基淀粉钠、硬脂酸镁和滑石粉添加到这些颗粒中,混合后在制片机上压缩以制得每片片重120毫克的片剂。
制剂实施例5
每个包括25mg活性成分的栓剂制备如下:
成分 量
活性成分 25mg
饱和脂肪酸甘油酯达到 2,000mg
使所述活性成分通过No.60目U.S.筛网,并悬浮在预先用必需的最小热熔化的饱和脂肪酸甘油酯中。然后将混合物倒入标称容量为2.0g的栓剂模具中,使其冷却。
制剂实施例6
每5.0mL剂量含50mg活性成分的悬浮液的制备如下:
混合所述活性成分、蔗糖和黄原胶,使其通过No.10目U.S.筛网,然后与先前制备的微晶纤维素和羧甲基纤维素钠的水溶液混合。用一些水稀释苯甲酸钠、香料和色素,并在搅拌下加入。然后添加足够的水以产生所需的体积。
制剂实施例7
皮下制剂可以如下制备:
成分 量
活性成分 5.0mg
玉米油 1.0mL
制剂实施例8
制备具有以下组成的注射剂:
制剂实施例9
制备具有以下组成的局部制剂:
合并所有上述除水以外的成分,并在搅拌下加热至60℃。然后在60℃剧烈搅拌下加入足量的水以乳化所述成分,然后加入适量(q.s.)至100克的水。
制剂实施例10
缓释组合物
本公开的缓释制剂可以如下制备:将化合物和pH-依赖性粘合剂以及任何任选的赋形剂紧密混合(干混)。然后将所述干混的混合物在强碱水溶液的存在下(该强碱水溶液喷雾到所述混合粉末中)制粒。将颗粒干燥,过筛,与任选的润滑剂(如滑石粉或硬脂酸镁)混合,然后压制成片剂。优选的强碱水溶液是碱金属氢氧化物(例如氢氧化钠或氢氧化钾)的溶液,优选氢氧化钠在水中的溶液(任选地包括至多25%的与水混溶的溶剂,例如低级醇)。
所得的片剂可以用任选的成膜剂包衣,以用于鉴定、掩味目的和提高吞咽的容易性。所述成膜剂的存在量通常为片剂重量的2%至4%。合适的成膜剂是本领域公知的,并且包括羟丙基甲基纤维素、阳离子甲基丙烯酸酯共聚物(甲基丙烯酸二甲基氨基乙基酯/甲基丙烯酸甲基丁酯共聚物 Pharma)等。这些成膜剂可任选地包括着色剂、增塑剂和其他补充组分。
优选地,所述压缩的片剂具有足以承受8Kp压缩的硬度。所述片剂的大小将主要取决于片剂中化合物的量。所述片剂将包括300至1100mg的化合物游离碱。优选地,所述片剂将包括范围为400-600mg,650-850mg和900-1100mg的化合物游离碱。
为了影响溶出速率,控制含化合物粉末的湿混合时间。优选地,粉末的总混合时间,即粉末暴露于氢氧化钠溶液的时间,为1至10分钟,优选为2至5分钟。制粒后,将颗粒从制粒机中取出,放入流化床干燥器中,在约60℃下干燥。
制剂实施例11
使用下面的成分制备片剂制剂:
将这些成分混合并压制成片剂。
实施例
包括以下实施例以说明本公开的特定实施方案。本领域技术人员应理解,以下实施例中公开的技术代表在本公开的实践中能很好地起作用的技术,因此可以认为构成其实践的特定模式。然而,根据本公开,本领域技术人员应当理解,可以在所公开的特定实施例中进行许多改变,并且在不脱离本公开的精神和范围的情况下仍可获得相似或相似的结果。
缩略语和缩写词列表
缩写 含义
℃ 摄氏度
Ac 乙酰基
aq. 水性
ATP 三磷酸腺苷
B2Pin2 双(频哪醇合)二硼
BOC 叔丁氧羰基
Br 宽峰
BSA 牛血清白蛋白
d 双峰
DCM 二氯甲烷
dd 双二重峰
ddd 双重双二重峰
DIPEA N,N-二异丙基乙胺(Hünig碱)
DMA 二甲基乙酰胺
DME 1,2-二甲氧基乙烷
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
dt 双三重峰
DTT 二硫苏糖醇(克莱兰德试剂)
EC50 最大有效浓度的一半
EDC 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺
EDTA 乙二胺四乙酸
EGFR 表皮生长因子受体
Eq 当量
ES/MS 电喷雾质谱
Et 乙基
EtOAc 乙酸乙酯
EtOH 乙醇
FBS 胎牛血清
g 克
HATU 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶3-氧化物六氟磷酸盐
HEPES 2-[4-(2-羟乙基)哌嗪-1-基]乙磺酸
HCl 盐酸
HPLC 高压液相色谱
Hrs 小时
均相时间分辨荧光,注册商标Cisbio Bioassays,parc marcelboiteux 30200codolet,法国
Hz 赫兹
IBD 炎症性肠病
IC50 最大抑制浓度的一半
i-pr 异丙基
J 耦合常数(MHz)
K3PO4 磷酸三钾
KOtBu 叔丁醇钾
KOAc 醋酸钾
LCMS 液相色谱-质谱
Li HMDS 双(三甲基甲硅烷基)酰胺锂
LiOH 氢氧化锂
LiI 碘化锂
LPS 脂多糖
M 摩尔
m 多重峰
M+ 质谱峰
M+H+ 质谱峰加氢
Me 甲基
MeCN 乙腈
MeOH 甲醇
MeLi 甲基锂
MeMgX 甲基卤化镁(格氏试剂),其中X为氟、氯、溴或碘
Me6Sn2 六甲基二锡烷(六甲基二锡)
mg 毫克
MgSO4 硫酸镁
MHz 兆赫
Min 分钟
ml/mL 毫升
mM 毫摩尔浓度
mmol 毫摩尔
MS 质谱
MsCl 甲磺酰氯
NBS N-溴琥珀酰亚胺
n- 正
nBu/Bu 正丁基
n-BuLi 正丁基锂
NaH 氢化钠
NaHCO3 碳酸氢钠
NaN3 叠氮化钠
Na3PO4 磷酸三钠
Na2SO4 硫酸钠
nL 纳升
nm 纳米
NMP 1-甲基吡咯烷-2-酮
NMR 核磁共振
NP-40 壬基苯氧基聚乙氧基乙醇
Pd-PEPPSITM–IPent[1,3-双(2,6-二-3-戊基苯基)咪唑-2-亚烷基](3-氯吡啶基)二氯化钯(II)
Pen-Strep 青霉素-链霉素(含5,000单位的青霉素G钠盐和5,000μg硫酸链霉素的0.85%的盐水)
Ph 苯基
q 四重峰
q.s. 足以实现所述功能的量
RP 反相
RPMI 罗斯威帕克纪念研究所(Roswell Park Memorial Institute)培养基
Rt 室温
s 单峰
sat. 饱和的
1-氯甲基-4-氟-1,4-重氮化双环[2.2.2]辛烷双(商标AirProducts and Chemicals)
SFC 超临界流体色谱
Thiol二氧化硅基钯清除剂,注册商标Silicycle
T 三重峰
THF 四氢呋喃
TFA 三氟乙酸
XPhos Pd G3 (2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)[2-(2'-氨基-1,1'-联苯)]甲磺酸钯(II)
1.比较实施例A
比较实施例A在国际专利申请PCT/US2016/038861中作为实施例193示出,其公开为WO 2016/210036 A1。比较实施例A的结构是:
2.中间体的合成
中间体I-1的制备:
3,3-二乙氧基-2-甲酰丙腈钾盐(I-1C):
在10℃向3,3-二乙氧基丙腈(I-1A,283.80g,1.98mol)和甲酸甲酯(I-1B,148.80g,2.48mol)于无水THF(1.1L)的溶液中添加于THF中的1.0M叔丁醇钾(2.2L,2.2mol)。在整个45分钟的添加过程中,温度保持在10℃至15℃的范围内。添加后,将所得浆液在环境温度下搅拌2小时。然后加入己烷(400mL)并继续搅拌另外的20分钟。过滤浆液并将滤饼用1/1己烷/THF洗涤并在真空烘箱中于60℃干燥过夜以提供I-1C。1H-NMR(CD3OD)与所需的结构一致。
吡咯并[1,2-b]哒嗪-3-甲腈(I-1E):
将3,3-二乙氧基-2-甲酰丙腈钾盐(I-1C,5.10g,24.36mmol)的搅拌的悬浮液冷却至0℃,并以反应内部温度不超过20℃的速率滴加浓HCl(7.11mL,85.26mmol)。添加完成后,将反应室温搅拌20分钟。向该反应混合物中加入1-氨基吡咯(I-1D,1.00g,12.18mmol)的甲醇(4.0mL)溶液。添加后,将该反应混合物90℃回流2小时。加热完成后,将反应冷却至室温并浓缩至原始体积的约一半。将饱和的碳酸氢钠水溶液小心地添加到所得残余物中直到鼓泡停止。用两份乙酸乙酯萃取溶液。合并的有机层经硫酸钠干燥,过滤,真空浓缩,所得残余物通过硅胶色谱法纯化(洗脱液:EtOAc/己烷),得到I-1E。
1H NMR(400MHz,氯仿-d)δ8.16-8.03(m,2H),7.93(ddd,J=2.6,1.4,0.6Hz,1H),7.04(dd,J=4.5,2.7Hz,1H),6.84(dd,J=4.6,1.4Hz,1H)。
7-溴吡咯并[1,2-b]哒嗪-3-甲腈(I-1F):
室温下向吡咯并[1,2-b]哒嗪-3-甲腈(I-1E,840.0mg,5.9mmol)于MeCN(30mL)的溶液中一次性添加N-溴琥珀酰亚胺。将该反应室温搅拌30分钟,然后倒入饱和碳酸氢钠水溶液中。将该溶液真空浓缩以除去乙腈。所得水层用三份EtOAc萃取。合并的有机层经硫酸钠干燥,过滤,真空浓缩,并通过硅胶色谱法纯化(洗脱液:EtOAc/己烷),得到I-1F。
1H NMR(400MHz,氯仿-d)δ8.28(d,J=2.1Hz,1H),8.10(d,J=2.1Hz,1H),7.12(d,J=4.8Hz,1H),6.93(d,J=4.8Hz,1H)。
7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡咯并[1,2-b]哒嗪-3-甲腈(I-1):
在微波瓶中装入7-溴吡咯并[1,2-b]哒嗪-3-甲腈(I-1F,416.5mg,1.9mmol)、双(频哪醇合)二硼(762.1mg,3.0mmol)、乙酸钾(552.3mg,5.6mmol)和双(三苯基膦)二氯化钯(II)(65.8mg,0.094mmol)。加入二噁烷(8.0mL)和DMF(4.0mL),并将该反应混合物用鼓泡的氩气脱气2分钟。将该小瓶密封并将反应在微波反应器中120℃加热60分钟。冷却后,将该反应混合物过滤并真空浓缩。将所得残余物在EtOAc和水之间分配。用第二份EtOAc萃取水层,并将合并的有机层用硫酸钠干燥,通过硅藻土塞过滤,并真空浓缩。所得残余物通过硅胶色谱法纯化(洗脱液:EtOAc/己烷),得到I-1。
1H NMR(400MHz,氯仿-d)δ8.31(d,J=2.3Hz,1H),8.14(d,J=2.2Hz,1H),7.52(d,J=4.6Hz,1H),6.84(d,J=4.6Hz,1H),1.41(s,12H).
中间体I-2的制备:
/>
6-溴-4-氯烟酸。向6-溴-4-氯烟酸甲酯(15g,59.89mmol)于甲醇(240mL)的溶液中添加氢氧化锂(2.93g,119.77mmol)的水(68mL)溶液。将该溶液加热至43℃过夜,然后冷却至室温。加入盐酸水溶液(1M,120mL)并真空除去挥发物。过滤所得浆液并用H2O洗涤以提供6-溴-4-氯烟酸。
ES/MS:238.0(M+H+)。
1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.03(s,1H)。
(R)-6-溴-4-氯-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺。向6-溴-4-氯烟酸(3g,12.69mmol)于DMF(42mL)的溶液中添加HATU(6.27g,16.49mmol)、(R)-4-氨基-3-氟-2-甲基丁-2-醇盐酸盐(2.4g,15.23mmol)和N,N-二异丙基乙胺(5.62ml,32.26mmol)。将所得溶液室温搅拌过夜,然后用乙酸乙酯稀释。有机溶液用饱和氯化锂水溶液洗涤(3次),然后经Na2SO4干燥,然后浓缩。残余物通过硅胶色谱法纯化(洗脱液:EtOAc/己烷)以提供(R)-6-溴-4-氯-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺。
ES/MS:341.1(M+H+)。
1H NMR(400MHz,DMSO-d6)δ8.88(t,J=5.5Hz,1H),8.41(s,1H),8.01(s,1H),4.82(s,1H),4.28(ddd,J=49.3,9.4,2.0Hz,1H),3.84–3.63(m,1H),3.40–3.22(m,1H),1.13(d,J=7.0Hz,6H)。
(R)-4-氯-6-(3-氰基吡咯并[1,2-b]哒嗪-7-基)-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺(I-5)。向(R)-6-溴-4-氯-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺(0.2g,0.59mmol)于DME(3.9mL)的溶液中添加7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡咯并[1,2-b]哒嗪-3-甲腈(0.24g,0.9mmol)、XPhos Pd G3(0.05g,0.06mmol)和磷酸钾水溶液(2M,0.59mL,1.18mmol)。将所得溶液用氩气脱气并在微波反应器中加热至120℃保持12分钟。粗反应混合物通过硅胶色谱法纯化(洗脱液:EtOAc/己烷)以得到(R)-4-氯-6-(3-氰基吡咯并[1,2-b]哒嗪-7-基)-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺。
ES/MS:402.2(M+H+)。
3.实施例过程和化合物实施例
过程1:实施例1:
(R)-6-(3-氰基吡咯并[1,2-b]哒嗪-7-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(甲基氨基)烟酰胺
6-氯-4-(甲基氨基)烟酸甲酯:向4,6-二氯烟酸甲酯(0.5g,2.43mmol)和甲胺盐酸盐(0.82g,12.16mmol)于乙腈(10mL)和水(0.3mL)的溶液中添加1,8-二氮杂双环(5.4.0)十一-7-烯(1.8ml,12.04mmol)。将所得溶液室温搅拌3小时。将该溶液真空浓缩至干并用乙酸乙酯稀释。用水和氯化钠水溶液洗涤所得溶液。所得有机层经硫酸钠干燥并真空浓缩。所得物质经正相SiO2色谱纯化(洗脱剂:乙酸乙酯/己烷)以提供所需产物。
ES/MS:201.180(M+H+)。
6-氯-4-(甲基氨基)烟酸:向6-氯-4-(甲基氨基)烟酸甲酯(0.38g,1.92mmol)于MeOH(10mL)、THF(5mL)和水(5mL)的溶液中添加氢氧化锂(0.12g,5.01mmol)。将该溶液室温搅拌18小时,用HCl(1N,5mL)中和,并真空浓缩至干。所得的粗物质用于后续步骤。
ES/MS:187.070(M+H+)。
(R)-6-氯-N-(2-氟-3-羟基-3-甲基丁基)-4-(甲基氨基)烟酰胺:向6-氯-4-(甲基氨基)烟酸(0.36g,1.92mmol)和(R)-4-氨基-3-氟-2-甲基丁-2-醇(0.31g,2.56mmol)于DMF(10mL)的溶液中添加HATU(0.97g,2.55mmol)和N,N-二异丙基乙胺(1.5ml,8.61mmol)。将所得溶液室温搅拌1小时并用乙酸乙酯稀释。用5%氯化锂水溶液(3×)洗涤该溶液,经硫酸钠干燥,并真空浓缩。所得物质经正相SiO2色谱纯化(洗脱剂:乙酸乙酯/己烷)以提供所需产物。
ES/MS:290.472(M+H+)。
(R)-6-(3-氰基吡咯并[1,2-b]哒嗪-7-基)-N-(2-氟-3-羟基-3-甲基丁基)-4-(甲基氨基)烟酰胺:向(R)-6-氯-N-(2-氟-3-羟基-3-甲基丁基)-4-(甲基氨基)烟酰胺(30mg,0.10mmol)、7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡咯并[1,2-b]哒嗪-3-甲腈(39mg,0.15mmol)和Xphos Pd G3(9mg,0.011mmol)于DME(1mL)的溶液中添加磷酸钾水溶液(2M,0.10mL,0.20mmol)。将所得溶液用氩气脱气2分钟并在微波条件下于120℃加热20分钟。过滤反应混合物并将所得固体用DMF洗涤。然后将滤液真空浓缩并将粗物质通过RP-HPLC纯化(洗脱液:水/MeCN*0.1%TFA)以得到产物,为三氟乙酸盐。
ES/MS:397.283(M+H+)。
1H NMR(400MHz,甲醇-d4)δ8.75(d,J=2.2Hz,1H),8.66(d,J=2.2Hz,1H),8.51(s,1H),8.02(d,J=5.1Hz,1H),7.76(s,1H),7.21(d,J=5.1Hz,1H),4.42(ddd,J=49.0,9.3,2.1Hz,1H),3.93(ddd,J=36.4,14.5,2.2Hz,1H),3.48(ddd,J=16.2,14.5,9.4Hz,1H),3.19(s,3H),1.28(d,J=1.7Hz,6H).
过程2:实施例2:
(R)-4-((氰基甲基)氨基)-6-(3-氰基吡咯并[1,2-b]哒嗪-7-基)-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺
(R)-6-氯-4-((氰基甲基)氨基)-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺:向(R)-4,6-二氯-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺(100mg,0.34mmol)和氨基乙腈盐酸盐(47.03mg,0.51mmol)于DMA(1mL)的浆液中添加N,N-二异丙基乙胺(0.2mL,1.12mmol)。然后将所得溶液在微波条件下于150℃加热30分钟。加入另外的氨基乙腈盐酸盐(47.03mg,0.51mmol)和N,N-二异丙基乙胺(0.2mL,1.12mmol)并将该反应在热条件下于130℃加热16小时。将该溶液冷却至室温并用乙酸乙酯稀释。将所得浆液过滤并将固体用EtOAc洗涤。合并所得滤液并用氯化氨水溶液洗涤。所得有机层经硫酸镁干燥并真空浓缩。所得物质经正相SiO2色谱纯化(洗脱剂:乙酸乙酯/己烷)以提供所需产物。
ES/MS:315.159(M+H+)。
(R)-4-((氰基甲基)氨基)-6-(3-氰基吡咯并[1,2-b]哒嗪-7-基)-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺:向(R)-6-氯-4-((氰基甲基)氨基)-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺(53mg,0.17mmol)、7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡咯并[1,2-b]哒嗪-3-甲腈(68mg,0.25mmol)和Xphos Pd G3(16mg,0.019mmol)于DME(2mL)的溶液中添加磷酸钾水溶液(2M,0.17mL,0.34mmol)。将所得溶液用氩气脱气2分钟并在微波条件下于120℃加热20分钟。将反应混合物过滤并将得到的固体用DMF和MeOH洗涤。然后将滤液真空浓缩并将粗物质通过RP-HPLC纯化(洗脱液:水/MeCN*0.1%TFA)以得到产物,为三氟乙酸盐。通过正相SiO2色谱法(洗脱液:甲醇/二氯甲烷)进一步纯化该材料并从乙腈和水(0.1%三氟乙酸)中冻干以提供所需的产物。
ES/MS:422.250(M+H+)。
1H NMR(400MHz,甲醇-d4)δ8.79(d,J=2.2Hz,1H),8.70(d,J=2.0Hz,2H),8.10(d,J=5.1Hz,1H),8.05(s,1H),7.25(d,J=5.1Hz,1H),4.73(s,2H),4.46(ddd,J=49.1,9.4,2.2Hz,1H),3.98(ddd,J=36.6,14.5,2.2Hz,1H),3.60–3.41(m,1H),1.31(d,J=1.7Hz,6H)。
过程3:实施例3:
4-(((R)-1-氰基乙基)氨基)-6-(3-氰基吡咯并[1,2-b]哒嗪-7-基)-N-((R)-2-氟-3-羟基-3-甲基丁基)烟酰胺
4-(((R)-1-氨基-1-氧丙烷-2-基)氨基)-6-氯-N-((R)-2-氟-3-羟基-3-甲基丁基)烟酰胺:向(R)-4,6-二氯-N-(2-氟-3-羟基-3-甲基丁基)烟酰胺(200mg,0.68mmol)和(R)-2-氨基丙酰胺盐酸盐(172mg,1.38mmol)于DMA(3mL)的浆液中添加N,N-二异丙基乙胺(0.6mL,3.37mmol)。然后将所得溶液在微波条件下于150℃加热60分钟。通过RP-HPLC(洗脱液:水/MeCN*0.1%TFA)纯化所得物质以得到产物,为三氟乙酸盐。
ES/MS:347.521(M+H+)。
表1:化合物
/>
表2:示例化合物的NMR数据
/>
/>
生物测定
进行生物测定以测量针对TNFα和IRAK4的活性。如表3中总结的,所测试的化合物是IRAK4的抑制剂。
基于IRAK4单核细胞TNFα细胞的测定过程:
将冷冻保存的人类单核细胞(干细胞技术)解冻,并在含有10%FBS的具有GlutaMAXTM(200mM L-丙氨酰-L-谷氨酰胺)(10mM HEPES、1X Pen-Strep、55μMβ-巯基乙醇、1mM丙酮酸钠)的RPMI中稀释至0.125X106细胞/ml并37℃恢复2小时。然后将细胞悬浮液以5,000个细胞/孔的密度铺板到黑色的384孔Greiner透明底部培养板上。将培养板用测试化合物预先点样,并在DMSO中连续稀释,其中使用Echo 550声学液体分配器输送40nL/孔以使最终DMSO浓度为0.1%。在37℃下用化合物处理铺板的细胞持续1小时。然后用50pg/ml的LPS(Sigma)刺激细胞,不包括用于未刺激的细胞对照孔的板的外部列。将细胞在37℃下再培育4小时。然后将细胞从培养基中旋转出来,并取出5μl样品并使用TR-FRET人TNFα检测系统(CisBio)分析总TNFα含量。该系统利用了两种标记的抗体(穴状化合物和XL665),它们与TNFα分子的两个不同表位结合并产生与样品中TNFα浓度成比例的FRET信号。将检测抗体以50:50的比例混合并将5μL分配到每个孔中。用透明密封件覆盖培养板并在室温下培育过夜。在次日早晨,使用Envision 2103多标记阅读器(PerkinElmer)分别在340nm/615nm/665nm激发/发射/FRET发射读取培养板。以615nm和665nm发射波长下的荧光强度表示为比率(665nm/615nm)。对照百分比计算如下:
%对照=100x(比率样品-比率0%刺激)/(比率100%刺激-比率0%刺激)
其中未刺激的细胞(0%刺激)为阴性对照,刺激的细胞(100%刺激)用作阳性对照。
IRAK4生物化学测定过程:
通过使用针对磷酸化肽底物的抗体检测磷酸化肽底物的形成来测量IRAK4酶(Carna Biosciences,Chuo-ku,Kobe,Japan)的活性。这是基于STK1KinEASE测定法(Cisbio,Bedford,Massachusetts)的时间分辨的荧光共振能量转移(TR-FRET)免疫测定法。该测定方法设计为简单的两步,在ProxiPlate-384 Plus培养板(Perkin Elmer,Waltham,Massachusetts)中进行终点分析(5μl酶反应,然后进行5μl终止和检测溶液)。星形孢菌素(Staurosporine),一种非选择性的激酶抑制剂被用作阳性对照。使用550液体处理系统将在DMSO中稀释的化合物点样到384孔板中,然后添加IRAK4酶和肽底物。使用Multi-Flo(Bio-Tek Instruments)输送反应溶液。将酶和肽溶液与化合物在室温下培育15分钟,然后再通过添加ATP引发反应。标准5μl反应混合物包括500μMATP、2μM肽(STK1肽)、于反应缓冲液(50mM HEPES,pH 7.0、0.02%NaN3、0.01%BSA,0.1mM正钒酸盐,5mM MgCl2,0.025%NP-40、1mM DTT)中的0.75nM IRAK4。在室温下培育120分钟后,添加5μl终止和检测溶液(1:100穴状化合物标记的抗磷酸化肽抗体溶液和于含有足够EDTA的50mM HEPES pH 7.0检测缓冲液中的125nM示踪剂)。然后将培养板在室温下进一步培育60分钟,并在Envision 2103多标记阅读器(PerkinElmer)上分别以340nm/615nm/665nm的激发/发射/FRET发射进行读数。发射波长在615nm和665nm处的荧光强度表示为比率(665nm/615nm)。抑制百分比计算如下:
%抑制=100x(比率样品-比率0%抑制)/(比率100%抑制-比率0%抑制)
0%抑制值来自缺乏抑制剂的对照孔。100%抑制值来自含有饱和量的已知抑制剂星形孢菌素的对照孔。
肝稳定性:
冷冻保存的肝细胞的代谢稳定性:通过向45mL InVitroGROTM HT培养基中加入1mLTorpedo抗生素混合物来制备完全的HT培养基。补充的KHB培养基由以下组成:具有丁胺卡那霉素(84μg/mL)、氯化钙(1mM)、庆大霉素(84μg/mL)、HEPES(20mM)、庚酸(4.2μM)和碳酸氢钠(28.5mM)的KrebsHenseleit缓冲液,并在37℃下使用1M NaOH或1M HCl将pH调节至7.4。从十个成年供体(Celsis,Lot:HBZ)收集人类冷冻保存的肝细胞。
从液氮中取出含有冷冻保存的肝细胞的小瓶并立即浸入37℃水浴中。将小瓶轻轻摇动直到内容物解冻,然后立即倒入50mL锥形管中的48mL预热的Complete HT培养基中。将残留在小瓶中的细胞重悬于1.0mL预热的完全HT培养基中并添加到锥形管中。将管加盖,然后轻轻倒转几次以重悬肝细胞。将细胞悬浮液在室温下以50×g离心5分钟并丢弃上清液。通过轻轻旋转离心管使细胞集结粒松散并添加补充的KHB培养基以达到2x 106细胞/mL的目标密度。使用血细胞计数器通过台盼蓝染料排除法测定总细胞数和活细胞比例。
对于培育,将等分试样的肝细胞悬浮液(250μL包括500,000个细胞)添加到24孔板中一式两份孔中补充KHB的250μL的2μM测试化合物或代谢稳定性对照中。培育的终浓度为1x 106细胞/mL和1μM测试化合物。在平行培育中将7-羟基香豆素和睾酮(已知可被肝细胞有效代谢的化合物)用作阳性对照(每种化合物的终浓度为2μM)。在37℃在95%空气/5%CO2(v/v)的潮湿气氛下轻轻摇动进行培育。在0、1、3和6小时后取出等分试样(50μL)并添加至100μL IS/Q淬灭溶液中。终止后,加入150μL水,将板以3000×g离心10分钟,然后在Micromass Quattro Premier质谱仪(与配备Leap Technologies HTC PAL自动进样器的Agilent 1200系列HPLC系统联合,如下所述)上分析上清液的等分试样。
液相色谱-质谱:通过在配备Leap Technologies HTC PAL自动进样器的Agilent1200系列HPLC系统联合的Micromass Quattro Premier XL串联三重四极杆质谱仪上测量的分析物/内标峰面积比(PAR)来进行测试化合物和代谢稳定性对照的定量。所用的色谱柱为MercuryMSTM、Synergi Max-RP(孔径/>粒径2.5μm,20×2.0mm)。流动相A由0.2%(v/v)甲酸于99%水/1%乙腈(v/v)中的溶液组成。流动相B由0.2%(v/v)甲酸于5%的水/95%乙腈(v/v)中的溶液组成。通过以下一系列线性梯度实现洗脱:初始条件为0%B,保持30s,然后在90s内增加到100%B,然后在1s内恢复到初始条件。使系统在两次进样之间至少重新平衡60s。进样量为10μL。
LTP血浆蛋白结合:
制备最终浓度为10mM的测试化合物于二甲亚砜(DMSO)中的储备溶液并将其用于所有实验中。
可商购的化学品购自Sigma-Aldrich(St.Louis,MO)和VWR(West Chester,PA)。细胞培养基(CCM)为具有10%(v/v)胎牛血清的Gibco Dulbecco's改良的Eagle培养基(DMEM)。
平衡透析测定:汇集的血浆(至少3名雄性和3名雌性)来自人、比格犬(beagledog)、斯普拉格-杜勒(Sprague-Dawley)大鼠、食蟹猴(cynomolgus monkey)和恒河猴(rhesus monkey)。EDTA钠用作抗凝剂。
在37℃下使用人类血浆与含有10%FBS的CCM进行竞争性平衡透析,基质的两面均掺杂有最终浓度为2μM的样品。在研究之前,将透析膜在pH7.4的0.133M磷酸盐缓冲液中浸泡约一小时。将掺杂的血浆(1mL)和CCM(1mL)置于组装的透析池的相对侧。为了评估回收率,在37℃水浴中平衡24小时后,将血浆样品排入预称重的装有1mL CCM(不含化合物)的聚丙烯管中并将CCM样品排入含有1mL相关空白血浆的预称重试管。测量并记录透析后血浆和CCM的重量以进行计算。
液相色谱-质谱:
通过在与配备Leap Technologies HTS PAL自动进样器的Agilent 1260系列HPLC系统联合的Q-Exactive质谱仪上测量的分析物/内标峰面积比(PAR)进行测试化合物的定量。流动相A由0.2%(v/v)甲酸于99%水/1%乙腈(v/v)中的溶液组成。流动相B由0.2%(v/v)甲酸于5%水/95%乙腈(v/v)中的溶液组成。进样量为10μL。
pK a测定:
样品制备:制备最终浓度为10mM的于二甲亚砜(DMSO)中的测试化合物储备溶液并将其用于所有实验。将所述DMSO储备液解冻,离心并在40℃水浴中超声处理,以利于溶解。
pKa分析:将所述10mM DMSO储备溶液用10mM HCl稀释100倍使最终化合物浓度为100μm和1%DMSO。然后将该化合物转移到96孔PCR板的24个连续孔中以进行水性方法(aqueous method)分析。对于在水性方法中未提供高质量数据的化合物,将所述10mM DMSO储备液用2mM HCl和甲醇稀释100倍,以使甲醇的最终浓度为60%,化合物浓度为100μm,而DMSO浓度为1%。将化合物转移到96孔板的24个连续孔中以使用助溶剂方法(co-solventmethod)进行分析。
分析:使用pKa PRO分析仪(AATI,Ames,IA)获得所有数据。对于水性方法,以24个不同的pH值并行进行电泳分离,从而提供对全部化合物电荷相对pH的直接测量。通过228nm的UV检测化合物。缓冲点之间的平均pH间隔为0.4个pH单位,覆盖了1.7-11.2的典型pH范围。
助溶剂方法适用于分析具有低水溶性(通常预测的固有溶解度<10μg/ml)的化合物。缓冲点之间的平均pH间隔为0.4个pH单位,覆盖1.7-11.2的pH范围。对每种化合物从60%的助溶剂缓冲液开始再减少到30%的助溶剂缓冲液来执行四次连续的CE运行。
诺氟沙星(Norfloxacin)用作每日性能指示标准。
结果计算:使用pKa软件(AATI,Ames,IA)通过关联移动性(mobility)和化合物分子量来预测pKa值的总数。
Charles River(以前的ChanTest)的自动化hERG分析
测定(Charles River)用于检查各种化合物对由KCNH2基因编码并在HEK293T细胞中稳定表达的克隆的hERG钾离子通道的体外作用。通过在HB-PS(HEPES缓冲的生理盐水溶液)中稀释DMSO储备溶液来制备载体、测试和对照制剂,并经由QPatch机器人移液系统将其递送至细胞以达到最终浓度为0.3%DMSO。将最终浓度为0.3、1、3、10和30μM的测试化合物按升序顺序施加于细胞(n≥3,其中n=细胞数/浓度),以通过溶液交换分开的至少3分钟间隔。阳性对照(50nM Cisparide)以相同的方式施加。在室温下,使用QPatch或QPatch/>系统中的多达48个并联膜片钳放大器记录细胞膜电流,并且仅使用具有经过验证的全细胞记录(密封电阻(seal resistance)≥200MΩ,泄漏电流(leakcurrent)≤25%通道电流)的细胞。使用由500ms预脉冲至-40mV,2秒激活脉冲至+40mV,然后是2秒测试脉冲至-40mV组成的刺激电压模式来测量hERG电流的开始和阻断。所述脉冲模式以10秒的间隔从-80mV的保持电位连续重复。在各个测试浓度,使用Nephelostar读取器测量从635nm激光源发出的光散射来进行测试化合物的溶解度的TurboSol分析。根据验证实验,高于背景水平四倍的光散射被认为是悬浮液中存在颗粒的指示。
体外分析的结果列于下表3:
表3
/>
Claims (4)
1.以下化合物或其药学上可接受的盐:
2.药物组合物,其包括权利要求1的化合物或其药学上可接受的盐,以及药学上可接受的载体。
3.权利要求1的化合物或权利要求2的组合物在制备用于在有需要的患者中治疗炎性病症的药物中的用途。
4.权利要求3的用途,其中所述炎性疾病选自IBD、SLE、牛皮癣或类风湿性关节炎。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311423711.5A CN117683034A (zh) | 2018-07-13 | 2019-07-11 | 吡咯并[1,2-b]哒嗪衍生物 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862697533P | 2018-07-13 | 2018-07-13 | |
US62/697,533 | 2018-07-13 | ||
PCT/US2019/041382 WO2020014468A1 (en) | 2018-07-13 | 2019-07-11 | Pyrrolo[1,2-b] pyridazine derivatives |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311423711.5A Division CN117683034A (zh) | 2018-07-13 | 2019-07-11 | 吡咯并[1,2-b]哒嗪衍生物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112513044A CN112513044A (zh) | 2021-03-16 |
CN112513044B true CN112513044B (zh) | 2023-11-07 |
Family
ID=67480334
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311423711.5A Pending CN117683034A (zh) | 2018-07-13 | 2019-07-11 | 吡咯并[1,2-b]哒嗪衍生物 |
CN201980046945.8A Active CN112513044B (zh) | 2018-07-13 | 2019-07-11 | 吡咯并[1,2-b]哒嗪衍生物 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311423711.5A Pending CN117683034A (zh) | 2018-07-13 | 2019-07-11 | 吡咯并[1,2-b]哒嗪衍生物 |
Country Status (22)
Country | Link |
---|---|
US (3) | US10875866B2 (zh) |
EP (1) | EP3820872B1 (zh) |
JP (2) | JP7167298B2 (zh) |
KR (2) | KR102583817B1 (zh) |
CN (2) | CN117683034A (zh) |
AR (1) | AR115731A1 (zh) |
AU (2) | AU2019302732B2 (zh) |
BR (1) | BR112020026675A2 (zh) |
CA (1) | CA3105485C (zh) |
CL (1) | CL2021000086A1 (zh) |
CO (1) | CO2021000153A2 (zh) |
CR (1) | CR20210014A (zh) |
EA (1) | EA202092858A1 (zh) |
IL (2) | IL309267A (zh) |
MX (1) | MX2021000462A (zh) |
PE (1) | PE20210404A1 (zh) |
PH (1) | PH12020552283A1 (zh) |
SG (1) | SG11202013003VA (zh) |
TW (1) | TWI721483B (zh) |
UA (1) | UA127506C2 (zh) |
WO (1) | WO2020014468A1 (zh) |
ZA (1) | ZA202100259B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI721483B (zh) * | 2018-07-13 | 2021-03-11 | 美商基利科學股份有限公司 | 吡咯并[1,2-b]嗒𠯤衍生物 |
CA3181637A1 (en) * | 2020-06-10 | 2021-12-16 | Ulf Bjorklund | Method for preparing a crystalline form of rabeximod |
CN117813307A (zh) | 2021-08-18 | 2024-04-02 | 新锐思生物制药股份有限公司 | 白介素-1受体相关激酶的双官能降解物及其治疗用途 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015103453A1 (en) * | 2014-01-03 | 2015-07-09 | Bristol-Myers Squibb Company | Heteroaryl substituted nicotinamide compounds |
WO2016210036A1 (en) * | 2015-06-24 | 2016-12-29 | Bristol-Myers Squibb Company | Heteroaryl substituted aminopyridine compounds |
Family Cites Families (90)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1434579B1 (en) | 2001-10-09 | 2011-06-08 | Amgen Inc. | Imidazole derivatives as antiinflammatory agents |
US20050288290A1 (en) | 2004-06-28 | 2005-12-29 | Borzilleri Robert M | Fused heterocyclic kinase inhibitors |
WO2008016643A2 (en) | 2006-08-01 | 2008-02-07 | Cytokinetics, Incorporated | Certain chemical entities, compositions, and methods |
EP2061786A2 (en) | 2006-09-07 | 2009-05-27 | Biogen Idec MA Inc. | Indazole derivatives as modulators of interleukin-1 receptor-associated kinase |
JP5107660B2 (ja) | 2007-03-28 | 2012-12-26 | 太平洋セメント株式会社 | セメント添加材及びセメント組成物 |
DE102009033208A1 (de) | 2009-07-15 | 2011-01-20 | Merck Patent Gmbh | Aminopyridinderivate |
AR077346A1 (es) | 2009-07-31 | 2011-08-17 | Biocryst Pharm Inc | Compuestos heterociclicos como inhibidores de janus quinasa |
JP2012254939A (ja) | 2009-10-07 | 2012-12-27 | Astellas Pharma Inc | オキサゾール化合物 |
RU2604062C2 (ru) | 2010-07-13 | 2016-12-10 | Ф.Хоффманн-Ля Рош Аг | ПРОИЗВОДНЫЕ ПИРАЗОЛО[1,5-a]ПИРИМИДИНА И ТИЕНО[3,2-b]ПИРИМИДИНА В КАЧЕСТВЕ МОДУЛЯТОРОВ IRAK-4 |
CN108864151A (zh) | 2010-11-19 | 2018-11-23 | 利亘制药公司 | 杂环胺及其用途 |
SG191205A1 (en) | 2010-12-20 | 2013-07-31 | Merck Serono Sa | Indazolyl triazole derivatives as irak inhibitors |
WO2012097013A1 (en) | 2011-01-10 | 2012-07-19 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
EP2688872A4 (en) | 2011-03-22 | 2014-08-27 | Merck Sharp & Dohme | AMIDOPYRAZOLHEMMER OF INTERLEUKIN RECEPTOR-MEDIATED KINASES |
WO2013042137A1 (en) | 2011-09-19 | 2013-03-28 | Aurigene Discovery Technologies Limited | Bicyclic heterocycles as irak4 inhibitors |
US9221809B2 (en) | 2011-10-31 | 2015-12-29 | Merck Sharp & Dohme Corp. | Aminopyrimidinones as interleukin receptor-associated kinase inhibitors |
ES2709003T3 (es) | 2011-11-09 | 2019-04-12 | Cancer Research Tech Ltd | Compuestos de 5-(piridin-2-il-amino)-pirazina-2-carbonitrilo y su uso terapéutico |
TW201728592A (zh) | 2012-01-10 | 2017-08-16 | 林伯士艾瑞斯公司 | Irak抑制劑及其用途 |
JP6096219B2 (ja) | 2012-01-13 | 2017-03-15 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | キナーゼ阻害剤として有用なトリアゾリルまたはトリアジアゾリル置換されたピリジル化合物 |
ES2630705T3 (es) * | 2012-01-13 | 2017-08-23 | Bristol-Myers Squibb Company | Compuestos de piridilo sustituidos con triazolilo útiles como inhibidores de cinasas |
US9242975B2 (en) | 2012-01-13 | 2016-01-26 | Bristol-Myers Squibb Company | Heterocyclic-substituted pyridyl compounds useful as kinase inhibitors |
AU2013289615B2 (en) | 2012-07-10 | 2017-06-08 | Ares Trading S.A. | Pyrimidine pyrazolyl derivatives |
WO2014011911A2 (en) | 2012-07-11 | 2014-01-16 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
BR112015000561A2 (pt) | 2012-07-11 | 2017-06-27 | Nimbus Iris Inc | inibidores de irak e usos dos mesmos |
WO2014011902A1 (en) | 2012-07-11 | 2014-01-16 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
EP2903617B1 (en) | 2012-10-08 | 2019-01-30 | Merck Sharp & Dohme Corp. | Inhibitors of irak4 activity |
EP2903613B1 (en) | 2012-10-08 | 2017-11-22 | Merck Sharp & Dohme Corp. | Pyrazole derivatives useful as inhibitors of irak4 activity |
CN104903301B (zh) | 2012-11-08 | 2017-08-29 | 百时美施贵宝公司 | 可用于调节IL‑12、IL‑23和/或IFNα的烷基酰胺取代的嘧啶化合物 |
EP2922840B1 (en) | 2012-11-08 | 2016-12-21 | Bristol-Myers Squibb Company | Bicyclic heterocycle substituted pyridyl compounds useful as kinase modulators |
WO2014074675A1 (en) | 2012-11-08 | 2014-05-15 | Bristol-Myers Squibb Company | Heteroaryl substituted pyridyl compounds useful as kinase modulators |
PT3495358T (pt) | 2012-11-08 | 2022-06-02 | Bristol Myers Squibb Co | Compostos heterocíclicos substituídos por amida úteis como moduladores de respostas de il-12, il-23 e/ou ifn-alfa |
JP6430390B2 (ja) | 2012-11-20 | 2018-11-28 | ジェネンテック, インコーポレイテッド | T790mを含むegfr変異体の阻害剤としてのアミノピリミジン化合物 |
CA2890911A1 (en) | 2013-01-10 | 2014-07-17 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
SI2953944T1 (sl) | 2013-02-07 | 2017-08-31 | Merck Patent Gmbh | Piridazinonamidni derivati |
AU2014214254B2 (en) | 2013-02-07 | 2018-03-29 | Merck Patent Gmbh | Macrocyclic Pyridazinone derivatives |
EP2970334B1 (en) | 2013-03-15 | 2018-05-23 | Biogen MA Inc. | Macrocyclic compounds as irak4 inhibitors for the treatment of inflammatory diseases |
EP3052494B1 (en) | 2013-06-28 | 2018-12-26 | H. Hoffnabb-La Roche Ag | Azaindazole compounds as inhibitors of t790m containing egfr mutants |
WO2015006181A1 (en) | 2013-07-11 | 2015-01-15 | Merck Sharp & Dohme Corp. | Substituted amidopyrazole inhibitors of interleukin receptor-associated kinases (irak-4) |
MX2016003843A (es) | 2013-09-27 | 2017-02-15 | Nimbus Iris Inc | Inhibidores de cinasas asociadas al receptor de interleucina 1 (irak) y usos de los mismos. |
WO2015068856A1 (en) | 2013-11-08 | 2015-05-14 | Takeda Pharmaceutical Company Limited | Pyrazole for the treatment autoimmune disorders |
TWI667233B (zh) | 2013-12-19 | 2019-08-01 | 德商拜耳製藥公司 | 新穎吲唑羧醯胺,其製備方法、含彼等之醫藥製劑及其製造醫藥之用途 |
CN106068264B (zh) | 2014-01-09 | 2019-06-21 | 默克专利有限公司 | 嘧啶吡唑基衍生物及其作为irak抑制剂的用途 |
MX2016009011A (es) | 2014-01-10 | 2017-01-23 | Aurigene Discovery Tech Ltd | Compuestos de indazol como inhibidores de cinasa-4 asociada al receptor de interleucina-1 (irak4). |
IL294895B2 (en) | 2014-01-13 | 2023-10-01 | Aurigene Oncology Ltd | History of bicyclic heterocyclyls as IRAK4 inhibitors |
ES2910128T3 (es) | 2014-04-04 | 2022-05-11 | Pfizer | Compuestos de heteroarilo o arilo fusionados con biciclo y su uso como inhibidores de IRAK4 |
EP3134091A4 (en) | 2014-04-22 | 2017-08-30 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
JP2017518348A (ja) | 2014-06-20 | 2017-07-06 | オーリジーン ディスカバリー テクノロジーズ リミテッドAurigene Discovery Technologies Limited | Irak4阻害剤としての置換インダゾール化合物 |
US10246456B2 (en) | 2014-07-18 | 2019-04-02 | Biogen Ma Inc. | IRAK4 inhibiting agents |
US9932350B2 (en) | 2014-09-30 | 2018-04-03 | Merck Sharp & Dohme Corp. | Inhibitors of IRAK4 activity |
US9943516B2 (en) | 2014-09-30 | 2018-04-17 | Merck Sharp & Dohme Corp. | Inhibitors of IRAK4 activity |
WO2016053769A1 (en) | 2014-09-30 | 2016-04-07 | Merck Sharp & Dohme Corp. | Inhibitors of irak4 activity |
WO2016053771A1 (en) | 2014-09-30 | 2016-04-07 | Merck Sharp & Dohme Corp. | Inhibitors of irak4 activity |
AU2015349899B9 (en) | 2014-11-20 | 2020-06-25 | Merck Patent Gmbh | Heteroaryl compounds as IRAK inhibitors and uses thereof |
JO3705B1 (ar) | 2014-11-26 | 2021-01-31 | Bayer Pharma AG | إندازولات مستبدلة جديدة، عمليات لتحضيرها، مستحضرات دوائية تحتوي عليها واستخدامها في إنتاج أدوية |
RU2730016C2 (ru) | 2015-02-05 | 2020-08-14 | Мерк Патент Гмбх | Макроциклические соединения в качестве irak1/4 ингибиторов и их применение |
MX2017009624A (es) | 2015-02-06 | 2017-11-20 | Merck Patent Gmbh | Macrociclos de piridazinona como inhibidores de cinasas asociadas al receptor de interleucina 1(irak) y sus usos. |
WO2016144846A1 (en) | 2015-03-12 | 2016-09-15 | Merck Sharp & Dohme Corp. | Pyrazolopyrimidine inhibitors of irak4 activity |
EP3268367B8 (en) | 2015-03-12 | 2022-11-16 | Merck Sharp & Dohme LLC | Carboxamide inhibitors of irak4 activity |
EP3268006B1 (en) | 2015-03-12 | 2020-01-08 | Merck Sharp & Dohme Corp. | Pyrrolotriazine inhibitors of irak4 activity |
WO2016144849A1 (en) | 2015-03-12 | 2016-09-15 | Merck Sharp & Dohme Corp. | Thienopyrazine inhibitors of irak4 activity |
WO2016144847A1 (en) | 2015-03-12 | 2016-09-15 | Merck Sharp & Dohme Corp. | Pyrrolopyridazine inhibitors of irak4 activity |
LT3286181T (lt) | 2015-04-22 | 2021-04-26 | Rigel Pharmaceuticals, Inc. | Pirazolo junginiai ir junginių gamybos bei naudojimo būdas |
TW201701879A (zh) | 2015-04-30 | 2017-01-16 | 拜耳製藥公司 | Irak4抑制劑組合 |
UY36747A (es) | 2015-06-24 | 2016-12-30 | Bristol Myers Squibb Company Una Corporación Del Estado De Delaware | Compuestos de aminopiridina sustituida con heteroarilo como inhibidores de quinasa y modulantes de irak-4 y composiciones farmacéuticas que los contienen |
TW201718571A (zh) | 2015-06-24 | 2017-06-01 | 必治妥美雅史谷比公司 | 經雜芳基取代之胺基吡啶化合物 |
WO2017004133A1 (en) | 2015-06-29 | 2017-01-05 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
WO2017004134A1 (en) | 2015-06-29 | 2017-01-05 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
EA201890308A1 (ru) | 2015-07-15 | 2018-08-31 | Ориджин Дискавери Текнолоджиз Лимитед | Замещенные азасоединения как ингибиторы irak-4 |
BR112018000624A2 (pt) | 2015-07-15 | 2018-09-18 | Aurigene Discovery Technologies Limited | compostos de indazol e azaindazol como inibidores de irak-4 |
EP3719016A1 (en) | 2015-08-04 | 2020-10-07 | Rigel Pharmaceuticals, Inc. | Benzazole compounds and methods for making and using the compounds |
AU2016304464B2 (en) | 2015-08-04 | 2020-11-19 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd | Pyrazole pyrimidine derivative and uses thereof |
AU2016305590A1 (en) | 2015-08-13 | 2018-02-15 | Pfizer Inc. | Bicyclic-fused heteroaryl or aryl compounds |
US10562902B2 (en) | 2015-08-13 | 2020-02-18 | Beijing Hanmi Pharmaceutical Co., Ltd. | IRAK4 inhibitor and use thereof |
KR102110573B1 (ko) | 2015-08-13 | 2020-05-13 | 베이징 한미 파마슈티컬 컴퍼니 리미티드 | Irak4억제제 및 이의 용도 |
HUE053705T2 (hu) | 2015-08-27 | 2021-07-28 | Pfizer | Biciklusos kondenzált heteroaril- vagy aril- vegyületek IRAK4 modulátorokként |
MX2018002986A (es) | 2015-09-18 | 2018-05-02 | Merck Patent Gmbh | Compuestos de heteroarilo como inhibidores de cinasas asociadas al receptor de interleucina 1 (irak) y sus usos. |
BR112018003812B1 (pt) | 2015-09-18 | 2024-04-30 | Merck Patent Gmbh | Compostos de heteroarila como inibidores de irak, seu uso, composição farmacêutica, e kit |
GB201518456D0 (en) | 2015-10-19 | 2015-12-02 | Galapagos Nv | Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory, autoimmune and/or proliferative diseases |
WO2017108744A1 (de) | 2015-12-22 | 2017-06-29 | Bayer Pharma Aktiengesellschaft | Neue substituierte indazole, verfahren zu ihrer herstellung, pharmazeutische präparate die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln |
CN108473498B (zh) | 2015-12-22 | 2021-11-02 | 豪夫迈·罗氏有限公司 | 作为IRAK4调节剂的吡唑并[1,5a]嘧啶衍生物 |
WO2017127430A1 (en) | 2016-01-20 | 2017-07-27 | Biogen Ma Inc. | Irak4 inhibiting agents |
ES2883298T3 (es) | 2016-04-29 | 2021-12-07 | Bayer Pharma AG | Síntesis de indazoles |
WO2017205766A1 (en) | 2016-05-27 | 2017-11-30 | Pharmacyclics Llc | Inhibitors of interleukin-1 receptor-associated kinase |
WO2017205762A1 (en) | 2016-05-27 | 2017-11-30 | Pharmacyclics Llc | Inhibitors of interleukin-1 receptor-associated kinase |
WO2017205769A1 (en) | 2016-05-27 | 2017-11-30 | Pharmacyclics Llc | Inhibitors of interleukin-1 receptor-associated kinase |
WO2017207385A1 (de) | 2016-05-31 | 2017-12-07 | Bayer Pharma Aktiengesellschaft | Substituierte 3-methylindazole, verfahren zu ihrer herstellung, pharmazeutische präparate, die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln |
EP3475263B1 (en) | 2016-06-27 | 2022-12-28 | Rigel Pharmaceuticals, Inc. | 2,4-diamino-pyrimidine compounds and their use as irak4 inhibitors |
US10414753B2 (en) | 2016-10-26 | 2019-09-17 | Rigel Pharmaceuticals, Inc. | Amide compounds and method for making and using |
CN109890829B (zh) | 2016-11-02 | 2022-07-15 | 豪夫迈·罗氏有限公司 | 作为IRAK4调节剂的吡唑并[1,5a]嘧啶衍生物 |
JOP20180011A1 (ar) * | 2017-02-16 | 2019-01-30 | Gilead Sciences Inc | مشتقات بيرولو [1، 2-b]بيريدازين |
TWI721483B (zh) * | 2018-07-13 | 2021-03-11 | 美商基利科學股份有限公司 | 吡咯并[1,2-b]嗒𠯤衍生物 |
-
2019
- 2019-07-05 TW TW108123710A patent/TWI721483B/zh active
- 2019-07-10 AR ARP190101944A patent/AR115731A1/es unknown
- 2019-07-11 US US16/508,979 patent/US10875866B2/en active Active
- 2019-07-11 CN CN202311423711.5A patent/CN117683034A/zh active Pending
- 2019-07-11 MX MX2021000462A patent/MX2021000462A/es unknown
- 2019-07-11 IL IL309267A patent/IL309267A/en unknown
- 2019-07-11 CR CR20210014A patent/CR20210014A/es unknown
- 2019-07-11 UA UAA202008192A patent/UA127506C2/uk unknown
- 2019-07-11 AU AU2019302732A patent/AU2019302732B2/en active Active
- 2019-07-11 BR BR112020026675-2A patent/BR112020026675A2/pt unknown
- 2019-07-11 CN CN201980046945.8A patent/CN112513044B/zh active Active
- 2019-07-11 CA CA3105485A patent/CA3105485C/en active Active
- 2019-07-11 IL IL279654A patent/IL279654B2/en unknown
- 2019-07-11 EP EP19746263.3A patent/EP3820872B1/en active Active
- 2019-07-11 WO PCT/US2019/041382 patent/WO2020014468A1/en unknown
- 2019-07-11 PE PE2021000046A patent/PE20210404A1/es unknown
- 2019-07-11 KR KR1020217003806A patent/KR102583817B1/ko active IP Right Grant
- 2019-07-11 JP JP2021500885A patent/JP7167298B2/ja active Active
- 2019-07-11 SG SG11202013003VA patent/SG11202013003VA/en unknown
- 2019-07-11 EA EA202092858A patent/EA202092858A1/ru unknown
- 2019-07-11 KR KR1020237032732A patent/KR20230144100A/ko not_active Application Discontinuation
-
2020
- 2020-12-03 US US17/110,734 patent/US11535622B2/en active Active
- 2020-12-23 PH PH12020552283A patent/PH12020552283A1/en unknown
-
2021
- 2021-01-05 ZA ZA2021/00259A patent/ZA202100259B/en unknown
- 2021-01-12 CL CL2021000086A patent/CL2021000086A1/es unknown
- 2021-01-12 CO CONC2021/0000153A patent/CO2021000153A2/es unknown
-
2022
- 2022-10-07 AU AU2022246450A patent/AU2022246450A1/en not_active Abandoned
- 2022-10-26 JP JP2022171477A patent/JP2022191496A/ja active Pending
- 2022-11-23 US US18/058,559 patent/US20230257386A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015103453A1 (en) * | 2014-01-03 | 2015-07-09 | Bristol-Myers Squibb Company | Heteroaryl substituted nicotinamide compounds |
WO2016210036A1 (en) * | 2015-06-24 | 2016-12-29 | Bristol-Myers Squibb Company | Heteroaryl substituted aminopyridine compounds |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI733982B (zh) | 吡咯并[1,2-b]嗒衍生物 | |
US11535622B2 (en) | Pyrrolo[1,2-b] pyridazine derivatives | |
JP2023002695A (ja) | IRAK4阻害剤としてのピロロ[1,2-b]ピリダジン誘導体 | |
CN112566697B (zh) | 作为IRAK4抑制剂的吡咯并[1,2-b]哒嗪衍生物 | |
TWI842978B (zh) | 衍生物 | |
AU2024203567A1 (en) | Pyrrolo[1,2-b] pyridazine derivatives | |
EA045296B1 (ru) | ПРОИЗВОДНЫЕ ПИРРОЛО[1,2-b]ПИРИДАЗИНА |
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 | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40045603 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |