JP2015509969A - Nox4阻害活性を示すチオフェン−ベースの化合物および療法におけるその使用 - Google Patents
Nox4阻害活性を示すチオフェン−ベースの化合物および療法におけるその使用 Download PDFInfo
- Publication number
- JP2015509969A JP2015509969A JP2014561449A JP2014561449A JP2015509969A JP 2015509969 A JP2015509969 A JP 2015509969A JP 2014561449 A JP2014561449 A JP 2014561449A JP 2014561449 A JP2014561449 A JP 2014561449A JP 2015509969 A JP2015509969 A JP 2015509969A
- Authority
- JP
- Japan
- Prior art keywords
- membered
- alkyl
- alkynyl
- alkenyl
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 119
- 238000002560 therapeutic procedure Methods 0.000 title claims description 10
- 108010082699 NADPH Oxidase 4 Proteins 0.000 title description 66
- 102000004070 NADPH Oxidase 4 Human genes 0.000 title description 66
- 230000002401 inhibitory effect Effects 0.000 title description 11
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 title description 8
- 229930192474 thiophene Natural products 0.000 title description 3
- 230000001747 exhibiting effect Effects 0.000 title description 2
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 101000968308 Homo sapiens Dual oxidase 1 Proteins 0.000 claims abstract description 4
- 101000968305 Homo sapiens Dual oxidase 2 Proteins 0.000 claims abstract description 4
- 102100021217 Dual oxidase 2 Human genes 0.000 claims abstract 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 80
- 229910052736 halogen Inorganic materials 0.000 claims description 56
- 150000002367 halogens Chemical class 0.000 claims description 56
- 125000003342 alkenyl group Chemical group 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 125000000304 alkynyl group Chemical group 0.000 claims description 40
- 201000010099 disease Diseases 0.000 claims description 40
- 208000035475 disorder Diseases 0.000 claims description 39
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 38
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 35
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 27
- 230000033115 angiogenesis Effects 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 14
- 125000001620 monocyclic carbocycle group Chemical group 0.000 claims description 13
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 12
- 208000006011 Stroke Diseases 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 8
- 208000019693 Lung disease Diseases 0.000 claims description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- 208000032456 Hemorrhagic Shock Diseases 0.000 claims description 6
- 206010049771 Shock haemorrhagic Diseases 0.000 claims description 6
- 208000010668 atopic eczema Diseases 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 210000003027 ear inner Anatomy 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 208000017169 kidney disease Diseases 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- 230000002314 neuroinflammatory effect Effects 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 208000023504 respiratory system disease Diseases 0.000 claims description 6
- 208000017520 skin disease Diseases 0.000 claims description 6
- ZZHVARLVSBEVPL-UHFFFAOYSA-N 5,5-dimethyl-2-[(2-phenylacetyl)amino]-4,7-dihydrothieno[2,3-c]pyran-3-carboxylic acid Chemical compound C1OC(C)(C)CC(C=2C(O)=O)=C1SC=2NC(=O)CC1=CC=CC=C1 ZZHVARLVSBEVPL-UHFFFAOYSA-N 0.000 claims description 5
- 208000020084 Bone disease Diseases 0.000 claims description 5
- 208000017701 Endocrine disease Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- 206010040070 Septic Shock Diseases 0.000 claims description 5
- 230000000172 allergic effect Effects 0.000 claims description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 5
- 230000002008 hemorrhagic effect Effects 0.000 claims description 5
- 208000019423 liver disease Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 230000002685 pulmonary effect Effects 0.000 claims description 5
- 230000001850 reproductive effect Effects 0.000 claims description 5
- 206010002199 Anaphylactic shock Diseases 0.000 claims description 4
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 4
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 4
- 206010069351 acute lung injury Diseases 0.000 claims description 4
- 208000003455 anaphylaxis Diseases 0.000 claims description 4
- 230000003176 fibrotic effect Effects 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 208000030159 metabolic disease Diseases 0.000 claims description 4
- 230000000414 obstructive effect Effects 0.000 claims description 4
- 230000000472 traumatic effect Effects 0.000 claims description 4
- LZNNMMKMGKFYLL-UHFFFAOYSA-N 2h-pyran-3-carboxylic acid Chemical compound OC(=O)C1=CC=COC1 LZNNMMKMGKFYLL-UHFFFAOYSA-N 0.000 claims description 3
- GUCPYIYFQVTFSI-UHFFFAOYSA-N 4-methoxybenzamide Chemical compound COC1=CC=C(C(N)=O)C=C1 GUCPYIYFQVTFSI-UHFFFAOYSA-N 0.000 claims description 3
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 3
- 210000004027 cell Anatomy 0.000 description 55
- 230000000694 effects Effects 0.000 description 39
- 102000004722 NADPH Oxidases Human genes 0.000 description 37
- 108010002998 NADPH Oxidases Proteins 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 125000003118 aryl group Chemical group 0.000 description 29
- -1 oxygen radicals Chemical class 0.000 description 25
- 125000005842 heteroatom Chemical group 0.000 description 21
- 239000000203 mixture Substances 0.000 description 19
- 229910052760 oxygen Inorganic materials 0.000 description 19
- 206010003246 arthritis Diseases 0.000 description 18
- 102000004190 Enzymes Human genes 0.000 description 16
- 108090000790 Enzymes Proteins 0.000 description 16
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 15
- 239000003642 reactive oxygen metabolite Substances 0.000 description 15
- 239000001301 oxygen Substances 0.000 description 14
- 239000003112 inhibitor Substances 0.000 description 13
- 230000036542 oxidative stress Effects 0.000 description 13
- 239000012981 Hank's balanced salt solution Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 241000124008 Mammalia Species 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 239000003963 antioxidant agent Substances 0.000 description 10
- 235000006708 antioxidants Nutrition 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 210000002216 heart Anatomy 0.000 description 10
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 10
- PHEDXBVPIONUQT-UHFFFAOYSA-N Cocarcinogen A1 Natural products CCCCCCCCCCCCCC(=O)OC1C(C)C2(O)C3C=C(C)C(=O)C3(O)CC(CO)=CC2C2C1(OC(C)=O)C2(C)C PHEDXBVPIONUQT-UHFFFAOYSA-N 0.000 description 9
- 206010020772 Hypertension Diseases 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 206010010904 Convulsion Diseases 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 230000001684 chronic effect Effects 0.000 description 8
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 8
- 230000001419 dependent effect Effects 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- HUDPLKWXRLNSPC-UHFFFAOYSA-N 4-aminophthalhydrazide Chemical compound O=C1NNC(=O)C=2C1=CC(N)=CC=2 HUDPLKWXRLNSPC-UHFFFAOYSA-N 0.000 description 7
- 206010019280 Heart failures Diseases 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentenylidene Natural products C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- JJCDCMDVPYDUEU-UHFFFAOYSA-N 4-chloro-1-(4-methylphenyl)pyrazolo[3,4-d]pyrimidine Chemical compound C1=CC(C)=CC=C1N1C2=NC=NC(Cl)=C2C=N1 JJCDCMDVPYDUEU-UHFFFAOYSA-N 0.000 description 6
- 206010016654 Fibrosis Diseases 0.000 description 6
- 206010022489 Insulin Resistance Diseases 0.000 description 6
- 208000032382 Ischaemic stroke Diseases 0.000 description 6
- 108010029485 Protein Isoforms Proteins 0.000 description 6
- 102000001708 Protein Isoforms Human genes 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000001413 cellular effect Effects 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 210000002889 endothelial cell Anatomy 0.000 description 6
- 230000004761 fibrosis Effects 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 230000035899 viability Effects 0.000 description 6
- 125000001054 5 membered carbocyclic group Chemical group 0.000 description 5
- 125000004008 6 membered carbocyclic group Chemical group 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 208000016192 Demyelinating disease Diseases 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- 108010082695 NADPH Oxidase 5 Proteins 0.000 description 5
- 102000004080 NADPH Oxidase 5 Human genes 0.000 description 5
- 101150036847 NOX1 gene Proteins 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 210000004204 blood vessel Anatomy 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 208000010643 digestive system disease Diseases 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 208000005069 pulmonary fibrosis Diseases 0.000 description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 206010012305 Demyelination Diseases 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 4
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 4
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 208000008589 Obesity Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 206010006451 bronchitis Diseases 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000006143 cell culture medium Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 210000001508 eye Anatomy 0.000 description 4
- 208000018685 gastrointestinal system disease Diseases 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000004020 luminiscence type Methods 0.000 description 4
- 210000003470 mitochondria Anatomy 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- 210000005166 vasculature Anatomy 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 3
- 208000017667 Chronic Disease Diseases 0.000 description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 102000003992 Peroxidases Human genes 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 238000003570 cell viability assay Methods 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application 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
- 238000007796 conventional method Methods 0.000 description 3
- 230000001351 cycling effect Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 230000003210 demyelinating effect Effects 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 208000037765 diseases and disorders Diseases 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- OYSLMAQEMAJMCL-UHFFFAOYSA-N ethyl thiophene-3-carboxylate Chemical compound CCOC(=O)C=1C=CSC=1 OYSLMAQEMAJMCL-UHFFFAOYSA-N 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 239000012894 fetal calf serum Substances 0.000 description 3
- 239000012997 ficoll-paque Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 108040007629 peroxidase activity proteins Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000007634 remodeling Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 238000013207 serial dilution Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 150000003577 thiophenes Chemical class 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZHALJTYSCWNFOY-UHFFFAOYSA-N 2-[4-(furan-2-carbonyl)piperazin-1-yl]acetamide Chemical compound C1CN(CC(=O)N)CCN1C(=O)C1=CC=CO1 ZHALJTYSCWNFOY-UHFFFAOYSA-N 0.000 description 2
- MUGSKSNNEORSJG-UHFFFAOYSA-N 3174-74-1 Chemical compound C1CC=CCO1 MUGSKSNNEORSJG-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 206010000599 Acromegaly Diseases 0.000 description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 229920000945 Amylopectin Polymers 0.000 description 2
- 206010003256 Arthritis gonococcal Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 2
- RZZPDXZPRHQOCG-OJAKKHQRSA-O CDP-choline(1+) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-O 0.000 description 2
- 206010051290 Central nervous system lesion Diseases 0.000 description 2
- 201000003883 Cystic fibrosis Diseases 0.000 description 2
- 102100025620 Cytochrome b-245 light chain Human genes 0.000 description 2
- 101710190086 Cytochrome b-245 light chain Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 102100021218 Dual oxidase 1 Human genes 0.000 description 2
- 206010048554 Endothelial dysfunction Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 2
- 208000022461 Glomerular disease Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 101001112229 Homo sapiens Neutrophil cytosol factor 1 Proteins 0.000 description 2
- 101001112224 Homo sapiens Neutrophil cytosol factor 2 Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 201000002980 Hyperparathyroidism Diseases 0.000 description 2
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- 208000003456 Juvenile Arthritis Diseases 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
- 208000016604 Lyme disease Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010061309 Neoplasm progression Diseases 0.000 description 2
- 206010029113 Neovascularisation Diseases 0.000 description 2
- 208000028389 Nerve injury Diseases 0.000 description 2
- 102100023620 Neutrophil cytosol factor 1 Human genes 0.000 description 2
- 102100023618 Neutrophil cytosol factor 2 Human genes 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- 206010039085 Rhinitis allergic Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 2
- 102000019197 Superoxide Dismutase Human genes 0.000 description 2
- 108010012715 Superoxide dismutase Proteins 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 208000037884 allergic airway inflammation Diseases 0.000 description 2
- 201000010105 allergic rhinitis Diseases 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 210000001736 capillary Anatomy 0.000 description 2
- 230000005779 cell damage Effects 0.000 description 2
- 208000037887 cell injury Diseases 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 230000007278 cognition impairment Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 210000003372 endocrine gland Anatomy 0.000 description 2
- 230000008694 endothelial dysfunction Effects 0.000 description 2
- 239000007920 enema Substances 0.000 description 2
- 229940095399 enema Drugs 0.000 description 2
- OAOWLYJFXFPOPW-UHFFFAOYSA-N ethyl 2h-pyran-3-carboxylate Chemical compound CCOC(=O)C1=CC=COC1 OAOWLYJFXFPOPW-UHFFFAOYSA-N 0.000 description 2
- PGQDXCJLWJZQSL-UHFFFAOYSA-N ethyl 5,5-dimethyl-2-[(2-phenylacetyl)amino]-4,7-dihydrothieno[2,3-c]pyran-3-carboxylate Chemical compound S1C=2COC(C)(C)CC=2C(C(=O)OCC)=C1NC(=O)CC1=CC=CC=C1 PGQDXCJLWJZQSL-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 239000012595 freezing medium Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000005265 lung cell Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000009456 molecular mechanism Effects 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 230000008764 nerve damage Effects 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- 201000001119 neuropathy Diseases 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 238000012261 overproduction Methods 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 210000000557 podocyte Anatomy 0.000 description 2
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 230000006697 redox regulation Effects 0.000 description 2
- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 2
- 230000036412 respiratory physiology Effects 0.000 description 2
- 201000002859 sleep apnea Diseases 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- YNVOMSDITJMNET-UHFFFAOYSA-M thiophene-3-carboxylate Chemical compound [O-]C(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-M 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 230000005751 tumor progression Effects 0.000 description 2
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 210000000264 venule Anatomy 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 1
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- JEEWRTJYBDZVBA-UHFFFAOYSA-N 2-benzamido-5,6-dihydro-4h-cyclopenta[b]thiophene-3-carboxylic acid Chemical compound S1C=2CCCC=2C(C(=O)O)=C1NC(=O)C1=CC=CC=C1 JEEWRTJYBDZVBA-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006076 2-ethyl-1-butenyl group Chemical group 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- YTPLMLYBLZKORZ-MICDWDOJSA-N 3-deuteriothiophene Chemical compound [2H]C=1C=CSC=1 YTPLMLYBLZKORZ-MICDWDOJSA-N 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 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 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010053555 Arthritis bacterial Diseases 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 208000012639 Balance disease Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102100025399 Breast cancer type 2 susceptibility protein Human genes 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010006448 Bronchiolitis Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 206010007749 Cataract diabetic Diseases 0.000 description 1
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010008690 Chondrocalcinosis pyrophosphate Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000003849 Cytochrome P450 Human genes 0.000 description 1
- 206010011903 Deafness traumatic Diseases 0.000 description 1
- 206010051055 Deep vein thrombosis 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
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 101100278667 Drosophila melanogaster Duox gene Proteins 0.000 description 1
- 201000009084 Dysgammaglobulinemia Diseases 0.000 description 1
- 206010014498 Embolic stroke Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 201000011275 Epicondylitis Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 206010016207 Familial Mediterranean fever Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000006587 Glutathione peroxidase Human genes 0.000 description 1
- 108700016172 Glutathione peroxidases Proteins 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000009292 Hemophilia A Diseases 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- 206010020877 Hypertrophic osteoarthropathy Diseases 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 208000001019 Inborn Errors Metabolism Diseases 0.000 description 1
- 208000004575 Infectious Arthritis Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 208000034800 Leukoencephalopathies Diseases 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- 208000032376 Lung infection Diseases 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000023637 Multiple injury Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- 208000003926 Myelitis Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 206010028570 Myelopathy Diseases 0.000 description 1
- 101150057734 NOX3 gene Proteins 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 208000005268 Neurogenic Arthropathy Diseases 0.000 description 1
- 206010029326 Neuropathic arthropathy Diseases 0.000 description 1
- 102100023617 Neutrophil cytosol factor 4 Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000002946 Noise-Induced Hearing Loss Diseases 0.000 description 1
- 208000011623 Obstructive Lung disease Diseases 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 201000000023 Osteosclerosis Diseases 0.000 description 1
- 206010033109 Ototoxicity Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 201000002451 Overnutrition Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000006735 Periostitis Diseases 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 102000007456 Peroxiredoxin Human genes 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010065159 Polychondritis Diseases 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 206010036346 Posterior capsule opacification Diseases 0.000 description 1
- 206010036626 Presbyacusis Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 241000872198 Serjania polyphylla Species 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 208000029033 Spinal Cord disease Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 101710197175 Sulfiredoxin Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000018359 Systemic autoimmune disease Diseases 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
- 208000002240 Tennis Elbow Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- AVRWEULSKHQETA-UHFFFAOYSA-N Thiophene-2 Chemical compound S1C=2CCCCCC=2C(C(=O)OC)=C1NC(=O)C1=C(F)C(F)=C(F)C(F)=C1F AVRWEULSKHQETA-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010043647 Thrombotic Stroke Diseases 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010047097 Vascular purpura Diseases 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 108010093894 Xanthine oxidase Proteins 0.000 description 1
- 102100033220 Xanthine oxidase Human genes 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000012801 analytical assay Methods 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 230000027746 artery morphogenesis Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N beta-hydroxyethanesulfonic acid Natural products OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 201000003163 breast adenoma Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000030570 cellular localization Effects 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- PRQROPMIIGLWRP-BZSNNMDCSA-N chemotactic peptide Chemical compound CSCC[C@H](NC=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PRQROPMIIGLWRP-BZSNNMDCSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 208000002849 chondrocalcinosis Diseases 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000007025 diabetic cataract Diseases 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 201000002664 drug-induced hearing loss Diseases 0.000 description 1
- 238000001378 electrochemiluminescence detection Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 230000005283 ground state Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 210000003566 hemangioblast Anatomy 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 201000008298 histiocytosis Diseases 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 208000016245 inborn errors of metabolism Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 208000015978 inherited metabolic disease Diseases 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000003733 intussusceptive angiogenesis Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000023569 ischemic bowel disease Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 201000004990 juvenile ankylosing spondylitis Diseases 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 208000036546 leukodystrophy Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 230000035168 lymphangiogenesis Effects 0.000 description 1
- 208000012804 lymphangiosarcoma Diseases 0.000 description 1
- 210000005073 lymphatic endothelial cell Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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 Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000004216 mammary stem cell Anatomy 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 210000003584 mesangial cell Anatomy 0.000 description 1
- 230000004066 metabolic change Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 230000023105 myelination Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001338 necrotic effect Effects 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
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 108010086154 neutrophil cytosol factor 40K Proteins 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 231100000262 ototoxicity Toxicity 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 235000020823 overnutrition Nutrition 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 210000003460 periosteum Anatomy 0.000 description 1
- 108030002458 peroxiredoxin Proteins 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 150000003219 pyrazolines Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound 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
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 208000009169 relapsing polychondritis Diseases 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000003307 reticuloendothelial effect Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 201000007321 sebaceous carcinoma Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 208000007056 sickle cell anemia Diseases 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000003839 sprouting angiogenesis Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 201000010965 sweat gland carcinoma Diseases 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 230000001720 vestibular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Reproductive Health (AREA)
- Physical Education & Sports Medicine (AREA)
- Emergency Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Dermatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Aは、5員−または6員−複素環または炭素環であり;
Bは、5員−または6員−単環式複素環または炭素環および9員−または10員−二環式複素環または炭素環から選択され;
各R1は、独立してハロゲン、R4O(CH2)q、R4S(CH2)q、R4R5N(CH2)q、CN(CH2)q、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され、それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
R2は、H、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され、それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
各R3は、独立してハロゲン、R6O(CH2)w、R6S(CH2)w、R6C(O)(CH2)w、R6S(O)2(CH2)w、R6OC(O)(CH2)w、R6C(O)O(CH2)w、R6OC(O)O(CH2)w、R6OC(O)(CH2)w、R6C(O)O(CH2)w、R6OC(O)O(CH2)w、R8R9N(CH2)w、R8R9NC(O)(CH2)w、R8R9NS(O)2(CH2)w、CN(CH2)w、R7(CH2)w、C1−C6アルキル、C2−C6アルケニル、およびC2−C6アルキニルから選択され、それらのアルキル、アルケニルおよびアルキニルは所望により少なくとも1個のハロゲンで置換されていてもよく;
各R4は、独立してH、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され;それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
各R5は、独立してH、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され;それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
各R6は、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、および5員−または6員−複素環または炭素環から選択され、それらのアルキル、アルケニル、アルキニル、複素環および炭素環は所望により少なくとも1個のハロゲンで置換されていてもよく;
各R7は、5員−もしくは6員−単環式複素環もしくは炭素環または9員−もしくは10員−二環式複素環もしくは炭素環から選択され、それらの複素環および炭素環は所望により少なくとも1個のハロゲンで置換されていてもよく;
各R8は、独立してH、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され;
各R9は、独立してH、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され;
m、n、p、各qおよび各wは、独立して0、1、2および3から選択される]
またはその医薬的に許容できる塩であって、Nox、好ましくはNox4と関連する状態または障害の処置に使用するための化合物が提供される。
2−(4−(tert−ブチル)ベンズアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸メチル、
2−(ベンゾフラン−2−カルボキサミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−(4−(tert−ブチル)ベンズアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸エチル、
2−(3,5−ジメトキシベンズアミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−(4−クロロベンズアミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−(2−フルオロベンズアミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−ベンズアミド−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−(5−(ベンゾ[d][1,3]ジオキソール−5−イル)−7−(トリフルオロメチル)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリミジン−3−カルボキサミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−(5−(ベンゾ[d][1,3]ジオキソール−5−イル)−7−(トリフルオロメチル)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリミジン−2−カルボキサミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
6−メチル−2−(5−フェニル−7−(トリフルオロメチル)−4,5,6,7−テトラヒドロピラゾロ[1,5−a]ピリミジン−2−カルボキサミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸エチル、
2−(3−モルホリノプロパンアミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸メチル、
6−メチル−2−(3−(4−メチルピペリジン−1−イル)プロパンアミド)−4,5,6,7−テトラヒドロベンゾ[b]−チオフェン−3−カルボン酸エチル、
2−(4−(ピペリジン−1−イルスルホニル)ベンズアミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−(2−(2,6−ジメチルモルホリノ)アセトアミド)−6−メチル−4,5,6,7−テトラヒドロベンゾ[b]−チオフェン−3−カルボン酸エチル、
2−(フラン−2−カルボキサミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸メチル、
2−(2−(2,4−ジクロロフェニル)−3−メチルキノリン−4−カルボキサミド)−6−メチル−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸プロピル、
5,5−ジメチル−2−(3−モルホリノプロパンアミド)−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、
5,5−ジメチル−2−(2−フェニルアセトアミド)−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸、
2−(2−モルホリノアセトアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸エチル、
2−(2−(3,4−ジメトキシフェニル)アセトアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸イソプロピル、または
2−(ニコチンアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸エチル;
これらはWO 2005/033102に述べられたものである。
A、R1、R2、R3、mおよびnは、本明細書中で前記に定めたものであり;
Q1、Q2およびQ3は、独立してC、N、OおよびSから選択され;
tは、1または2であり;
p1およびp2は、p1+p2が0〜3となるような0〜3の整数である。
Q1およびQ2のうち一方はヘテロ原子であり、他方はCである。
A、R1、R2、R3、mおよびnは、本明細書中で前記に定めたものであり;
R10は、HまたはR3であり;
R10がHである場合にはp3は0から3までの整数であり、R10がR3である場合にはp3は0から2までの整数である。
Aは、5員−または6員−モノ不飽和複素環または炭素環であり;
Bは、5員−または6員−単環式複素環または炭素環および9員−または10員−二環式複素環または炭素環から選択され;
各R1は、独立してハロゲン、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され、それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
R2は、H、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され、それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
R3は、ハロゲン、R6O(CH2)q、R6S(CH2)q、R6C(O)(CH2)q、R7(CH2)q、C1−C6アルキル、C2−C6アルケニル、およびC2−C6アルキニルから選択され、それらのアルキル、アルケニルおよびアルキニルは所望により少なくとも1個のハロゲンで置換されていてもよく;
nは、0または1である。
またはこれらのいずれかの医薬的に許容できる塩。
2−(2−(4−ベンジルピペラジン−1−イル)アセトアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸エチル、
2−(2−(4−(フラン−2−カルボニル)ピペラジン−1−イル)アセトアミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−(ベンゾフラン−2−カルボキサミド)−5,5−ジメチル−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、
5,5−ジメチル−2−(2−フェニルアセトアミド)−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、および
2−(4−メトキシベンズアミド)−5,5−ジメチル−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、
またはこれらのいずれかの医薬的に許容できる塩。
(A)本明細書に定める本発明化合物;および
(B)他の療法剤;
その際、(A)および(B)を医薬的に許容できる賦形剤との混合物中に配合する。
(1)前記に定めた本発明化合物、他の療法剤、および医薬的に許容できる賦形剤、たとえば佐剤、希釈剤またはキャリヤーを含有する、医薬配合物;ならびに
(2)構成要素として下記のものを含む部分のキット:
(a)前記に定めた本発明化合物を、医薬的に許容できる賦形剤、たとえば佐剤、希釈剤またはキャリヤーと混合したものを含有する、医薬配合物;ならびに
(b)他の療法剤を、医薬的に許容できる賦形剤、たとえば佐剤、希釈剤またはキャリヤーと混合したものを含有する、医薬配合物;
それらの構成要素(a)および(b)は、他方と組み合わせて投与するのに適した形態でそれぞれ提供される。
細胞ベースのアッセイおよび分析化学
1 細胞生存性
1.1 Celltiter−Blue細胞生存性アッセイ(Promega)
このアッセイは、生存性の尺度として細胞がレサズリン(resazurin)を還元してレゾルフィン(resorufin)にする能力に基づく。TREx(商標)−293 Nox4細胞をT−225フラスコ内で培養し、トリプシン処理により採集し、細胞培地に再懸濁した。90μl中20,000個の細胞を96ウェルの細胞培養プレート(透明な底を備えた黒色のもの)に播種した。90μlの細胞培地のみを含むバックグラウンドプレートも1つ用意した。
このアッセイは、膜の統合性の尺度として周囲の細胞培地における乳酸デヒドロゲナーゼ(LDH)活性に基づく。膜の統合性はアポトーシス、ネクローシスまたは化学物質による影響を受ける可能性がある。TREx(商標)−293 Nox4細胞をT−225フラスコ内で培養し、トリプシン処理により採集し、HBSSに再懸濁して100,000個/mlにした。90μlの細胞懸濁液をV底ポリプロピレン製96ウェルプレートの各ウェルに添加した。HBSSのみを含むバックグラウンドプレートを1つ用意した。化合物をHBSSに希釈して最終濃度の10倍にし、10μlを各ウェルに添加した。化合物を10μMの最終濃度で二重に試験した。
[(実験量-自然量)/(総量-自然量)]*100%
上記2種類の細胞生存性アッセイで試験した場合、本発明化合物はいずれも有意の細胞毒性を示さなかった。
Amplex(登録商標)Redベースのアッセイによる用量応答測定を下記に従って実施した:化合物の系列希釈を、リキッドハンドラーJanus(登録商標)(Perkin Elmer)およびスケジューリングソフトウェアOverlord(Process Analysis and Automation)に基づくシステムを用いて実施した。
DMSO溶液をPBS,pH7.4中に希釈して最終濃度100μMにした。2種類の試料を調製した:1つは即時分析用、2つ目は37℃で24時間の貯蔵用。UVおよびESI−MS検出を備えた逆相HPLCシステムで分析を実施した。純度を220nmにおける試料ピークの相対面積と定義した。同一性を試料クロマトグラムのMSにおける分子イオンの存在により判定した。安定性は、24時間後の試料ピークと0時間目のクロマトグラムのものとの相対面積の比であった。純度および安定性の数値を切り捨てて10%増分でレポートした(すなわち、96%を90%とレポートする)。IPS分析において、被験化合物はプラスの同一性をもち、90%以上の純度であり、80%以上の安定性をもっていた。
Nox2に対する本発明化合物の活性
本発明化合物のNox4特異性を評価するために、多数の本発明化合物をNox2からの反応性酸素種(ROS)産生に対するそれらの潜在阻害作用について試験した。
PLB985細胞(ヒト急性骨髄性白血病細胞系)およびヒト末梢血単核細胞(PBMC)において、ホルボール12−ミリステート 13−アセテート(PMA)(30ng/ml)による刺激後のNox2からのROS産生阻害を、イソルミノール増強化学発光により評価した。本発明化合物およびジフェニレンヨードニウムクロリド(DPI)を、200μMから0,01μMまでの3倍希釈シリーズにおいて力価判定した。すべての試料を二重試験として分析した。
2.1 イソルミノールアッセイ
イソルミノール依存性化学発光(Dahlgren et al. 1999)を用いてROSを測定した。イソルミノールは、生体膜を通過できない疎水性色素である。したがって、この方法を用いて細胞外ROSが測定される。イソルミノールはROSによって励起され、励起された分子が基底状態に戻る際に放出ROSの量に比例して発する光を測定する。この反応はペルオキシダーゼにより触媒および増幅される。天然ペルオキシダーゼはこれを行なうことができるが、それの分泌は限られており、したがって追加のペルオキシダーゼ(この場合には西洋わさびペルオキシダーゼII)を添加する必要がある。
FluoStar Optima(BMG Labtech)および白色96ウェルプレートを用いて発光を検出した。測定は67秒で23サイクル、37℃で振とうしながら行なわれた。これら23サイクルから曲線下面積(AUC)値を計算した。結果を阻害剤無添加のPMA刺激細胞と比較した変化率として評価した。非線形回帰およびIC50計算をMac OS X用のPrism 5により実施した。
3.1 ヒトPBMC
人血を1日目のバフィーコートでKomponentlab, Sahlgrenska University hospital(スウェーデン、ゲーテボルグ)から購入した。
赤血球を全血からデキストラン沈降により除去した。無赤血球画分を、Ficoll−Paque Plus(0.75mg/mlのNaClを補充)を用いて製造業者の指示に従って密度勾配により分離した。PBMCを血漿とFicoll−Paque Plus試薬の界面から単離した。このPBMCを混在血小板が除去されるまでHBSS中で洗浄した。細胞数および生存性をトリパンブルー排除により判定した。
細胞をKreher et al. 2003に従って凍結保存した。要約すると、単離した細胞を20×106個/mlで室温の凍結用媒体A(60%のウシ胎仔血清,40%のRPMI 1640)に再懸濁した。等容量の室温の凍結用媒体B(20%のDMSO,80%のウシ胎仔血清)を滴加した。15×106個の細胞を凍結チューブに小分けし、予冷した(4℃)のCryogenic Controlled−Rate Freezing Containerに入れて−80℃に置いた。24時間後、試料を長期保存用の−150℃のフリーザーへ移した。
細胞を37℃の水浴内で迅速に融解し、室温のHBSSにピペットで装入し、遠心した(250×g,20℃,5分間)。HBSS中での洗浄(2×)後、細胞をHBSSに2×106個/mlの濃度で再懸濁した。細胞数および生存性をトリパンブルー排除により判定した。アッセイプレート当たり1つのバイアルを用い、分析直前に融解および調製した。
総細胞数(バイアル当たり):9〜9.75×106個
生存性:92〜95%
アッセイ濃度生存細胞:2×106個/ml
3.2 PLB985
PLB985細胞を、10%のウシ胎仔血清(FBS)およびペニシリン/ストレプトマイシン100U/mlを補充したRPMI 1640(=完全増殖培地)中、37℃、5% CO2で培養した。細胞をほぼ週2回、継代した。好中球へ分化させるために、細胞を遠心沈降させ(250g,5分間,室温)、1.25%のDMSOを補充した完全増殖培地に5日間、再懸濁しておいた(Zhen et al.1993, Tucker et al.1987)。分析当日に、分化した細胞をペレット化し(250g,5分間,室温)、HBSS中で2回洗浄し、HBSS中に2×106個/mlで再懸濁した。細胞数および生存性をトリパンブルー排除により判定した。細胞を使用時まで室温に保存した。
総細胞数:94×106個
生存性:92%
アッセイ濃度生存細胞:2×106個/ml
3.3 試薬
アッセイプレート,白色96ウェル(Nunc 236108)
デキストランT500(Pharmacosmos 5510 0500 4006)
DMSO(Sigma: D5879)
DPI
ウシ胎仔血清(VWR: LONZ14-801F)
Ficoll Paque Plus (GE Healthcare 71-7167-00)
fMLF(Sigma: F3506)
HBSS(自家調製: 5.4mM KCl, 0.3mM Na2HPO4×2H2O, 0.4mM KH2PO4, 4.2mM NaHCO3, 1.3mM CaCl2×2H2O, 0.5mM MgCl2×6H2O, 0.6mM MgSO4×7H2O, 137mM NaCl, 5.6mM D-グルコース)
HRP画分II(Sigma P8250)
イソルミノール(4-アミノフタルヒドラジド) (Sigma A8264)
PMA(Sigma P8139)
RPMI 1640(VWR: LONZ12-702F/12)
3.4 被験化合物
本発明化合物の100mM DMSO原液を試験に用いた。
イソルミノール緩衝液は、イソルミノール(0,0175mg/ml)およびHRP画分II(1,75U/ml)を含有する。この緩衝液は、これらの成分を4×作業濃度でHBSS中に希釈することにより調製された。
4.1 物質調製
被験化合物をDMSO中に100×作業濃度で希釈し、最終濃度として200μMから0.01μMまでの3倍希釈系列で力価判定した。DPIを100×作業濃度に希釈し、被験化合物と同じ希釈系列で力価判定した。DPIも1μMの最終濃度ですべてのプレートに対照として用いた。その際、DMSO中に100×作業濃度で希釈を行なった。PMAをイソルミノール緩衝液中に4×作業濃度で希釈した。
イソルミノール緩衝液中に4×作業濃度に希釈した25μlのPMAを各ウェルに添加した。非刺激対照ウェルにはイソルミノール緩衝液のみを添加した。その後、24μlのHBSS、および1μlの被験溶液またはDPI溶液を、試験プレートの各ウェルに添加した(最終DMSO濃度=1.25%)。最後に、50μlの細胞懸濁液(2×106個/ml)を各ウェルに添加し、続いて直ちに発光測定を開始した。
結果を、PMAの存在下での発光と比較した指定濃度の被験物質の存在下で得られた発光の%として表わす。図2AおよびBならびに図3AおよびBに、若干の本発明化合物についての結果を示す。
発作の処置における活性のインビボ試験
発作モデル
この例に用いた発作疾患モデルは、虚血発作のメカニズムを模倣するために一過性中大脳動脈閉塞(transient middle cerebral artery occlusion)(tMCAO)を施したマウスであった。先の記載に従って体重20gの雄マウスに60分間のtMCAOを施した(Elevers M et al., Sci. Signal 3: ra1, 2010; Bena_Erro A et al., Sci Signal 2: ra67)。擬似手術したマウスを対照として用いた。
この試験で行なった腹腔内投与のために、3.5mgの2−(2−(4−(フラン−2−カルボニル)ピペラジン−1−イル)アセトアミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチルを1mlのDMSOおよび5mlのPBS中20% Cremophor ELPに溶解し、続いてPBSを追加した。実験に用いた投与量は3.2mg/kgであり、対照には同じ注射容量のビヒクルを用いた。投与を各マウスに2時間目および12時間目に行なった。
梗塞サイズおよびNox4阻害剤の効果を判定するために、マウスをtCMCAOの24時間後にと殺し、脳の病変体積を先に記載された方法に従って測定した(Kleinschnitz et al, 前記参照)。
本発明化合物で処置したグループのマウスは有意に低い脳病変体積を示した(図4)。
Claims (16)
- 式(I)の化合物
Aは、5員−または6員−複素環または炭素環であり;
Bは、5員−または6員−単環式複素環または炭素環および9員−または10員−二環式複素環または炭素環から選択され;
各R1は、独立してハロゲン、R4O(CH2)q、R4S(CH2)q、R4R5N(CH2)q、CN(CH2)q、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され、それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
R2は、H、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され、それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
各R3は、ハロゲン、R6O(CH2)w、R6S(CH2)w、R6C(O)(CH2)w、R6S(O)2(CH2)w、R6OC(O)(CH2)w、R6C(O)O(CH2)w、R6OC(O)O(CH2)w、R6OC(O)(CH2)w、R6C(O)O(CH2)w、R6OC(O)O(CH2)w、R8R9N(CH2)w、R8R9NC(O)(CH2)w、R8R9NS(O)2(CH2)w、CN(CH2)w、R7(CH2)w、C1−C6アルキル、C2−C6アルケニル、およびC2−C6アルキニルから選択され、それらのアルキル、アルケニルおよびアルキニルは所望により少なくとも1個のハロゲンで置換されていてもよく;
各R4は、独立してH、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され;それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
各R5は、独立してH、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され;それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
各R6は、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、および5員−または6員−複素環または炭素環から選択され、それらのアルキル、アルケニル、アルキニル、複素環および炭素環は所望により少なくとも1個のハロゲンで置換されていてもよく;
各R7は、5員−もしくは6員−単環式複素環もしくは炭素環または9員−もしくは10員−二環式複素環もしくは炭素環から選択され、それらの複素環および炭素環は所望により少なくとも1個のハロゲンで置換されていてもよく;
各R8は、独立してH、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され;
各R9は、独立してH、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され;
m、n、p、各qおよび各wは、独立して0、1、2および3から選択される]
またはその医薬的に許容できる塩であって、
内分泌障害、心血管障害、呼吸器障害、代謝障害、皮膚障害、骨障害、神経炎症性および/または神経変性性の障害、腎疾患、生殖障害、眼および/または水晶体を冒す疾患、ならびに/あるいは内耳を冒す状態、炎症性障害、肝疾患、痛み、癌、たとえば肺癌、アレルギー性障害、外傷性障害、敗血症性、出血性およびアナフィラキシー性のショック、胃腸系の疾患または障害、血管新生、血管新生依存性状態、肺感染症、急性肺傷害、肺動脈性高血圧症、閉塞性肺障害、脳血管偶発症候、ならびに線維性肺疾患から選択される、ニコチンアミドアデニンジヌクレオチドリン酸オキシダーゼに関連する状態または障害の処置に使用するための化合物。 - Aは、モノ不飽和5員−または6員−複素環または炭素環である、請求項1に記載の化合物またはその医薬的に許容できる塩。
- Bは、5員−または6員−単環式複素環および9員−または10員−二環式複素環から選択される、請求項1もしくは2に記載の化合物またはその医薬的に許容できる塩。
- Bは、5員−または6員−単環式複素環である、請求項3に記載の化合物またはその医薬的に許容できる塩。
- Bは、5員−または6員−単環式複素環または炭素環である、請求項1もしくは2に記載の化合物またはその医薬的に許容できる塩。
- 各R1は、独立してハロゲン、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され、それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよい、請求項1〜5のいずれか1項に記載の化合物またはその医薬的に許容できる塩。
- R2は、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され、それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよい、請求項1〜6のいずれか1項に記載の化合物またはその医薬的に許容できる塩。
- 各R3は、ハロゲン、R6O(CH2)q、R6S(CH2)q、R6C(O)(CH2)q、R7(CH2)q、C1−C6アルキル、C2−C6アルケニル、およびC2−C6アルキニルから選択され、それらのアルキル、アルケニルおよびアルキニルは所望により少なくとも1個のハロゲンで置換されていてもよい、請求項1〜7のいずれか1項に記載の化合物またはその医薬的に許容できる塩。
- nは0または1である、請求項1〜8のいずれか1項に記載の化合物またはその医薬的に許容できる塩。
- nは1である、請求項9に記載の化合物またはその医薬的に許容できる塩。
- Aは、5員−または6員−モノ不飽和複素環または炭素環であり;
Bは、5員−または6員−単環式複素環または炭素環および9員−または10員−二環式複素環から選択され;
各R1は、独立してハロゲン、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され、それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
R2は、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、およびC3−C6シクロアルキルから選択され、それらのアルキル、アルケニル、アルキニルおよびシクロアルキルは所望により少なくとも1個のハロゲンで置換されていてもよく;
R3は、ハロゲン、R6O(CH2)q、R6S(CH2)q、R6C(O)(CH2)q、R7(CH2)q、C1−C6アルキル、C2−C6アルケニル、およびC2−C6アルキニルから選択され、それらのアルキル、アルケニルおよびアルキニルは所望により少なくとも1個のハロゲンで置換されていてもよく;
nは0または1である、
請求項1に記載の化合物またはその医薬的に許容できる塩。 - 2−(2−(4−ベンジルピペラジン−1−イル)アセトアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸エチル、
2−(2−(4−(フラン−2−カルボニル)ピペラジン−1−イル)アセトアミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−(ベンゾフラン−2−カルボキサミド)−5,5−ジメチル−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、
5,5−ジメチル−2−(2−フェニルアセトアミド)−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、および
2−(4−メトキシベンズアミド)−5,5−ジメチル−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、
から選択される、請求項1に記載の化合物またはその医薬的に許容できる塩。 - 障害または状態が糖尿病である、請求項1〜12のいずれか1項に記載の化合物またはその医薬的に許容できる塩。
- 障害または状態が脳血管偶発症候である、請求項1〜12のいずれか1項に記載の化合物またはその医薬的に許容できる塩。
- 療法に使用するための、
2−(2−(4−ベンジルピペラジン−1−イル)アセトアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸エチル、
2−(2−(4−(フラン−2−カルボニル)ピペラジン−1−イル)アセトアミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−(ベンゾフラン−2−カルボキサミド)−5,5−ジメチル−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、
5,5−ジメチル−2−(2−フェニルアセトアミド)−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、および
2−(4−メトキシベンズアミド)−5,5−ジメチル−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、
から選択される化合物またはその医薬的に許容できる塩。 - 2−(2−(4−ベンジルピペラジン−1−イル)アセトアミド)−4,5,6,7−テトラヒドロベンゾ[b]チオフェン−3−カルボン酸エチル、
2−(2−(4−(フラン−2−カルボニル)ピペラジン−1−イル)アセトアミド)−5,6−ジヒドロ−4H−シクロペンタ[b]チオフェン−3−カルボン酸エチル、
2−(ベンゾフラン−2−カルボキサミド)−5,5−ジメチル−5,7−ジヒドロ−4H−チエノ[2,3−c]ピラン−3−カルボン酸エチル、
から選択される化合物またはその医薬的に許容できる塩、および所望により少なくとも1種類の医薬的に許容できる賦形剤を含む、医薬組成物。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261611684P | 2012-03-16 | 2012-03-16 | |
EP12159969 | 2012-03-16 | ||
US61/611,684 | 2012-03-16 | ||
EP12159969.0 | 2012-03-16 | ||
US201261697879P | 2012-09-07 | 2012-09-07 | |
US61/697,879 | 2012-09-07 | ||
PCT/EP2013/055218 WO2013135803A1 (en) | 2012-03-16 | 2013-03-14 | Thiophene-based compounds exhibiting nox4 inhibitory activity and use thereof in therapy |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2015509969A true JP2015509969A (ja) | 2015-04-02 |
Family
ID=49160281
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014561449A Pending JP2015509969A (ja) | 2012-03-16 | 2013-03-14 | Nox4阻害活性を示すチオフェン−ベースの化合物および療法におけるその使用 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20150051220A1 (ja) |
EP (1) | EP2825165A1 (ja) |
JP (1) | JP2015509969A (ja) |
CN (1) | CN104487070A (ja) |
CA (1) | CA2867412A1 (ja) |
IN (1) | IN2014DN08368A (ja) |
WO (1) | WO2013135803A1 (ja) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030232994A1 (en) * | 2001-10-04 | 2003-12-18 | Shao-Po Lu | Bicyclic thiophene derivatives and combinatorial libraries thereof |
WO2006007864A1 (en) * | 2004-07-17 | 2006-01-26 | Max Planck Geselllschaft Zur Förderung Der Wissenschaft | Treating neurodegenerative conditions |
JP2007507530A (ja) * | 2003-10-03 | 2007-03-29 | アンフォラ ディスカバリー コーポレーション | Atp利用酵素阻害活性を示すチオフェンベース化合物、組成物、およびその使用 |
WO2008028094A1 (en) * | 2006-08-31 | 2008-03-06 | Abbott Laboratories | Compounds as cb2 cannabinoid receptor ligands |
JP2011507910A (ja) * | 2007-12-21 | 2011-03-10 | ユニバーシティー オブ ロチェスター | 真核生物の寿命を変更するための方法 |
WO2011097607A1 (en) * | 2010-02-08 | 2011-08-11 | Southern Research Institute | Anti-viral treatment and assay to screen for anti-viral agent |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE422887T1 (de) * | 2001-05-04 | 2009-03-15 | Amgen Inc | Kondensierte heterozyklische verbindungen |
SE0300988D0 (sv) * | 2003-04-03 | 2003-04-03 | Astrazeneca Ab | New use |
US7501405B2 (en) * | 2003-04-11 | 2009-03-10 | High Point Pharmaceuticals, Llc | Combination therapy using an 11β-hydroxysteroid dehydrogenase type 1 inhibitor and an antihypertensive agent for the treatment of metabolic syndrome and related diseases and disorders |
US20060089374A1 (en) * | 2003-07-17 | 2006-04-27 | Glenn Cornett | Enantiomeric compositions of cicletanine, alone and in combination with other agents, for the treatment of disease |
PE20110235A1 (es) * | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
EP2305679A1 (en) * | 2009-09-28 | 2011-04-06 | GenKyoTex SA | Pyrazoline dione derivatives as nadph oxidase inhibitors |
-
2013
- 2013-03-14 CA CA2867412A patent/CA2867412A1/en not_active Abandoned
- 2013-03-14 EP EP13709123.7A patent/EP2825165A1/en not_active Withdrawn
- 2013-03-14 WO PCT/EP2013/055218 patent/WO2013135803A1/en active Application Filing
- 2013-03-14 US US14/385,541 patent/US20150051220A1/en not_active Abandoned
- 2013-03-14 IN IN8368DEN2014 patent/IN2014DN08368A/en unknown
- 2013-03-14 JP JP2014561449A patent/JP2015509969A/ja active Pending
- 2013-03-14 CN CN201380025277.3A patent/CN104487070A/zh active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030232994A1 (en) * | 2001-10-04 | 2003-12-18 | Shao-Po Lu | Bicyclic thiophene derivatives and combinatorial libraries thereof |
JP2007507530A (ja) * | 2003-10-03 | 2007-03-29 | アンフォラ ディスカバリー コーポレーション | Atp利用酵素阻害活性を示すチオフェンベース化合物、組成物、およびその使用 |
WO2006007864A1 (en) * | 2004-07-17 | 2006-01-26 | Max Planck Geselllschaft Zur Förderung Der Wissenschaft | Treating neurodegenerative conditions |
WO2008028094A1 (en) * | 2006-08-31 | 2008-03-06 | Abbott Laboratories | Compounds as cb2 cannabinoid receptor ligands |
JP2011507910A (ja) * | 2007-12-21 | 2011-03-10 | ユニバーシティー オブ ロチェスター | 真核生物の寿命を変更するための方法 |
WO2011097607A1 (en) * | 2010-02-08 | 2011-08-11 | Southern Research Institute | Anti-viral treatment and assay to screen for anti-viral agent |
Non-Patent Citations (4)
Title |
---|
AL-OBAID A. M., PHARMAZIE, vol. V53 N1, JPN5015004823, 1998, DE, pages 24 - 28, ISSN: 0003407957 * |
GADAD A. K., INDIAN JOURNAL OF CHEMISTRY, vol. V33B N3, JPN5015004824, March 1994 (1994-03-01), IN, pages 298 - 301, ISSN: 0003407958 * |
MKRTCHYAN A. P., CHEMISTRY OF HETEROCYCLIC COMPOUNDS, vol. V38 N2, JPN5015004820, 2002, pages 238 - 241, ISSN: 0003407955 * |
MKRTCHYAN A. P., PHARMACEUTICAL CHEMISTRY JOURNAL, vol. V18 N4, JPN5015004821, 1984, pages 268 - 271, ISSN: 0003407956 * |
Also Published As
Publication number | Publication date |
---|---|
CA2867412A1 (en) | 2013-09-19 |
EP2825165A1 (en) | 2015-01-21 |
WO2013135803A1 (en) | 2013-09-19 |
CN104487070A (zh) | 2015-04-01 |
IN2014DN08368A (ja) | 2015-05-08 |
US20150051220A1 (en) | 2015-02-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4500055B2 (ja) | ピラゾロ[1,5−a]ピリミジン誘導体およびそれを含有するNAD(P)Hオキシダーゼ阻害剤 | |
CN102159573B (zh) | 作为nadph氧化酶抑制剂的吡唑并吡啶衍生物 | |
JP6376707B2 (ja) | サーチュイン調節剤としての置換架橋尿素類似体 | |
CN102137862A (zh) | 作为nadph氧化酶抑制剂的吡唑并吡啶衍生物 | |
CN102137863A (zh) | 作为nadph氧化酶抑制剂的吡唑并吡啶衍生物 | |
EP2911667B1 (en) | Triazine derivatives for the treatment of conditions associated with nicotinamide adenine dinucleotide phosphate oxidase | |
JP7455762B2 (ja) | 選択的なNox阻害活性を有する新規のスルホンアミド誘導体 | |
JP6768662B2 (ja) | Nadphオキシダーゼに関連する状態の処置に使用するための化合物 | |
JP2015509969A (ja) | Nox4阻害活性を示すチオフェン−ベースの化合物および療法におけるその使用 | |
US10173988B2 (en) | N2-(3,4-dimethylphenyl)-6-((4-(p-tolyl)piperazin-1-yl)methyl)-1,3,5-triazine-2,4-diamine | |
RU2809030C2 (ru) | Новые производные сульфонамида, обладающие селективной nox-ингибирующей активностью | |
US20110288176A1 (en) | Ethacrynic acid-containing composition for prevention or treatment of transglutaminase-related diseases and method for prevention or treatment of transglutaminase-related diseases using the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20160310 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20160921 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160928 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20161220 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20170522 |