CN109843279A - 包含ssao/vap-1抑制剂和sglt2抑制剂的药物组合、其用途 - Google Patents
包含ssao/vap-1抑制剂和sglt2抑制剂的药物组合、其用途 Download PDFInfo
- Publication number
- CN109843279A CN109843279A CN201780063937.5A CN201780063937A CN109843279A CN 109843279 A CN109843279 A CN 109843279A CN 201780063937 A CN201780063937 A CN 201780063937A CN 109843279 A CN109843279 A CN 109843279A
- Authority
- CN
- China
- Prior art keywords
- inhibitor
- pharmaceutical composition
- disease
- aminomethyl
- ssao
- 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
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 84
- 102100027159 Membrane primary amine oxidase Human genes 0.000 title claims abstract description 80
- 101710132836 Membrane primary amine oxidase Proteins 0.000 title claims abstract description 80
- 239000003112 inhibitor Substances 0.000 title claims abstract description 67
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 claims abstract description 56
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 48
- 230000003405 preventing effect Effects 0.000 claims abstract description 21
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 18
- 201000011510 cancer Diseases 0.000 claims abstract description 14
- 206010061218 Inflammation Diseases 0.000 claims abstract description 12
- 230000004054 inflammatory process Effects 0.000 claims abstract description 12
- 208000030533 eye disease Diseases 0.000 claims abstract description 11
- 201000001880 Sexual dysfunction Diseases 0.000 claims abstract description 5
- 231100000872 sexual dysfunction Toxicity 0.000 claims abstract description 5
- 208000035475 disorder Diseases 0.000 claims abstract 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 52
- 201000010099 disease Diseases 0.000 claims description 40
- 206010022489 Insulin Resistance Diseases 0.000 claims description 32
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 30
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
- 239000011737 fluorine Substances 0.000 claims description 29
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 21
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 20
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 18
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 17
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 15
- 206010056997 Impaired fasting glucose Diseases 0.000 claims description 15
- 208000004930 Fatty Liver Diseases 0.000 claims description 13
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 13
- 208000001280 Prediabetic State Diseases 0.000 claims description 13
- 208000010706 fatty liver disease Diseases 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 230000008859 change Effects 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 206010016654 Fibrosis Diseases 0.000 claims description 10
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 239000001301 oxygen Chemical group 0.000 claims description 9
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 9
- 229940126842 sergliflozin Drugs 0.000 claims description 9
- HFLCZNNDZKKXCS-OUUBHVDSSA-N sergliflozin Chemical compound C1=CC(OC)=CC=C1CC1=CC=CC=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HFLCZNNDZKKXCS-OUUBHVDSSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 230000004761 fibrosis Effects 0.000 claims description 8
- 201000001421 hyperglycemia Diseases 0.000 claims description 8
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 8
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 229960003834 dapagliflozin Drugs 0.000 claims description 7
- ZXOCGDDVNPDRIW-NHFZGCSJSA-N Tofogliflozin Chemical compound O.C1=CC(CC)=CC=C1CC1=CC=C(CO[C@@]23[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C2=C1 ZXOCGDDVNPDRIW-NHFZGCSJSA-N 0.000 claims description 6
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 6
- 229950000991 ipragliflozin Drugs 0.000 claims description 6
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 claims description 6
- 230000004060 metabolic process Effects 0.000 claims description 6
- 229950006667 tofogliflozin Drugs 0.000 claims description 6
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 230000006698 induction Effects 0.000 claims description 5
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Chemical group 0.000 claims description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 3
- 210000001367 artery Anatomy 0.000 claims description 3
- 229960001713 canagliflozin Drugs 0.000 claims description 3
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 claims description 3
- 239000000835 fiber Substances 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 208000009928 nephrosis Diseases 0.000 claims description 3
- 231100001027 nephrosis Toxicity 0.000 claims description 3
- 231100000419 toxicity Toxicity 0.000 claims description 3
- 230000001988 toxicity Effects 0.000 claims description 3
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 2
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 2
- 208000002177 Cataract Diseases 0.000 claims description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 2
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 2
- 206010023421 Kidney fibrosis Diseases 0.000 claims description 2
- 206010054805 Macroangiopathy Diseases 0.000 claims description 2
- 208000034189 Sclerosis Diseases 0.000 claims description 2
- 208000007718 Stable Angina Diseases 0.000 claims description 2
- 208000007814 Unstable Angina Diseases 0.000 claims description 2
- 230000007882 cirrhosis Effects 0.000 claims description 2
- 206010061989 glomerulosclerosis Diseases 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- 210000004072 lung Anatomy 0.000 claims description 2
- 230000007170 pathology Effects 0.000 claims description 2
- 230000033764 rhythmic process Effects 0.000 claims description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 2
- 206010056340 Diabetic ulcer Diseases 0.000 claims 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims 1
- 206010025482 malaise Diseases 0.000 claims 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 65
- 239000008103 glucose Substances 0.000 description 64
- 150000001875 compounds Chemical class 0.000 description 54
- 210000004369 blood Anatomy 0.000 description 34
- 239000008280 blood Substances 0.000 description 34
- 239000000203 mixture Substances 0.000 description 32
- 235000001727 glucose Nutrition 0.000 description 31
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 27
- 238000011282 treatment Methods 0.000 description 24
- 210000002381 plasma Anatomy 0.000 description 21
- -1 4- methyl amyl Chemical group 0.000 description 20
- 239000002552 dosage form Substances 0.000 description 19
- 125000003118 aryl group Chemical group 0.000 description 17
- 239000013078 crystal Substances 0.000 description 17
- 239000012453 solvate Substances 0.000 description 17
- 208000008589 Obesity Diseases 0.000 description 15
- 235000019197 fats Nutrition 0.000 description 15
- 235000020824 obesity Nutrition 0.000 description 15
- 239000000470 constituent Substances 0.000 description 14
- 229940125396 insulin Drugs 0.000 description 14
- 102000004877 Insulin Human genes 0.000 description 13
- 108090001061 Insulin Proteins 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 238000010189 synthetic method Methods 0.000 description 13
- 210000004185 liver Anatomy 0.000 description 12
- 238000005259 measurement Methods 0.000 description 12
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 235000005911 diet Nutrition 0.000 description 8
- 230000037213 diet Effects 0.000 description 8
- 208000016097 disease of metabolism Diseases 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 230000002757 inflammatory effect Effects 0.000 description 8
- 208000030159 metabolic disease Diseases 0.000 description 8
- 230000000291 postprandial effect Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 210000002784 stomach Anatomy 0.000 description 8
- 208000004611 Abdominal Obesity Diseases 0.000 description 7
- 206010065941 Central obesity Diseases 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 206010033307 Overweight Diseases 0.000 description 7
- 108091006269 SLC5A2 Proteins 0.000 description 7
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 150000003626 triacylglycerols Chemical class 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 6
- 208000001145 Metabolic Syndrome Diseases 0.000 description 6
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 6
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 230000001934 delay Effects 0.000 description 6
- 230000003176 fibrotic effect Effects 0.000 description 6
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 6
- 201000008980 hyperinsulinism Diseases 0.000 description 6
- 230000001590 oxidative effect Effects 0.000 description 6
- 210000000496 pancreas Anatomy 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 208000011580 syndromic disease Diseases 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 230000002641 glycemic effect Effects 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 238000007410 oral glucose tolerance test Methods 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 206010019668 Hepatic fibrosis Diseases 0.000 description 4
- 208000017442 Retinal disease Diseases 0.000 description 4
- 206010038923 Retinopathy Diseases 0.000 description 4
- 125000002877 alkyl aryl group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 230000005784 autoimmunity Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 231100000167 toxic agent Toxicity 0.000 description 4
- 239000003440 toxic substance Substances 0.000 description 4
- YPMOAQISONSSNL-UHFFFAOYSA-N 8-hydroxyoctyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCCCCCCO YPMOAQISONSSNL-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 108090000854 Oxidoreductases Proteins 0.000 description 3
- 102000004316 Oxidoreductases Human genes 0.000 description 3
- 208000031816 Pathologic Dilatation Diseases 0.000 description 3
- 206010035664 Pneumonia Diseases 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000007446 glucose tolerance test Methods 0.000 description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 3
- 235000009200 high fat diet Nutrition 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 2
- 102100039160 Amiloride-sensitive amine oxidase [copper-containing] Human genes 0.000 description 2
- 108010028700 Amine Oxidase (Copper-Containing) Proteins 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 108010079340 Benzylamine Oxidase Proteins 0.000 description 2
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 2
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 2
- 206010066786 Diabetic keratopathy Diseases 0.000 description 2
- 208000032928 Dyslipidaemia Diseases 0.000 description 2
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 2
- 206010018473 Glycosuria Diseases 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- 206010024612 Lipoma Diseases 0.000 description 2
- 102000010909 Monoamine Oxidase Human genes 0.000 description 2
- 108010062431 Monoamine oxidase Proteins 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- YIQKLZYTHXTDDT-UHFFFAOYSA-H Sirius red F3B Chemical compound C1=CC(=CC=C1N=NC2=CC(=C(C=C2)N=NC3=C(C=C4C=C(C=CC4=C3[O-])NC(=O)NC5=CC6=CC(=C(C(=C6C=C5)[O-])N=NC7=C(C=C(C=C7)N=NC8=CC=C(C=C8)S(=O)(=O)[O-])S(=O)(=O)[O-])S(=O)(=O)O)S(=O)(=O)O)S(=O)(=O)[O-])S(=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+] YIQKLZYTHXTDDT-UHFFFAOYSA-H 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 208000004608 Ureteral Obstruction Diseases 0.000 description 2
- 206010069351 acute lung injury Diseases 0.000 description 2
- 125000003302 alkenyloxy group Chemical group 0.000 description 2
- 125000004647 alkyl sulfenyl group Chemical group 0.000 description 2
- 125000001118 alkylidene group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000008365 aqueous carrier Substances 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 235000021588 free fatty acids Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000001969 hypertrophic effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000004153 islets of langerhan Anatomy 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 208000013223 septicemia Diseases 0.000 description 2
- 241000894007 species Species 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- 125000004822 1,1-dimethylpropylene group Chemical group [H]C([H])([H])C([*:1])(C([H])([H])[H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- VUAXHMVRKOTJKP-UHFFFAOYSA-N 2,2-dimethylbutyric acid Chemical compound CCC(C)(C)C(O)=O VUAXHMVRKOTJKP-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 101150073604 Adgre1 gene Proteins 0.000 description 1
- 102000011690 Adiponectin Human genes 0.000 description 1
- 108010076365 Adiponectin Proteins 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical class NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 102100034613 Annexin A2 Human genes 0.000 description 1
- 108090000668 Annexin A2 Proteins 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 102000013918 Apolipoproteins E Human genes 0.000 description 1
- 108010025628 Apolipoproteins E Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 239000011547 Bouin solution Substances 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 101150008656 COL1A1 gene Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 208000010667 Carcinoma of liver and intrahepatic biliary tract Diseases 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 101150091877 Ccn2 gene Proteins 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 101000774560 Crotalus atrox Zinc metalloproteinase-disintegrin-like VAP1 Proteins 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 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
- 206010012655 Diabetic complications Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102000008214 Glutamate decarboxylase Human genes 0.000 description 1
- 108091022930 Glutamate decarboxylase Proteins 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 1
- 241000197195 Gonioma <angiosperm> Species 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
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010073069 Hepatic cancer Diseases 0.000 description 1
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 description 1
- 101001135589 Homo sapiens Tyrosine-protein phosphatase non-receptor type 22 Proteins 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 201000003803 Inflammatory myofibroblastic tumor Diseases 0.000 description 1
- 206010067917 Inflammatory myofibroblastic tumour Diseases 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000001344 Macular Edema Diseases 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000007727 Muscle Tissue Neoplasms Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 201000004404 Neurofibroma Diseases 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108010003894 Protein-Lysine 6-Oxidase Proteins 0.000 description 1
- 102000004669 Protein-Lysine 6-Oxidase Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 108091006277 SLC5A1 Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- QLXKHBNJTPICNF-QMCAAQAGSA-N Sergliflozin etabonate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](COC(=O)OCC)O[C@H]1OC1=CC=CC=C1CC1=CC=C(OC)C=C1 QLXKHBNJTPICNF-QMCAAQAGSA-N 0.000 description 1
- 101150035628 Serpine1 gene Proteins 0.000 description 1
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 102000005353 Tissue Inhibitor of Metalloproteinase-1 Human genes 0.000 description 1
- 108010031374 Tissue Inhibitor of Metalloproteinase-1 Proteins 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 208000007587 Transfusion-Related Acute Lung Injury Diseases 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102100033138 Tyrosine-protein phosphatase non-receptor type 22 Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 102000004248 Zinc Transporter 8 Human genes 0.000 description 1
- 108090000702 Zinc Transporter 8 Proteins 0.000 description 1
- 101150063830 abcB4 gene Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000006319 alkynyl amino group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 208000009887 angiolipoma Diseases 0.000 description 1
- 208000000252 angiomatosis Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002300 anti-fibrosis Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000018093 autoimmune cholangitis Diseases 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 238000011325 biochemical measurement Methods 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- SIHHLZPXQLFPMC-UHFFFAOYSA-N chloroform;methanol;hydrate Chemical compound O.OC.ClC(Cl)Cl SIHHLZPXQLFPMC-UHFFFAOYSA-N 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- IBAHLNWTOIHLKE-UHFFFAOYSA-N cyano cyanate Chemical compound N#COC#N IBAHLNWTOIHLKE-UHFFFAOYSA-N 0.000 description 1
- 125000000392 cycloalkenyl 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
- 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 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004050 enoyl group Chemical group 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000001610 euglycemic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 206010016629 fibroma Diseases 0.000 description 1
- 206010049444 fibromatosis Diseases 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 150000002304 glucoses Chemical class 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 210000004349 growth plate Anatomy 0.000 description 1
- 125000000232 haloalkynyl group Chemical group 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 108010049074 hemoglobin B Proteins 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 208000023589 ischemic 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
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)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
- 125000005956 isoquinolyl group Chemical group 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
- 230000000366 juvenile effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 201000002250 liver carcinoma Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000018191 liver inflammation Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 125000001288 lysyl group Chemical group 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 201000010230 macular retinal edema Diseases 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
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000024305 myofibroblastoma 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004957 naphthylene group Chemical group 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000004316 oxathiadiazolyl group Chemical group O1SNN=C1* 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002205 phenol-chloroform extraction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 230000000207 pro-atherogenic effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 208000004644 retinal vein occlusion Diseases 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 208000010157 sclerosing cholangitis 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
- 229950000378 sergliflozin etabonate Drugs 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000000528 statistical test Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 102000013498 tau Proteins Human genes 0.000 description 1
- 108010026424 tau Proteins Proteins 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
- 210000001550 testis Anatomy 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 238000013293 zucker diabetic fatty rat Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP16194572.0 | 2016-10-19 | ||
| EP16194572 | 2016-10-19 | ||
| PCT/EP2017/076300 WO2018073154A1 (en) | 2016-10-19 | 2017-10-16 | Combinations comprising an ssao/vap-1 inhibitor and a sglt2 inhibitor, uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109843279A true CN109843279A (zh) | 2019-06-04 |
Family
ID=57178303
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201780063937.5A Pending CN109843279A (zh) | 2016-10-19 | 2017-10-16 | 包含ssao/vap-1抑制剂和sglt2抑制剂的药物组合、其用途 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US20210212968A1 (enExample) |
| EP (1) | EP3528800A1 (enExample) |
| JP (1) | JP2019531320A (enExample) |
| KR (1) | KR20190070956A (enExample) |
| CN (1) | CN109843279A (enExample) |
| AU (1) | AU2017344882A1 (enExample) |
| BR (1) | BR112019005930A2 (enExample) |
| CA (1) | CA3041169A1 (enExample) |
| CL (1) | CL2019000935A1 (enExample) |
| EA (1) | EA201990951A1 (enExample) |
| IL (1) | IL265989A (enExample) |
| MX (1) | MX2019004549A (enExample) |
| PH (1) | PH12019500845A1 (enExample) |
| WO (1) | WO2018073154A1 (enExample) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113893256A (zh) * | 2020-07-06 | 2022-01-07 | 诺未科技（北京）有限公司 | 化合物或其可药用盐、二聚体或三聚体在制备治疗癌症的药物中的应用 |
| CN115666577A (zh) * | 2020-03-25 | 2023-01-31 | 拓臻股份有限公司 | 呼吸道病症的治疗 |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20190110736A (ko) | 2018-03-21 | 2019-10-01 | 주식회사유한양행 | 신규의 트라이아졸론 유도체 또는 이의 염 및 이를 포함하는 약학 조성물 |
| KR20190110740A (ko) | 2018-03-21 | 2019-10-01 | 주식회사유한양행 | 신규의 아릴 또는 헤테로아릴 트라이아졸론 유도체 또는 이의 염 및 이를 포함하는 약학 조성물 |
| SG11202103062UA (en) * | 2018-09-28 | 2021-04-29 | Acucela Inc | Inhibitors of vap-1 |
| MX2021003731A (es) | 2018-09-28 | 2021-08-05 | Acucela Inc | Inhibidores de vap-1. |
| JP7414230B2 (ja) * | 2018-11-09 | 2024-01-16 | 国立大学法人 琉球大学 | 抗血液悪性腫瘍薬 |
| CN121081472A (zh) | 2018-12-13 | 2025-12-09 | 拓臻股份有限公司 | 一种THRβ受体激动剂化合物及其制备方法和用途 |
| TWI835945B (zh) * | 2018-12-14 | 2024-03-21 | 南韓商柳韓洋行股份有限公司 | 3,3-二氟烯丙胺化物或其鹽及包含彼的醫藥組合物 |
| TW202039486A (zh) * | 2018-12-14 | 2020-11-01 | 南韓商柳韓洋行股份有限公司 | 三唑并吡啶-3-酮化物或其鹽及包含彼之醫藥組合物 |
| CN114375193B (zh) | 2019-09-12 | 2024-05-14 | 拓臻制药公司 | 甲状腺激素受体β激动剂化合物 |
| EP4051669A4 (en) | 2019-10-29 | 2023-12-13 | Eccogene (Shanghai) Co., Ltd. | SSAO INHIBITORS AND THEIR USE |
| KR20230023642A (ko) * | 2020-05-13 | 2023-02-17 | 테른스 파마슈티칼스, 인크. | 간 장애의 조합 치료 |
| AU2021332217A1 (en) | 2020-08-25 | 2023-05-11 | Eli Lilly And Company | Polymorphs of an ssao inhibitor |
| US20240148767A1 (en) * | 2021-03-04 | 2024-05-09 | The Governors Of The University Of Alberta | The use of empagliflozin for the treatment of ulcerative colitis and crohn's disease |
| JP2024543419A (ja) * | 2021-11-11 | 2024-11-21 | ターンズ・ファーマシューティカルズ・インコーポレイテッド | Ｓｓａｏ阻害剤による肝障害の治療 |
| EP4429665A1 (en) * | 2021-11-11 | 2024-09-18 | Terns Pharmaceuticals, Inc. | Combination of a ssao inhibitor and thr-beta agonist for use in the treatment of liver disorders |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104520268A (zh) * | 2012-05-02 | 2015-04-15 | 法马克西斯制药公司 | Ssao的取代的3-卤代烯丙基胺抑制剂及其用途 |
Family Cites Families (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1145635C (zh) | 1999-08-31 | 2004-04-14 | 橘生药品工业株式会社 | 吡喃葡糖氧基吡唑衍生物、含该衍生物的药物组合物及其制备中的中间体 |
| US6515117B2 (en) | 1999-10-12 | 2003-02-04 | Bristol-Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
| PH12000002657B1 (en) | 1999-10-12 | 2006-02-21 | Bristol Myers Squibb Co | C-aryl glucoside SGLT2 inhibitors |
| CA2429833A1 (en) | 2000-11-30 | 2002-06-06 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxybenzylbenzene derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| HU228915B1 (en) | 2000-12-28 | 2013-06-28 | Kissei Pharmaceutical | Glucopyranosyloxypyrazole derivatives and use thereof |
| KR100945455B1 (ko) | 2002-03-22 | 2010-03-05 | 깃세이 야쿠힌 고교 가부시키가이샤 | 글루코피라노실옥시벤질 벤젠 유도체의 결정 |
| DE10231370B4 (de) | 2002-07-11 | 2006-04-06 | Sanofi-Aventis Deutschland Gmbh | Thiophenglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
| ES2567571T3 (es) | 2003-03-14 | 2016-04-25 | Astellas Pharma Inc. | Derivados de C-glucósido y sales de los mismos |
| EP2514756B1 (en) | 2003-08-01 | 2014-12-17 | Mitsubishi Tanabe Pharma Corporation | Novel compounds having inhibitory activity against sodium-dependant glucose transporter |
| PL1730131T3 (pl) | 2004-03-16 | 2012-10-31 | Boehringer Ingelheim Int | Glukopiranozylo-podstawione pochodne benzenu, środki lecznicze zawierające te związki, ich zastosowanie i sposób ich wytwarzania |
| TW200637839A (en) | 2005-01-07 | 2006-11-01 | Taisho Pharmaceutical Co Ltd | 1-thio-d-glucitol derivatives |
| TW200637869A (en) | 2005-01-28 | 2006-11-01 | Chugai Pharmaceutical Co Ltd | The spiroketal derivatives and the use as therapeutical agent for diabetes of the same |
| UA91546C2 (uk) | 2005-05-03 | 2010-08-10 | Бьорінгер Інгельхайм Інтернаціональ Гмбх | КРИСТАЛІЧНА ФОРМА 1-ХЛОР-4-(β-D-ГЛЮКОПІРАНОЗ-1-ИЛ)-2-[4-((S)-ТЕТРАГІДРОФУРАН-3-ІЛОКСИ)-БЕНЗИЛ]-БЕНЗОЛУ, СПОСІБ ЇЇ ОДЕРЖАННЯ ТА ЇЇ ЗАСТОСУВАННЯ ПРИ ПРИГОТУВАННІ ЛІКАРСЬКИХ ЗАСОБІВ |
| US7772191B2 (en) | 2005-05-10 | 2010-08-10 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
| ATE517099T1 (de) | 2006-02-15 | 2011-08-15 | Boehringer Ingelheim Int | Glucopyranosyl-substituierte benzonitril-derivate,pharmazeutische zusammensetzungen mit derartigen verbindungen, ihre verwendung und herstellungsverfahren dafür |
| WO2007140191A2 (en) | 2006-05-23 | 2007-12-06 | Theracos, Inc. | Glucose transport inhibitors and methods of use |
| US7919598B2 (en) | 2006-06-28 | 2011-04-05 | Bristol-Myers Squibb Company | Crystal structures of SGLT2 inhibitors and processes for preparing same |
| TWI499414B (zh) | 2006-09-29 | 2015-09-11 | Lexicon Pharmaceuticals Inc | 鈉與葡萄糖第２型共同運輸體（ｃｏ-ｔｒａｎｓｐｏｒｔｅｒ ２）的抑制物與其應用方法 |
| UY30730A1 (es) | 2006-12-04 | 2008-07-03 | Mitsubishi Tanabe Pharma Corp | Forma cristalina del hemihidrato de 1-(b (beta)-d-glucopiranosil) -4-metil-3-[5-(4-fluorofenil) -2-tienilmetil]benceno |
| US7846945B2 (en) | 2007-03-08 | 2010-12-07 | Lexicon Pharmaceuticals, Inc. | Piperdine-based inhibitors of sodium glucose co-transporter 2 and methods of their use |
| TW200904405A (en) | 2007-03-22 | 2009-02-01 | Bristol Myers Squibb Co | Pharmaceutical formulations containing an SGLT2 inhibitor |
| WO2009014970A1 (en) | 2007-07-26 | 2009-01-29 | Lexicon Pharmaceuticals, Inc. | Methods and compounds useful for the preparation of sodium glucose co-transporter 2 inhibitors |
| HUE035130T2 (en) | 2007-09-10 | 2018-05-02 | Janssen Pharmaceutica Nv | A method for preparing compounds useful as SGLT inhibitors |
| WO2009066152A2 (en) | 2007-11-21 | 2009-05-28 | Pharmaxis Ltd. | Haloallylamine inhibitors of ssao/vap-1 and uses therefor |
| TW201011043A (en) | 2008-06-20 | 2010-03-16 | Chugai Pharmaceutical Co Ltd | Crystal of spiroketal derivatives and process for preparation of spiroketal derivatives |
| TWI472521B (zh) | 2008-07-17 | 2015-02-11 | Lexicon Pharmaceuticals Inc | （２ｓ，３ｒ，４ｒ，５ｓ，６ｒ）－２－（４－氯－３－（４－乙氧苄基）苯基）－６－（甲硫）四氫－２ｈ－哌喃－３，４，５－三醇的固體形態與其使用方法 |
| CN102149717B (zh) | 2008-08-28 | 2014-05-14 | 辉瑞大药厂 | 二氧杂-双环[3.2.1]辛烷-2，3，4-三醇衍生物 |
| FI2395968T3 (fi) | 2009-02-13 | 2024-02-27 | Boehringer Ingelheim Int | Glukopyranosylidifenylimetaanijohdannaisia sisältävä farmaseuttinen koostumus, niiden farmaseuttinen annostusmuoto, niiden valmistusmenetelmä ja niiden käyttö potilaan glukemiasäädön parantamiseksi |
| TW201103534A (en) | 2009-04-16 | 2011-02-01 | Taisho Pharmaceutical Co Ltd | Pharmaceutical compositions |
| CA2775962C (en) | 2009-09-30 | 2017-09-05 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
| EA020798B1 (ru) | 2009-09-30 | 2015-01-30 | Бёрингер Ингельхайм Интернациональ Гмбх | СПОСОБ ПОЛУЧЕНИЯ КРИСТАЛЛИЧЕСКОЙ ФОРМЫ 1-ХЛОР-4-(β-D-ГЛЮКОПИРАНОЗ-1-ИЛ)-2-[4-((S)-ТЕТРАГИДРОФУРАН-3-ИЛОКСИ)БЕНЗИЛ]БЕНЗОЛА |
-
2017
- 2017-10-16 US US16/341,460 patent/US20210212968A1/en not_active Abandoned
- 2017-10-16 EP EP17804068.9A patent/EP3528800A1/en not_active Withdrawn
- 2017-10-16 MX MX2019004549A patent/MX2019004549A/es unknown
- 2017-10-16 CA CA3041169A patent/CA3041169A1/en not_active Abandoned
- 2017-10-16 EA EA201990951A patent/EA201990951A1/ru unknown
- 2017-10-16 CN CN201780063937.5A patent/CN109843279A/zh active Pending
- 2017-10-16 JP JP2019520691A patent/JP2019531320A/ja active Pending
- 2017-10-16 WO PCT/EP2017/076300 patent/WO2018073154A1/en not_active Ceased
- 2017-10-16 KR KR1020197014347A patent/KR20190070956A/ko not_active Withdrawn
- 2017-10-16 BR BR112019005930A patent/BR112019005930A2/pt not_active IP Right Cessation
- 2017-10-16 AU AU2017344882A patent/AU2017344882A1/en not_active Abandoned
-
2019
- 2019-04-08 CL CL2019000935A patent/CL2019000935A1/es unknown
- 2019-04-11 IL IL265989A patent/IL265989A/en unknown
- 2019-04-17 PH PH12019500845A patent/PH12019500845A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104520268A (zh) * | 2012-05-02 | 2015-04-15 | 法马克西斯制药公司 | Ssao的取代的3-卤代烯丙基胺抑制剂及其用途 |
| US20150158813A1 (en) * | 2012-05-02 | 2015-06-11 | Pharmaxis Ltd. | Substituted 3-haloallylamine inhibitors of assao and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| 贾伟平: "《医师考核培训规范教程.内分泌代谢科分册》", 31 March 2016, 上海科学技术出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115666577A (zh) * | 2020-03-25 | 2023-01-31 | 拓臻股份有限公司 | 呼吸道病症的治疗 |
| CN113893256A (zh) * | 2020-07-06 | 2022-01-07 | 诺未科技（北京）有限公司 | 化合物或其可药用盐、二聚体或三聚体在制备治疗癌症的药物中的应用 |
| WO2022007134A1 (zh) * | 2020-07-06 | 2022-01-13 | 诺未科技（北京）有限公司 | 化合物或其可药用盐、二聚体或三聚体在制备治疗癌症的药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA3041169A1 (en) | 2018-04-26 |
| IL265989A (en) | 2019-06-30 |
| BR112019005930A2 (pt) | 2019-06-11 |
| PH12019500845A1 (en) | 2019-12-02 |
| US20210212968A1 (en) | 2021-07-15 |
| EP3528800A1 (en) | 2019-08-28 |
| WO2018073154A1 (en) | 2018-04-26 |
| EA201990951A1 (ru) | 2019-11-29 |
| JP2019531320A (ja) | 2019-10-31 |
| KR20190070956A (ko) | 2019-06-21 |
| CL2019000935A1 (es) | 2019-08-09 |
| AU2017344882A1 (en) | 2019-03-28 |
| MX2019004549A (es) | 2019-06-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109843279A (zh) | 包含ssao/vap-1抑制剂和sglt2抑制剂的药物组合、其用途 | |
| US20240156848A1 (en) | Pharmaceutical composition, methods for treating and uses thereof | |
| US20180104198A1 (en) | Pharmaceutical Composition, Methods for Treating and Uses Thereof | |
| US20240398729A1 (en) | Methods and Compositions for the Treatment of Cytoplasmic Glycogen Storage Disorders | |
| US12427161B2 (en) | Methods for treating and pharmaceutical compositions | |
| US20210346418A1 (en) | Pharmaceutical composition, methods for treating and uses thereof | |
| US20220323473A1 (en) | Methods of treating diseases | |
| US20140088027A1 (en) | Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof | |
| JP2020147585A (ja) | 肝臓の疾患を治療するためのオメガ３脂肪酸とｓｇｌｔ−２阻害薬との併用剤 | |
| TW200911275A (en) | Pharmaceutical composition comprising a pyrazole-O-glucoside derivative | |
| CN109364269A (zh) | 一种预测及治疗2型糖尿病的组合物、评价方法及其制剂 | |
| CN109771411A (zh) | 二氢槲皮素用于制备治疗脂肪肝的药物中的用途 | |
| CN111989103A (zh) | 药物组合物、其治疗方法和用途 | |
| US11813275B2 (en) | Pharmaceutical composition, methods for treating and uses thereof | |
| US9283243B2 (en) | CD36 inhibition to control obesity and insulin sensitivity | |
| CN102283858A (zh) | 枸杞多糖在防治慢性应激和创伤后应激障碍的药物中的应用 | |
| KR102785819B1 (ko) | Lcn2 단백질 또는 그를 코딩하는 폴리뉴클레오티드를 유효성분으로 포함하는 발기부전 예방 또는 치료용 약학 조성물 | |
| US20210196747A1 (en) | Metabolism improving agent | |
| KR101844816B1 (ko) | 구아나벤즈를 포함하는 식욕부진증의 개선 또는 치료용 조성물 및 이를 이용한 방법 | |
| CN102813670A (zh) | 枸杞多糖在制备防治慢性应激的药物中的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190604 |