CN115666560A - 用于治疗covid-19的血栓素a2受体拮抗剂的方法和药物组合物 - Google Patents
用于治疗covid-19的血栓素a2受体拮抗剂的方法和药物组合物 Download PDFInfo
- Publication number
- CN115666560A CN115666560A CN202180037977.9A CN202180037977A CN115666560A CN 115666560 A CN115666560 A CN 115666560A CN 202180037977 A CN202180037977 A CN 202180037977A CN 115666560 A CN115666560 A CN 115666560A
- Authority
- CN
- China
- Prior art keywords
- thromboxane
- receptor antagonist
- pulmonary
- covid
- feiqu
- 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
- 208000025721 COVID-19 Diseases 0.000 title claims abstract description 77
- 238000000034 method Methods 0.000 title claims description 44
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 6
- 102000003938 Thromboxane Receptors Human genes 0.000 title description 32
- 108090000300 Thromboxane Receptors Proteins 0.000 title description 31
- 229940044551 receptor antagonist Drugs 0.000 title description 4
- 239000002464 receptor antagonist Substances 0.000 title description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 239000003769 thromboxane A2 receptor blocking agent Substances 0.000 claims abstract description 16
- 229940123987 Thromboxane A2 receptor antagonist Drugs 0.000 claims abstract description 14
- BBPRUNPUJIUXSE-DXKRWKNPSA-N ifetroban Chemical compound CCCCCNC(=O)C1=COC([C@H]2[C@H]([C@@H]3CC[C@H]2O3)CC=2C(=CC=CC=2)CCC(O)=O)=N1 BBPRUNPUJIUXSE-DXKRWKNPSA-N 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 208000037847 SARS-CoV-2-infection Diseases 0.000 claims abstract description 6
- 230000002685 pulmonary effect Effects 0.000 claims description 32
- 206010037423 Pulmonary oedema Diseases 0.000 claims description 21
- 208000005333 pulmonary edema Diseases 0.000 claims description 21
- 208000007536 Thrombosis Diseases 0.000 claims description 20
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 20
- 230000005980 lung dysfunction Effects 0.000 claims description 11
- 208000004756 Respiratory Insufficiency Diseases 0.000 claims description 5
- 238000011161 development Methods 0.000 claims description 5
- 201000004193 respiratory failure Diseases 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 208000034841 Thrombotic Microangiopathies Diseases 0.000 claims description 4
- WOHSQDNIXPEQAE-QBKVZTCDSA-M sodium;3-[2-[[(1s,2r,3s,4r)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoate Chemical group [Na+].CCCCCNC(=O)C1=COC([C@H]2[C@H]([C@@H]3CC[C@H]2O3)CC=2C(=CC=CC=2)CCC([O-])=O)=N1 WOHSQDNIXPEQAE-QBKVZTCDSA-M 0.000 claims description 4
- 208000024891 symptom Diseases 0.000 claims description 4
- 238000011084 recovery Methods 0.000 claims description 3
- 206010059245 Angiopathy Diseases 0.000 claims 1
- 230000001732 thrombotic effect Effects 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 abstract description 2
- 229940099508 TP receptor antagonist Drugs 0.000 description 65
- 210000004072 lung Anatomy 0.000 description 25
- 150000002148 esters Chemical class 0.000 description 24
- -1 SQ29548 Chemical class 0.000 description 23
- 210000001519 tissue Anatomy 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 230000001965 increasing effect Effects 0.000 description 13
- 230000036470 plasma concentration Effects 0.000 description 12
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 11
- 208000002815 pulmonary hypertension Diseases 0.000 description 11
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 230000002792 vascular Effects 0.000 description 10
- 206010016654 Fibrosis Diseases 0.000 description 9
- 206010021143 Hypoxia Diseases 0.000 description 9
- 208000004852 Lung Injury Diseases 0.000 description 9
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 230000006378 damage Effects 0.000 description 9
- 239000012530 fluid Substances 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 208000000059 Dyspnea Diseases 0.000 description 8
- 206010013975 Dyspnoeas Diseases 0.000 description 8
- 206010069363 Traumatic lung injury Diseases 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 230000004761 fibrosis Effects 0.000 description 8
- 208000018875 hypoxemia Diseases 0.000 description 8
- 150000002535 isoprostanes Chemical class 0.000 description 8
- 231100000515 lung injury Toxicity 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 7
- 238000009825 accumulation Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 210000002889 endothelial cell Anatomy 0.000 description 7
- 230000035699 permeability Effects 0.000 description 7
- YIBNHAJFJUQSRA-YNNPMVKQSA-N prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 229960001138 acetylsalicylic acid Drugs 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 238000006213 oxygenation reaction Methods 0.000 description 6
- 150000003180 prostaglandins Chemical class 0.000 description 6
- 210000003492 pulmonary vein Anatomy 0.000 description 6
- 241001678559 COVID-19 virus Species 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 101150100032 Tbxa2r gene Proteins 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 230000003511 endothelial effect Effects 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 239000008184 oral solid dosage form Substances 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- DYWAPFDKPAHSED-UHFFFAOYSA-N 2-cycloheptyloxepane Chemical group C1CCCCCC1C1OCCCCC1 DYWAPFDKPAHSED-UHFFFAOYSA-N 0.000 description 4
- 206010003178 Arterial thrombosis Diseases 0.000 description 4
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 4
- ZBVKEHDGYSLCCC-UHFFFAOYSA-N Seratrodast Chemical compound O=C1C(C)=C(C)C(=O)C(C(CCCCCC(O)=O)C=2C=CC=CC=2)=C1C ZBVKEHDGYSLCCC-UHFFFAOYSA-N 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 210000002808 connective tissue Anatomy 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- KPSZWAJWFMFMFF-UHFFFAOYSA-N hept-5-enoic acid Chemical compound CC=CCCCC(O)=O KPSZWAJWFMFMFF-UHFFFAOYSA-N 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000008297 liquid dosage form Substances 0.000 description 4
- 238000005399 mechanical ventilation Methods 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 210000001616 monocyte Anatomy 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 210000001147 pulmonary artery Anatomy 0.000 description 4
- 230000004088 pulmonary circulation Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 230000008728 vascular permeability Effects 0.000 description 4
- KYWCWBXGRWWINE-UHFFFAOYSA-N 4-methoxy-N1,N3-bis(3-pyridinylmethyl)benzene-1,3-dicarboxamide Chemical compound COC1=CC=C(C(=O)NCC=2C=NC=CC=2)C=C1C(=O)NCC1=CC=CN=C1 KYWCWBXGRWWINE-UHFFFAOYSA-N 0.000 description 3
- ZWAVGFSZMACJHA-PMNBYGLBSA-N 7-[2-Trifluoromethyl-4-(2-hydroxyphenyl)-1,3-dioxan-cis-5-yl]-hept-5z-enoic acid Chemical compound OC(=O)CCC\C=C/C[C@@H]1CO[C@H](C(F)(F)F)O[C@@H]1C1=CC=CC=C1O ZWAVGFSZMACJHA-PMNBYGLBSA-N 0.000 description 3
- 241000711573 Coronaviridae Species 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical group CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- 206010025080 Lung consolidation Diseases 0.000 description 3
- 206010035664 Pneumonia Diseases 0.000 description 3
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 3
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 3
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 3
- 108010000499 Thromboplastin Proteins 0.000 description 3
- 102000002262 Thromboplastin Human genes 0.000 description 3
- 206010047249 Venous thrombosis Diseases 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 238000011888 autopsy Methods 0.000 description 3
- 210000001772 blood platelet Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002591 computed tomography Methods 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 206010016256 fatigue Diseases 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 230000000893 fibroproliferative effect Effects 0.000 description 3
- 230000003176 fibrotic effect Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 230000004199 lung function Effects 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 208000013220 shortness of breath Diseases 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000001960 triggered effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WHUIENZXNGAHQI-YGPRPMEGSA-N (z)-6-[(2r,4r,5s)-2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl]hex-4-enoic acid Chemical compound C1([C@@H]2O[C@@H](OC[C@@H]2C\C=C/CCC(=O)O)C=2C(=CC=CC=2)Cl)=CC=CC=C1O WHUIENZXNGAHQI-YGPRPMEGSA-N 0.000 description 2
- RNAMYOYQYRYFQY-UHFFFAOYSA-N 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-n-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine Chemical compound N1=C(N2CCC(F)(F)CC2)N=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1NC1CCN(C(C)C)CC1 RNAMYOYQYRYFQY-UHFFFAOYSA-N 0.000 description 2
- PXGPLTODNUVGFL-NAPLMKITSA-N 8-epi-prostaglandin F2alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@H]1C\C=C/CCCC(O)=O PXGPLTODNUVGFL-NAPLMKITSA-N 0.000 description 2
- 208000010470 Ageusia Diseases 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 206010002653 Anosmia Diseases 0.000 description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 208000032382 Ischaemic stroke Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 208000024248 Vascular System injury Diseases 0.000 description 2
- 208000012339 Vascular injury Diseases 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- 206010069675 Ventilation perfusion mismatch Diseases 0.000 description 2
- 206010069351 acute lung injury Diseases 0.000 description 2
- 235000019666 ageusia Nutrition 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 230000007885 bronchoconstriction Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000004413 cardiac myocyte Anatomy 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 229950004274 ifetroban Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000000865 liniment Substances 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
- 230000004060 metabolic process Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229960001006 picotamide Drugs 0.000 description 2
- 230000010118 platelet activation Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000003331 prothrombotic effect Effects 0.000 description 2
- 230000008695 pulmonary vasoconstriction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000008458 response to injury Effects 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 230000037390 scarring Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000002924 silencing RNA Substances 0.000 description 2
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 230000025033 vasoconstriction Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 210000000264 venule Anatomy 0.000 description 2
- NIONDZDPPYHYKY-SNAWJCMRSA-N (2E)-hexenoic acid Chemical compound CCC\C=C\C(O)=O NIONDZDPPYHYKY-SNAWJCMRSA-N 0.000 description 1
- GQGRDYWMOPRROR-ZIFKCHSBSA-N (e)-7-[(1r,2r,3s,5s)-3-hydroxy-5-[(4-phenylphenyl)methoxy]-2-piperidin-1-ylcyclopentyl]hept-4-enoic acid Chemical compound O([C@H]1C[C@@H]([C@@H]([C@H]1CC\C=C\CCC(O)=O)N1CCCCC1)O)CC(C=C1)=CC=C1C1=CC=CC=C1 GQGRDYWMOPRROR-ZIFKCHSBSA-N 0.000 description 1
- IOFUFYLETVNNRF-OWOJBTEDSA-N (e)-7-[2-morpholin-4-yl-3-oxo-5-[(4-phenylphenyl)methoxy]cyclopentyl]hept-4-enoic acid Chemical compound OC(=O)CC\C=C\CCC1C(OCC=2C=CC(=CC=2)C=2C=CC=CC=2)CC(=O)C1N1CCOCC1 IOFUFYLETVNNRF-OWOJBTEDSA-N 0.000 description 1
- SXHUZJPIRVLMHY-AZPSIHDESA-N (z)-7-[(1r,3s,4s,5s)-3-[[(2r)-2-cyclopentyl-2-hydroxyacetyl]amino]-6,6-dimethyl-4-bicyclo[3.1.1]heptanyl]hept-5-enoic acid Chemical compound C1([C@@H](O)C(=O)N[C@@H]2[C@@H](C\C=C/CCCC(O)=O)[C@@H]3C[C@H](C2)C3(C)C)CCCC1 SXHUZJPIRVLMHY-AZPSIHDESA-N 0.000 description 1
- RJNDVCNWVBWHLY-BHQIHCQQSA-N (z)-7-[3-[[2-(phenylcarbamoyl)hydrazinyl]methyl]-7-oxabicyclo[2.2.1]heptan-2-yl]hept-5-enoic acid Chemical compound OC(=O)CCC\C=C/CC1C(O2)CCC2C1CNNC(=O)NC1=CC=CC=C1 RJNDVCNWVBWHLY-BHQIHCQQSA-N 0.000 description 1
- RIIKDGPBTPECSW-UHFFFAOYSA-N 1-tert-butyl-3-[5-cyano-2-[3-[4-(difluoromethoxy)phenyl]phenoxy]phenyl]sulfonylurea Chemical compound CC(C)(C)NC(=O)NS(=O)(=O)c1cc(ccc1Oc1cccc(c1)-c1ccc(OC(F)F)cc1)C#N RIIKDGPBTPECSW-UHFFFAOYSA-N 0.000 description 1
- KJYIVXDPWBUJBQ-UHHGALCXSA-N 11-dehydro-thromboxane B2 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1OC(=O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O KJYIVXDPWBUJBQ-UHHGALCXSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- NNJBQTDFDVLWEQ-UHFFFAOYSA-N 2-(sulfonylamino)benzoic acid Chemical class OC(=O)C1=CC=CC=C1N=S(=O)=O NNJBQTDFDVLWEQ-UHFFFAOYSA-N 0.000 description 1
- IULOBWFWYDMECP-UHFFFAOYSA-N 2-[4-[2-[(4-chlorophenyl)sulfonylamino]ethyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CCNS(=O)(=O)C1=CC=C(Cl)C=C1 IULOBWFWYDMECP-UHFFFAOYSA-N 0.000 description 1
- VLMZAUCKMYJSGM-UHFFFAOYSA-N 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 VLMZAUCKMYJSGM-UHFFFAOYSA-N 0.000 description 1
- ISSKMEQROMFEHL-UHFFFAOYSA-N 2-[5-[2-(benzenesulfonamido)ethyl]thiophen-2-yl]oxyacetic acid Chemical compound S1C(OCC(=O)O)=CC=C1CCNS(=O)(=O)C1=CC=CC=C1 ISSKMEQROMFEHL-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- KFXPOIKSDYRVKS-ONEGZZNKSA-N 4-Heptenoic acid Chemical compound CC\C=C\CCC(O)=O KFXPOIKSDYRVKS-ONEGZZNKSA-N 0.000 description 1
- UHZXPFSCJFEFPS-UHFFFAOYSA-N 7-(cyclohepten-1-yl)-2,3,4,5-tetrahydrooxepine Chemical class C1CCCCC=C1C1=CCCCCO1 UHZXPFSCJFEFPS-UHFFFAOYSA-N 0.000 description 1
- YPWFNLSXQIGJCK-UHFFFAOYSA-N 7-oxabicyclo[2.2.1]heptane Chemical class C1CC2CCC1O2 YPWFNLSXQIGJCK-UHFFFAOYSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
- 102100035765 Angiotensin-converting enzyme 2 Human genes 0.000 description 1
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 1
- 229940124638 COX inhibitor Drugs 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 201000006306 Cor pulmonale Diseases 0.000 description 1
- 208000028399 Critical Illness Diseases 0.000 description 1
- 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 1
- 206010011906 Death Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 229920002306 Glycocalyx Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000946124 Homo sapiens Lipocalin-1 Proteins 0.000 description 1
- 101000715050 Homo sapiens Thromboxane A2 receptor Proteins 0.000 description 1
- 101000796134 Homo sapiens Thymidine phosphorylase Proteins 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 208000020875 Idiopathic pulmonary arterial hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010024769 Local reaction Diseases 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 235000010654 Melissa officinalis Nutrition 0.000 description 1
- 244000062730 Melissa officinalis Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000020128 Mitral stenosis Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 208000004186 Pulmonary Heart Disease Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- LDXDSHIEDAPSSA-OAHLLOKOSA-N Ramatroban Chemical compound N([C@@H]1CCC=2N(C3=CC=CC=C3C=2C1)CCC(=O)O)S(=O)(=O)C1=CC=C(F)C=C1 LDXDSHIEDAPSSA-OAHLLOKOSA-N 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Natural products CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000000740 bleeding effect Effects 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
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- PWTCIBWRMQFJBC-ZEMKZVSASA-N domitroban Chemical compound N([C@H]1[C@H]2CC[C@H](C2)[C@@H]1C\C=C/CCCC(=O)O)S(=O)(=O)C1=CC=CC=C1 PWTCIBWRMQFJBC-ZEMKZVSASA-N 0.000 description 1
- 229950010759 domitroban Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960003699 evans blue Drugs 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 108010052295 fibrin fragment D Proteins 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 210000004517 glycocalyx Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 201000011200 hepatorenal syndrome Diseases 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 230000002706 hydrostatic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 210000001865 kupffer cell Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 229950005596 linotroban Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000003584 mesangial cell Anatomy 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 208000006887 mitral valve stenosis Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000015001 muscle soreness Diseases 0.000 description 1
- 210000000651 myofibroblast Anatomy 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 231100000255 pathogenic effect Toxicity 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000009325 pulmonary function Effects 0.000 description 1
- 230000036593 pulmonary vascular resistance Effects 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 229950004496 ramatroban Drugs 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 229960003090 seratrodast Drugs 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 208000008203 tachypnea Diseases 0.000 description 1
- 206010043089 tachypnoea Diseases 0.000 description 1
- XUTLOCQNGLJNSA-RGVLZGJSSA-N terbogrel Chemical compound CC(C)(C)\N=C(/NC#N)NC1=CC=CC(C(=C/CCCC(O)=O)\C=2C=NC=CC=2)=C1 XUTLOCQNGLJNSA-RGVLZGJSSA-N 0.000 description 1
- 229950006665 terbogrel Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- 230000000287 tissue oxygenation Effects 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 229950007952 vapiprost Drugs 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2063—Proteins, e.g. gelatin
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及血栓素A2受体拮抗剂(例如3‑[2‑[[(1S,2R,3S,4R)‑3‑[4‑(戊基氨基甲酰基)‑1,3‑噁唑‑2‑基]‑7‑氧杂双环[2.2.1]庚烷‑2‑基]甲基]苯基]丙酸(艾非曲班)或其一个或多于一个药学上可接受的盐的混合物)在治疗人类的SARS‑CoV‑2感染中的用途，以及其药物组合物，该药物组合物包含以治疗和/或预防由这种感染引起的病症的有效量的血栓素A2受体拮抗剂(例如艾非曲班)。
Description
技术领域
本发明涉及有效量的血栓素A2受体拮抗剂(例如艾非曲班(Ifetroban))及其药物组合物用于在治疗哺乳动物(例如人)的SARS-CoV-2感染(例如COVID-19)以治疗该疾病中使用。
背景技术
冠状病毒疾病2019(COVID-19)是一种由冠状病毒SARS-CoV-2引起的高度传染性严重急性呼吸***综合征(SARS)。人暴露后，冠状病毒在附着于肺II型肺泡细胞、动脉和静脉内皮细胞以及动脉平滑肌细胞的细胞膜上的血管紧张素转换酶2(ACE2)后进入呼吸道细胞。冠状病毒复制、细胞破坏和扩散到其他器官(例如心脏、大脑、肾、肠道)导致有症状的COVID-19。潜在疾病(例如肥胖症、高血压、糖尿病)和宿主防御受损使某些群体更容易患上严重疾病(例如患有合并症的老年人)。从2020年3月到2021年2月，仅在美国，COVID-19就造成超过500,000人死亡。
COVID-19的早期症状包括肺功能障碍(例如咳嗽、呼吸急促、低氧血症)、发烧、疲劳、肌肉酸痛、头痛、味觉或嗅觉丧失、恶心和腹泻。一些人从呼吸困难迅速发展为呼吸衰竭(例如，需要机械通气)、心力衰竭、重症监护室治疗，甚至死亡。COVID-19的并发症可能包括肺炎、肺水肿、急性呼吸窘迫综合征(ARDS)、肺纤维化、血栓、心肌病、心力衰竭、急性肾损伤和神经***问题(如脑雾)。COVID-19的严重疾病通常见于年龄为60岁以上的人，但年轻人更容易发生动脉血栓形成，包括心肌梗塞和缺血性中风。从COVID-19中恢复可能需要数月时间，所谓的长新冠者(long-hauler)可能会出现长期症状，包括咳嗽、呼吸困难、疲劳、身体疼痛、关节疼痛、味觉和嗅觉丧失、睡眠困难、头痛和脑雾。(Marshall 2020)一些患者的持续健康问题可能归因于肺纤维化的发展。(McDonald 2021)
住院患者中获得授权或批准的COVID-19治疗目前的目标是抑制病毒复制(例如，瑞德西韦)、抑制炎症(例如，***)和增强免疫反应(例如，恢复期血浆和单克隆抗体)。目前疫苗可用并且将其施用于数百万人，以预防在SARS-CoV-2暴露后疾病进展。然而，原始SARS-CoV-2的变体正在出现，并且可能对某些抗体和疫苗具有抗药性。此类变体可能成为可能更具传染性和/或毒性的优势菌株。此外，COVID-19仍然是一种治疗选择不够有效的传染性疾病。
肺动脉高血压是肺循环中的血压升高，这可能是由于肺动脉收缩、肺血管阻塞(例如，有凝块、血栓、炎性细胞或栓子)、肺静脉收缩，其由于毛细血管后(post-capillary)肺血管收缩或血流的下游阻塞(例如，二尖瓣狭窄)产生肺毛细血管高血压。(Ganter,Jakob等人2006)使用右心导管***术的侵入性评估得出结论，76％的COVID-19患者存在毛细血管后肺动脉高血压。COVID-19患者的肺动脉楔压高于ARDS患者，并且与肺顺应性呈负相关。(Caravita,Baratto等人2020)毛细血管后肺血管收缩、肺毛细血管压力升高和肺动脉楔压升高迫使血管液进入气道，导致肺水肿。
肺水肿是终末气道(例如肺泡)中的液体积聚，它会干扰正常的气体交换(例如血液氧合)，降低肺顺应性并导致呼吸困难。肺水肿可以是由肺微血管静水压力增加和/或微血管通透性增加引起的，并且毛细血管压力和通透性的组合增加会加剧水肿的形成。在血管内皮损伤、内皮细胞间隙(inter-endothelial cell gaps)形成和/或血管腔内衬的内皮糖萼破坏后，通透性可能会增加。在COVID-19肺炎中，肺实变的区域(即充满液体而不是空气的正常可压缩肺组织)比正常充气的肺实质更不透射线，并且在射线照相术和计算机断层扫描(CT)扫描中清晰可见。肺水肿是ARDS的标志，其中肺毛细血管通透性升高。在COVID-19中，肺毛细血管压力和通透性都可能升高，导致肺水肿严重。
呼吸衰竭是肺气体交换受损导致血液氧合不足，这可能归因于肺功能障碍、肺损伤和/或通气-灌注不匹配。需要提供补充氧，但可能不足以使血氧饱和度正常化，这会导致气管插管和机械通气。患有COVID-19的重症患者可能会从呼吸急促和低氧血症发展为ARDS样呼吸衰竭，死亡率为39％。(Hasan,Capstick等人2020)
纤维化是在修复或反应过程中器官或组织中过量纤维***(例如胶原蛋白)的形成。纤维组织的形成是一个生理过程，并且纤维组织是身体中器官或组织的正常组成部分。通常，作为伤口愈合过程的一部分，纤维***会沉积在损伤部位，这可能导致暂时或永久性瘢痕。成纤维细胞是纤维化中的效应细胞并且存在于身体的每个组织中，其为损伤后的组织修复提供结构支撑和支架。在病理性纤维化中，肌成纤维细胞在对损伤和/或触发信号的纤维增殖反应中产生紧密的纤维***。由此产生的疤痕可能会永久性地损害受影响组织的结构和功能，如肝硬化或肺纤维化。肺纤维化是纤维蛋白、细胞外基质、***和肺瘢痕的过度沉积。瘢痕可以改变肺结构，取代功能组织，并导致肺功能障碍。临床、影像学和尸检数据表明，肺纤维化在严重急性呼吸窘迫综合征(SARS)病理学中发展，目前的证据表明肺纤维化也会使COVID-19复杂化。感染SARS-CoV-2后，末端气道和肺血管***的损伤会引发纤维化以应对肺损伤。在COVID-19患者住院和康复期间，用医学成像(即高分辨率计算机断层扫描)可以看到纤维化肺瘢痕。尸检时，死于COVID-19肺炎的患者表现出弥漫性肺泡损伤的特征，肺实变区域伴有液体积聚、纤维增殖以及细胞外基质和纤维蛋白在肺泡腔内沉积。(Ojo,Balogun等人2020)
血栓形成是由对血管损伤、疾病、血栓前因素和/或血流停滞的局部反应引起的具有血小板聚集物、凝固的血块或两者的血管的阻塞。止血是对血管损伤的生理反应，其中血小板的粘附、血液凝固和纤维蛋白沉积限制了失血和出血。危及生命的血栓形成是心肌梗塞(即冠状动脉或支架血栓形成)、缺血性中风(即向脑组织供血的动脉血栓形成)和静脉血栓栓塞(即腿部静脉凝块脱落引起的肺栓塞)的原因)。COVID-19患者通常会出现动脉和/或静脉血栓形成，特别是小动脉中的大量富含血小板的血栓，称为血栓性微血管病。在肺循环中，这与弥漫性水肿肺组织区域有关。COVID-19中的血栓形成通常还会影响除肺部以外的器官，包括大脑、心脏、肝和肾。(Gu,Tyagi等人2021)在突发性大血管闭塞性卒中患者中，COVID-19患者明显比没有COVID-19的患者年轻，分别为59±13和74±17；P＝0.004。(Majidi,Fifi等人2020)
血栓素(Tx)A2是一种短寿命的多不饱和脂肪酸，它是脂肪酸环加氧酶(COX)1和COX-2代谢以及随后***素(PG)内过氧化物(即PGH2)通过TxA合酶代谢的产物。COX抑制剂阻断PGH2和TxA2的合成。TxA合酶抑制剂选择性抑制TxA2合成而不抑制PGH2形成。TxA2的非活性代谢物可以在血浆中测量为TxB2，循环TxA2代谢物的尿***可以测量为2,3-丁炔-TXB2和11-去氢-TXB2。TxA2主要由活化的血小板和巨噬细胞产生，并且是血小板聚集、血管收缩、肺静脉收缩、支气管收缩、血管内皮通透性、组织因子表达和其他生物活性的有效介质。PGH2和TxA2的生物合成受到阿司匹林(乙酰水杨酸)和其他非甾体抗炎药的抑制。低剂量阿司匹林(81-100mg/天，口服)选择性抑制血小板PGH2和TxA2合成。阿司匹林是一种有效的抗血栓药物，可用于心肌梗塞和中风的二级预防。阿司匹林还可以防止静脉血栓形成中的血小板活化。(Tarantino,Amadio等人2016)COVID-19患者的血浆TxB2水平升高，血浆TxB2浓度与血栓形成和全因死亡率相关。无论COVID-19患者是否用阿司匹林治疗，都可以看到TxB2与血栓形成和死亡率的关联。(Barrett,Lee等人2020)在COVID-19住院患者中，使用低剂量阿司匹林与机械通气、ICU入院率和住院死亡率的降低的风险独立相关。(Chow,Khanna等人2021)与倾向评分匹配的COVID-19对照相比，给予高剂量阿司匹林(1,000mg/天)的COVID-19患者死亡率也有所降低。(Liu,Huang等人2021)
血栓素-***素(TP)受体介导TxA2、PGH2和某些异前列烷的直接细胞作用。TP受体在血小板、平滑肌细胞、内皮细胞、成纤维细胞、单核细胞、心肌细胞、肾小球系膜细胞、枯否细胞、少突胶质细胞、传入神经末梢、星形胶质细胞和未成熟胸腺细胞上表达。(Nakahata2008)TP受体激活导致血小板聚集、选择性肺静脉收缩、组织选择性血管内皮通透性和内皮细胞和单核细胞上的组织因子表达。(Bode,Mackman 2004)TP受体活性的后果可以包括动脉和/或静脉血栓形成、肺静脉收缩、肺动脉高压(特别是肺毛细血管压力升高)、肺血管通透性、肺水肿和猝死。这些TP依赖性作用可以被TP受体拮抗剂(如艾非曲班)抑制。
发明内容
根据上述背景，本发明提供了通过向有需要的患者施用治疗有效量的TP受体拮抗剂来治疗COVID-19的方法。
根据上述背景和其他文献，本发明部分地涉及在需要治疗的受试者中治疗或改善COVID-19的方法，该方法包括向患者施用治疗有效量的TP受体拮抗剂。COVID-19相关的肺毛细血管高压导致低氧血症，并通过测量动脉血氧饱和度得到证实。COVID-19相关的肺水肿导致呼吸困难，并被放射学证实为肺实变。COVID-19相关的纤维化限制了肺功能，并在放射学上得到证实。COVID-19相关的肺血栓性微血管病导致通气-灌注不匹配，并通过血浆纤维蛋白D-二聚体和动脉血氧饱和度升高得到证实。TP受体拮抗剂可以口服、鼻内、吸入、直肠、***、舌下、口腔、肠胃外或经皮施用。在某些优选的实施例中，该方法进一步包括向患者长期施用TP受体拮抗剂。在某些实施例中，TP受体拮抗剂包含治疗有效量的3-[2-[[(1S,2R,3S,4R)-3-[4-(戊基氨基甲酰基)-1,3-噁唑-2-基]-7-氧杂双环[2.2.1]庚烷-2-基]甲基]苯基]丙酸(艾非曲班)及其药学上可接受的盐。在某些其他实施例中，TP受体拮抗剂包含治疗有效量的3-[2-[[(1S,2R,3S,4R)-3-[4-(戊基氨基甲酰基)-1,3-噁唑-2-基]-7-氧杂双环[2.2.1]庚烷-2-基]甲基]苯基]丙酸单钠盐(艾非曲班钠)。在某些优选的实施例中，患者的肺功能得到维持或改善。
本发明的某些实施例涉及方法，其中预防性施用TP受体拮抗剂以预防患者的呼吸衰竭、和/或预防性地施用以预防患者的肺水肿。在某些优选的实施例中，治疗有效量是从约10mg至约1,500mg。在某些优选的实施例中，TP受体拮抗剂是艾非曲班钠并且治疗有效量是从约50mg至约250mg/天。在某些实施例中，口服施用艾非曲班。在某些实施例中，本发明涉及在有需要的患者中治疗和/或改善COVID-19的方法，该方法包括向有需要的患者施用治疗有效量的TP受体拮抗剂以提供约0.1ng/mL至约10,000ng/mL的所希望的TP受体拮抗剂的血浆浓度。
本发明还涉及通过施用本文所述的TP受体拮抗剂为患有COVID-19的人类患者提供缓解呼吸短促或低氧血症的方法。
本发明进一步涉及通过施用本文所述的TP受体拮抗剂来减少患有COVID-19的人类患者的肺水肿来改善血液氧合和向组织输送氧的方法。
本发明进一步涉及通过施用本文所述的TP受体拮抗剂来降低与COVID-19相关的肺毛细血管高压来改善血液氧合和向组织输送氧的方法。
本发明进一步涉及通过施用本文所述的TP受体拮抗剂来降低与COVID-19相关的肺血栓性微血管病来改善血液氧合和向组织输送氧的方法。
本发明进一步涉及治疗患有COVID-19的人类患者的肺功能障碍的方法，该方法包括向人类患者长期施用治疗有效量的TP受体拮抗剂。在某些优选的实施例中，血栓素A2受体拮抗剂是3-[2-[[(1S,2R,3S,4R)-3-[4-(戊基氨基甲酰基)-1,3-噁唑-2-基]-7-氧杂双环[2.2.1]庚烷-2-基]甲基]苯基]丙酸(艾非曲班)及其药学上可接受的盐，并且在某些最优选的实施例中，TP受体拮抗剂是3-[2-[[(1S,2R,3S,4R)-3-[4-(戊基氨基甲酰基)-1,3-噁唑-2-基]-7-氧杂双环[2.2.1]庚烷-2-基]甲基]苯基]丙酸单钠盐(艾非曲班钠)。治疗有效量可以是例如从约50mg至约300mg。可以以从约50或100mg至约250mg/天的量施用TP受体拮抗剂。在某些实施例中，TP受体拮抗剂是艾非曲班或其药学上可接受的盐，并且日剂量是从约50mg至约250mg/天。在某些实施例中，口服施用艾非曲班。在某些实施例中，肺功能障碍是肺水肿和肺硬化。在某些实施例中，治疗有效量的艾非曲班提供改善的肺力学(lungmechanics)和患者的血液氧合。
本发明还涉及在需要治疗的一个或多个哺乳动物或者一个或多个人类中治疗COVID-19的方法和组合物，该方法包括向有需要的一个或多个受试者或者一个或多个患者施用治疗有效量的TP受体拮抗剂。优选地，治疗方法包括施用组合物，该组合物包括以有效改善肺功能的量向有需要的COVID-19患者施用治疗有效量的TP受体拮抗剂。进一步提供了在需要此类治疗的一个或多个受试者或者一个或多个患者中预防肺纤维化的方法，该方法包括以有效减少没有这样的治疗时可能发生的纤维化组织形成的量施用包含TP受体拮抗剂的组合物。
具体实施方式
根据上述背景，认为向有需要的一个或多个受试者或者一个或多个患者施用治疗有效量的TP受体拮抗剂可以治疗与SARS-CoV-2感染或COVID-19相关的肺功能障碍。短语“治疗有效量”是指以适用于任何治疗的合理收益/风险比产生一些所希望的局部或全身作用的物质的量。这种物质的有效量将根据所治疗的受试者和疾病病症、受试者的体重和年龄、受试者是禁食还是进食、疾病病症的严重程度、施用方式等而变化，这可以由本领域的普通技术人员容易确定。
TP受体是位于血小板、免疫细胞、平滑肌、内皮细胞、成纤维细胞和心肌细胞中的跨膜G蛋白偶联受体，其持续激活可以对肺部产生有害后果。例如，在全表型关联研究(PheWAS)中发现了人类TP受体基因TBXA2R的功能获得性突变，因为这种突变与转移性癌症以及肺心病、肺动脉高压、原发性肺动脉高压和肺移植的发病率高于正常水平有关。(Pulley,Jerome等人2018,Werfel,Hicks等人2020)
West已经表明，在肺动脉高压压力超负荷模型(West,Voss等人2016)和杜氏肌营养不良模型(West,Galindo等人2019)中，用艾非曲班阻断TP受体可以显著降低右心室纤维化并改善心功能。
在住院的COVID-19患者中，TxA2的合成(由TxB2的血浆浓度证明)与死亡率密切相关。(Barrett,Lee等人2020)患有COVID-19的重症患者可能会被诊断为成人呼吸窘迫综合征(ARDS)，其特征是肺损伤导致肺水肿、肺血管通透性增加和终末气道积液。然而，COVID-19中的心肺动力学与典型的ARDS在以下方面略有不同：“COVID-19患者的肺血管阻力正常，与对照受试者的相似[1.6(1.1-2.5)比1.6(0.9-2.0)WU,P＝0.343]，低于ARDS患者报告的水平(P<0.01)。76％的COVID-19患者和19％的对照受试者存在肺动脉高压(P<0.001)，并且其总是出现在毛细血管后。COVID-19患者的肺动脉楔压高于ARDS患者，并且与肺顺应性呈负相关(r＝-0.46，P＝0.038)。”(Caravita,Baratto等人2020)请注意，COVID-19患者的肺动脉高压是毛细血管后的，这反映在较高的肺动脉楔压(肺毛细血管血压的估计值)上，并且与肺顺应性成反比-较高的肺硬化在很大程度上由于肺水肿。TP受体依赖性毛细血管后肺动脉高压可由选择性肺静脉收缩导致，其将肺动脉楔压升高。(Wakerlin,Finn等人1995)COVID-19尸检后肺组织显示血小板聚集物阻塞了微血管***。(Ackermann,Verleden等人2020)负责COVID-19患者肺病理的一种或多种介质尚不清楚，但TxA2合成增加和导致的血小板聚集、肺静脉收缩和血管内皮通透性增加与TxA2和TP受体激活的主要致病作用一致。
在SARS-CoV-2介导的肺损伤中，由于毛细血管后肺动脉高压导致的肺毛细血管压力升高会极大地扩大肺积液，使肺水的淋巴引流不堪重负，并导致肺水肿。已知肺循环中升高的TxA2和TP受体激活导致肺动脉高压，这是由于选择性肺静脉收缩(即毛细血管后肺微静脉和静脉的收缩)导致肺毛细血管血压升高。(Yoshimura,Tod等人1989)用TP受体拮抗剂(如艾非曲班)治疗COVID-19可降低升高的肺毛细血管压力、减少肺水肿、改善肺力学、缩短住院时间并提高生存率。用艾非曲班早期治疗SARS-CoV-2感染可预防毛细血管后肺动脉高压、肺水肿和肺硬化的发展。
肺毛细血管压力升高会促进肺积液，当肺血管通透性增加时，这种情况可能会被极大地扩大。稳定的TxA2模拟物U-46,619(9,11-二脱氧基-9α,11α-甲烷环氧基***素F2α)激活TP受体。在临床前研究中，U-16,619输注强烈增加了肺中的血浆液和蛋白质积累，这种作用被TP受体拮抗剂SQ29548完全阻断。在心脏和肾中观察到血浆液和蛋白质积累的较小的TP受体依赖性增加。作者得出结论：“目前的研究结果表明，TxA2受体激活会急剧增加血细胞比容，可能是通过诱导血浆液从血管室向间质转移。…这一假设在使用埃文斯蓝染料作为白蛋白外渗的可靠标志物的研究中得到证实；结果表明，白蛋白和可能的其他蛋白质的微血管移位中存在器官特异性增加。”(Bertolino,Valentin等人1995)这些对经血管液体和蛋白质通量的影响不仅需要增加毛细血管血压，还需要增加血管通透性。
在急性肺损伤患者中，用艾非曲班阻断TP受体选择性地放松肺静脉并降低毛细血管后阻力，从而降低肺毛细血管压力。(Schuster,Kozlowski等人2001)在冠状病毒介导的肺损伤COVID-19患者中，TP受体依赖性肺静脉收缩会加重肺液体积聚并扩大肺水肿，而这种危及生命的疾病过程可以通过用艾非曲班的TP受体阻断得到改善。
肺损伤激发触发TxA2的释放，并且TxA2合成或活性的抑制改善许多但不是所有这些早期肺损伤反应(例如，肺动脉高压、低氧血症、肺水肿)。特别是，用艾非曲班(也称为SQ34451和BMS-180291)或密切相关的7-氧杂双环[2.2.1]庚烷化合物(即SQ29548、SQ28668和SQ30741)阻断TP受体抑制了肺损伤相关的肺动脉高压、低氧血症、和肺水肿(Schumacher,Adams等人1987,Kuhl,Bolds等人1988,Klausner,Paterson等人1989,Sandberg,Edberg等人1994,Smith,Murphy等人1994,Thies,Corbin等人1996,Quinn和Slotman 1999,Collins,Blum等人2001,Kobayashi,Horikami等人2016)。
由于肺水肿、支气管收缩和肺顺应性降低以及肺泡气体交换单元的通气和灌注不匹配，COVID-19患者表现出呼吸急促和动脉血氧饱和度低。COVID-19中低氧血症的原因很复杂，尚未完全了解。在细菌感染(即脓毒症)后肺损伤的动物模型中，与脓毒症对照组相比，艾非曲班阻断TP受体可改善全身和肺血管收缩，并显著增加动脉和组织氧合。(Quinn和Slotman 1999)在COVID-19患者中可能会看到类似的艾非曲班缓解低氧血症。
异前列烷(例如8-异-PGF2α和8-异-PGE2)在结构上与***素相似，也能激活TP受体(Acquaviva,Vecchio等人2013)；然而，它们是通过在氧衍生的自由基对含有酯化花生四烯酸酯部分的磷脂的攻击之后，与PGH2和TxA2不同的途径以非酶促方式产生的。游离异前列烷通过磷脂酶A2从氧化的磷脂中释放出来。游离异前列烷是由独立于环氧合酶和TxA合酶的机制产生的TP受体激活剂，因此对非甾体抗炎药和TxA合酶抑制剂不敏感。异前列烷特别令人感兴趣，因为它们的合成是由氧化应激触发的，它们的TP受体依赖性作用被艾非曲班和其他TP受体拮抗剂阻断，并且它们在急性肺损伤或ARDS患者中释放。(Carpenter,Price等人1998；Nanji,Liong等人2013；West,Voss等人2016)
许多COVID-19患者出现肺纤维化，特别是如果他们在机械通气和重症监护后存活下来。COVID-19的长期症状类似于特发性肺纤维化引起的症状，包括咳嗽、呼吸困难和疲劳。目前，有COVID-19尸检证据表明弥漫性肺泡损伤(DAD)进展为纤维化。作者总结说：“虽然我们在致命病例中观察到纤维化DAD，但幸存的患者是否有发生肺纤维化的风险以及这种并发症的发生频率将需要进一步的临床和放射学随访研究。”(Li,Wu等人2021)
肺纤维化的发病机制已被建模并发现是由游离异前列烷的产生引发的。8-异-PGF2α激活TP受体，导致潜在的TGFβ(已知的纤维增殖性障碍的介质)激活。在博来霉素肺纤维化模型中，艾非曲班阻断了纤维化的发展。(Suzuki,Kropski等人2021)在恢复期的COVID-19患者中，预防和治疗COVID-19相关的肺纤维化有望成为一个公共卫生问题，有效的治疗将采用临床有效剂量的TP受体拮抗剂方案，如艾非曲班。
TxA2和TP受体激活最公认的生物学效应是血小板依赖性血栓形成。艾非曲班和其他TP受体拮抗剂阻断TxA2介导的血栓形成。小鼠慢性缺氧产生肺动脉高压和肺血管内血栓形成，这两种情况在COX-2敲除小鼠中均得到增强，并通过艾非曲班治疗加以预防。(Cathcart,Tamosiuniene等人2008)。在纽约市大型卫生***中因COVID-19住院的患者中，血栓性事件发生率为16.0％。在829名COVID-19ICU患者中，29.4％具有血栓性事件(13.6％静脉和18.6％动脉)。在2,505名COVID-19非ICU患者中，11.5％具有血栓性事件(3.6％静脉和8.4％动脉)。COVID-19患者的血栓性事件概率明显高于其他肺损伤住院患者(2009年流感大流行期间血栓性事件的发生率为5.9％)。Bilaloglu,Aphinyanaphongs等人2020)除了血小板介导的血栓形成外，TxA2和TP受体激活还可触发由内皮细胞和单核细胞上的组织因子表达引发的血液凝固。(Bode,Mackman 2014)因此，在SARS-CoV-2受损的肺循环中，肺微静脉、血小板、单核细胞和内皮细胞中的强TP受体信号产生一种不寻常的血栓前状态，这种状态可以通过TP受体阻断来缓解，尤其用艾非曲班的有效剂量方案。
根据本发明，认为通过TP受体增加的异前列烷信号传导有助于COVID-19中的肺纤维化，因此用口服活性TP受体拮抗剂艾非曲班治疗将阻止肺纤维化的进展，改善肺功能测试，并从COVID-19中实现更完整的恢复。
如本文所用，术语“TP受体拮抗剂”是指当以治疗有效剂量使用时，在标准生物测定中或在体内或离体，将TP受体的表达或活性抑制至少或至少约30％、50％、60％、75％、90％、95％、96％、97％、98％、99％或100％的化合物。在某些实施例中，TP受体拮抗剂抑制TxA2与受体的结合。TP受体拮抗剂包括竞争性拮抗剂(即，与激动剂竞争受体占据的拮抗剂)和非竞争性拮抗剂。TP受体拮抗剂包括受体的抗体。抗体可以是单克隆的。它们可以是人或人源化抗体。TP受体拮抗剂可以是通过沉默RNA(即，siRNA)技术阻止受体表达的分子。TP受体拮抗剂还包括具有TP受体拮抗剂活性和TxA合酶抑制剂活性的TxA合酶抑制剂。
TP受体拮抗剂
大约40年来，TP受体拮抗剂的发现和开发一直是许多制药公司的目标。这些公司鉴定的某些单独的化合物，无论是否伴随TxA2合酶抑制活性，包括艾非曲班(SQ34451；BMS-180291；Bristol-Myers Squibb)、SQ29548(BMS)、SQ28668(BMS)、SQ30741(BMS)、AA-2414(Abbott)、R68070(Janssen)、BAY u 3405(Bayer)、吡考他胺(picotamide)(Sandoz)、特波格雷(terbogrel)(BI)、L670596(Merck)、L655240(Merck)、ICI-192605(Zeneca)、ICI-185282(Zeneca)、ICI-159995(Zeneca)、SKF-88046(Smith-Kline)、EP-092(U.Edinburgh)、NTP-42(ATXA)、S-1452(Shionogi)、GR32191B(Glaxo)、和S-18886(Servier)。临床前药理学已经确定，这类化合物具有通过抑制***素内过氧化物和TxA2途径获得的有效抗血栓活性。这些化合物还可预防由TxA2和其他类花生酸(包括作用于血管床内的TP受体的某些异前列烷)诱导的血管收缩，因此可能有益于预防和/或治疗肺动脉高压、纤维增生性障碍、肝肾综合征和/或肝性脑病。
用于本发明的合适的TP受体拮抗剂可以包括，例如但不限于小分子，例如艾非曲班{BMS；[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(戊基氨基)羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]甲基]苯丙酸；或IUPAC命名法：3-[2-[[(1S,2R,3S,4R)-3-[4-(戊基氨基甲酰基)-1,3-噁唑-2-基]-7-氧杂双环[2.2.1]庚烷-2-基]甲基]苯基]丙酸}，以及美国专利申请公开号2009/0012115中描述的其他物质，其披露内容特此通过引用以其全文并入。
适用于本文的额外的TP受体拮抗剂还描述于：美国专利号4,839,384(Ogletree)；美国专利号5,066,480(Ogletree,等人)；美国专利号5,100,889(Misra,等人)；美国专利号5,312,818(Rubin,等人)；美国专利号5,399,725(Poss,等人)；和美国专利号6,509,348(Ogletree)，其披露内容特此通过引用以其全文并入。
这些可以包括但不限于：
如美国专利号5,100,889中披露的间亚苯基7-氧杂双环-庚基取代的杂环酰胺***素类似物，包括：
[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-环己基丁基)氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]甲基]苯丙酸(SQ 33,961)或其酯或盐；
[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[[(4-氯-苯基)-丁基]氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]甲基]苯丙酸或其酯或盐；
[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-环己基丁基)-氨基]羰基]-2-噁唑基]-7-氧杂双环]2.2.1]庚-2-基]苯乙酸或其酯或盐；
[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(4-环己基-丁基)氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]甲基]苯氧基]乙酸或其酯或盐；
[1S-(1α,2α,3α,4α)]-2-[[3-[4-[[(7,7-二甲基辛基)-氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-甲基]苯丙酸或其酯或盐；
如1992年3月31日发布的美国专利号5,100,889中披露的7-氧杂二环庚基取代的杂环酰胺***素类似物，包括：
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[(4-环己基丁基)氨基]-羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[(4-环己基-丁基)氨基]羰基]-2-噻唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[(4-环己基-丁基)甲基氨基]羰基]-2-噁唑基]-7-氧杂双环-[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[(1-吡咯烷基)-羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[(环己基-氨基)-羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[(2-环己基-乙基)氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[[2-(4-氯-苯基)乙基]氨基]羰基]-2-噁唑基]-7-氧杂双环-[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[(4-氯苯基)氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[[4-(4-氯-苯基)丁基]氨基]羰基]-2-噁唑基]-7-氧杂双环-[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4α-[[-(6-环己基-己基)氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸,或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[(6-环己基-己基)氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[(丙基氨基)-羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[(4-丁基苯基)氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[(2,3-二氢-1H-吲哚-1-基)羰基]-2-噁唑基]-7-氧杂双环(2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[(4-环己基-丁基)氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-N-(苯基磺酰基)-4-己烯酰胺；
[1S-[lα,2α(Z),3α,4α)]]-6-[3-[4-[[(4-环己基-丁基)氨基]羰基]-2-噁唑基]-N-(甲基磺酰基)-7-氧杂双环[2-2.1]庚-2-基]-4-己烯酰胺；
[1S-(1α,2α(Z),3α,4α)]-7-[3-[4-[[(4-环己基-丁基)氨基]羰基]-2-噁唑基]-7-氧杂双环(2.2.1]庚-2-基]-5-庚烯酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[(4-环己基-丁基)氨基]羰基]-lH-咪唑-2-基]-7-氧杂双环-[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-[1α,2α,3α,4α]-6-[3-[4-[[(7,7-二甲基辛基)氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
[1S-(1α,2α(E),3α,4α)]-6-[3-[4-[[(4-环己基-丁基)氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸；
[1S-(1α,2α,3α,4α)-3-[4-[[(4-(环己基丁基)-氨基]羰基]-2-噁唑基]-7-氧杂双环[2.2.1]庚烷-2-己酸或其酯或盐；
[1S-(1α,2α(Z),3α,4α)]-6-[3-[4-[[(4-环己基-丁基)氨基]羰基]-2-噁唑基]-7-氧杂双环-[2.2.1]庚-2-基]-4-己烯酸或其酯或盐；
美国专利号4,537,981中披露的7-氧杂双环庚烷和7-氧杂双环庚烯化合物，Snitman等人，其披露内容特此通过引用以其全文并入，例如：
[1S-(1α,2α(Z),3α(1E,3S*,4R*),4α)]]-7-[3-(3-羟基-4-苯基-1-戊烯基)-7-氧杂双环[2.2.1]庚-2-基]-5-庚烯酸(SQ 29,548)；
美国专利号4,416,896中披露的7-氧杂双环庚烷取代的氨基***素类似物，Nakane等人，其披露内容特此通过引用以其全文并入，例如：
[1S-(1α,2α(Z),3α,4α)]-7-[3-[[2-(苯基氨基)羰基]-肼基]甲基]-7-氧杂双环[2.2.1]庚-2-基]-5-庚烯酸；
美国专利号4,663,336中披露的7-氧杂双环庚烷取代的二酰胺***素类似物，Nakane等人，其披露内容特此通过引用以其全文并入，例如：
[1S-[1α,2α(Z),3α,4α]]-7-[3-[[[[(1氧代庚基)氨基]乙酰基]氨基]甲基]-7-氧杂双环[2.2.1]-庚-2-基]-5-庚烯酸和对应的四唑，和
[1S-[lα,2α(Z),3α,4α]]-7-[3-[[[[(4-环己基-1-氧代丁基)-氨基]乙酰基]氨基]甲基]-7-氧杂双环]2.2.1]庚-2-基]-5-庚烯酸；
如美国专利号4,977,174中披露的7-氧杂双环庚烷咪唑***素类似物，其披露内容特此通过引用以其全文并入，例如：
[1S-[1α,2α(Z),3α,4α]]-6-[3-[[4-(4-环己基-1-羟基丁基)-1H-咪唑-1-基]甲基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其甲基酯；
[1S-[1α,2α(Z),3α,4α]]-6-[3-[[4-(3-环己基-丙基)-1H-咪唑-1-基]甲基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其甲基酯；
[1S-[1α,2α(Z),3α,4α]]-6-[3-[[4-(4-环己基-1-氧代丁基)-1H-咪唑-1-基]甲基]-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其甲基酯；
[1S-[1α,2α(Z),3α,4α]]-6-[3-(1H-咪唑-1-基甲基)-7-氧杂双环[2.2.1]庚-2-基]-4-己烯酸或其甲基酯；或
[1S-[1α,2α(Z),3α,4α]]-6-[3-[[4-[[(4-环己基-丁基)氨基]羰基]-lH-咪唑-1-基]甲基-7-氧杂双环-[2.2.1]-庚-2-基]-4-己烯酸或其甲基酯；
美国专利号4,258,058中披露的苯氧基烷基羧酸，Witte等人，其披露内容特此通过引用以其全文并入，包括：
BM 13.177：2-[4-[2-(苯磺酰胺)乙基]苯氧基]乙酸(磺曲苯，BoehringerMannheim)；
美国专利号4,443,477中披露的磺酰氨基苯基羧酸，Witte等人，其披露内容特此通过引用以其全文并入，包括：
BM 13.505：2-[4-[2-[(4-氯苯基)磺酰基氨基]乙基]苯基]乙酸(达曲班，Boehringer Mannheim)；
美国专利号4,752,616中披露的芳基硫代烷基苯基羧酸，其披露内容特此通过引用以其全文并入，包括4-(3-((4-氯苯基)磺酰基)丙基)苯乙酸。
适用于本文的血栓素A2受体拮抗剂的其他实例包括但不限于：
R68070：5-[(E)-[吡啶-3-基-[3-(三氟甲基)苯基]亚甲基]氨基]氧基戊酸(利多格雷，Janssen)，
L670596：(-)6,8-二氟-9-p-甲基磺酰基苄基-1,2,3,4-四氢咔唑-1-基-乙酸(Merck)，
L655240：3-[1-[(4-氯苯基)甲基]-5-氟-3-甲基-2-吲哚基]-2,2-二甲基丙酸(Merck-Frosst)，
ICI-192,605：4(Z)-6-[(2,4,5-顺式)2-氯苯基1)-4-(2-羟基苯基)-1,3-二噁烷-5-基]己烯酸(ICI，Zeneca)，
ICI-185282：(Z)-7-[(2S,4S,5R)-4-(2-羟基苯基)-2-(三氟甲基)-1,3-二噁烷-5-基]庚-5-烯酸(ICI，Zeneca)，
ICI-159995：5(Z)-7-[2,2-二甲基-4-苯基-1,3-二噁烷-顺式-5-基]庚酸(ICI，Zeneca)，
SKF-88046：N,N'-双[7-(3-氯苯氨基磺酰基)-1,2,3,4-四氢-异喹啉基]二磺酰基亚胺(Smith Kline)，
EP-092：(Z,2-内型-3-氧代)-7-(3-乙酰基-2-二环[2.2.1]庚基-5-庚-3Z-烯酸，4-苯基-缩氨基硫脲化合物(Univ.Edinburgh)，
AH-23848：(E)-7-[2-吗啉-4-基-3-氧代-5-[(4-苯基苯基)甲氧基]环戊基]庚-4-烯酸(Glaxo)，
GR-32,191B：(Z)-7-[(1R,2R,3S,5S)-3-羟基-5-[(4-苯基苯基)甲氧基]-2-哌啶-1-基环戊基]庚-4-烯酸(伐哌前列素(vapiprost)；Glaxo)，
BAY u 3405：3-[[(4-氟苯基)-磺酰基]氨基]-1,2,3,4-四氢-9H-咔唑-9-丙酸；(雷马曲班(ramatroban)；Bayer)，
ONO-3708：((1S,2S,3S,5R)-3-((R)-2-环戊基-2-羟基乙酰氨基)-6,6-二甲基二环[3.1.1]庚烷-2-基)庚-5-烯酸(ONO)，
S-1452：(Z)-7-[(1R,2S,3S,4S)-3-(苯磺酰胺)-2-二环[2.2.1]庚烷基]庚-5-烯酸(多米曲班，
Shionogi)，
S-18886：3-[(6R)-6-[(4-氯苯基)磺酰基氨基]-2-甲基-5,6,7,8-四氢萘-1-基]丙酸(特卢曲班，Servier)，
AA-2414：7-苯基-7-(2,4,5-三甲基-3,6-二氧代环己-1,4-二烯-1-基)庚酸(塞曲司特(seratrodast)，Abbott)，
NTP-42：1-叔丁基-3-[5-氰基-2-[3-[4-(氟甲氧基)苯基]苯氧基]苯基]磺酰脲(ATXA Therapeutics)，
Picotamide：4-甲氧基-1-N,3-N-双(吡啶-3-基甲基)苯-1,3-二甲酰胺(Sandoz)，
Linotroban：5(2-(苯基磺酰基氨基)乙基)-噻吩基氧基-乙酸(Nycomed)，
本发明优选的TP受体拮抗剂是艾非曲班或其任何药学上可接受的盐。在某些优选的实施例中，优选的TP受体拮抗剂是艾非曲班钠(化学上称为3-[2-[[(1S,2R,3S,4R)-3-[4-(戊基氨基甲酰基)-1,3-噁唑-2-基]-7-氧杂双环[2.2.1]庚烷-2-基]甲基]苯基]丙酸单钠盐。
治疗方法
在本发明的某些实施例中，提供了通过向有需要的一个或多个患者施用治疗有效量的TP受体拮抗剂来治疗和/或改善患者或患者群体中的COVID-19的方法。治疗有效量的TP受体拮抗剂的施用可以通过任何治疗上有用的施用途径来完成，这些途径包括但不限于口服、鼻内、吸入、直肠、***、舌下、口腔、肠胃外或经皮。
在某些优选的实施例中，将TP受体拮抗剂口服施用。在某些优选的实施例中，将TP受体拮抗剂通过肠胃外注射施用。在某些优选的实施例中，将TP受体拮抗剂通过直接吸入肺中施用。在某些优选的实施例中，TP受体拮抗剂的血浆浓度范围从约0.1ng/mL至约10,000ng/mL。优选地，TP受体拮抗剂的血浆浓度范围从约1ng/mL至约1,000ng/mL。当TP受体拮抗剂是艾非曲班时，在某些实施例中用于治疗COVID-19的所希望的血浆浓度应大于约10ng/mL(艾非曲班游离酸)。TP受体拮抗剂(例如艾非曲班)的一些治疗作用可以在大于约1ng/mL的浓度下观察到。施用剂量应根据患者的年龄、体重和状况、进食或禁食状态，以及施用途径、剂型和方案以及所希望的结果进行调整。
为了获得治疗COVID-19患者所希望的TP受体拮抗剂的血浆浓度，TP受体拮抗剂的日剂量优选为约0.1mg至约5,000mg。在某些优选的实施例中，TP受体拮抗剂是长期施用的。日剂量的范围可以从约1mg至约1,000mg；约10mg至约1,000mg；约50mg至约250mg；约100mg至约500mg；约200mg至约500mg；约300mg至约500mg；或从约400mg至约500mg/天。在某些优选的实施例中，当动物是人类患者时，治疗有效量是从约50mg至约2,000mg/天、或从约10mg至250mg/天、或从约200mg至约1,000mg/天，并且在某些实施例中，更优选从约50至约500mg/天、或从约100mg至约500mg/天。
日剂量可以分次施用或以一次推注或单位剂量或以多剂量同时施用。在这方面，艾非曲班可以口服、鼻内、吸入、直肠、***、舌下、口腔、肠胃外或经皮施用。在某些优选的实施例中，上述药物组合物的治疗有效量是从约10mg至约300mg艾非曲班(或其药学上可接受的盐)/天。在某些优选的实施例中，治疗有效量是从约50至约250mg/天，并且在某些实施例中，从约150mg至约350mg/天将产生用于治疗COVID-19的治疗上有效的血浆水平的艾非曲班游离酸。在某些优选的实施例中，艾非曲班钠从约10mg至约250mg(艾非曲班游离酸量)的日剂量将产生用于治疗COVID-19的治疗上有效的血浆水平的艾非曲班游离酸。
优选地，用于治疗COVID-19的治疗上有效的血浆浓度的TP受体拮抗剂范围为从约1ng/mL至约1,000ng/mL。当TP受体拮抗剂是艾非曲班时，对TP受体活化产生抑制作用并因此血小板活化减少的所希望的血浆浓度应大于约10ng/mL(艾非曲班游离酸)。TP受体拮抗剂(例如艾非曲班)的一些抑制作用可以在大于约1ng/mL的浓度下观察到。
施用剂量必须根据患者的年龄、体重和状况，以及施用途径、剂型和方案以及所希望的结果进行仔细地调整。然而，为了获得所希望的TP受体拮抗剂血浆浓度，应被施用的TP受体拮抗剂的日剂量范围从约1mg至约5000mg。优选地，TP受体拮抗剂的日剂量范围为从约1mg至约1000mg；约10mg至约1000mg；约50mg至约500mg；约100mg至约500mg；约200mg至约500mg；约300mg至约500mg；以及约400mg至约500mg/天。在某些优选的实施例中，艾非曲班钠的日剂量从约10mg至约250mg(艾非曲班游离酸量)将产生有效血浆水平的艾非曲班游离酸。
药物组合物
本发明的TP受体拮抗剂可以通过任何药学上有效的途径施用。例如，TP受体拮抗剂可以以这样的方式配制，使得它们可以口服、鼻内、吸入、直肠、***、舌下、口腔、肠胃外或透皮施用，并因此相应地配制。
在某些实施例中，TP受体拮抗剂可以配制成药学上可接受的口服剂型。口服剂型可以包括但不限于口服固体剂型和口服液体剂型。口服固体剂型可以包括但不限于片剂、胶囊、囊片、粉剂、丸剂、多颗粒剂、珠、球体及其任何组合。这些口服固体剂型可以配制成立即释放、控制释放、持续(延长)释放或改良释放制剂。
本发明的口服固体剂型还可以含有药学上可接受的赋形剂，例如填充剂、稀释剂、润滑剂、表面活性剂、助流剂、粘合剂、分散剂、助悬剂、崩解剂、增粘剂、成膜剂、制粒助剂、调味剂、甜味剂、包衣剂、增溶剂及其组合。
取决于所希望的释放曲线，本发明的口服固体剂型可以含有适量的控释剂、缓释剂或改良释放剂。
口服液体剂型包括但不限于溶液、乳液、悬浮液和糖浆。这些口服液体剂型可以与本领域技术人员已知的用于制备液体剂型的任何药学上可接受的赋形剂一起配制。例如，水、甘油、简单糖浆、酒精及其组合。
在本发明的某些实施例中，TP受体拮抗剂可以配制成适合肠胃外使用的剂型。例如，该剂型可以是冻干粉剂、溶液剂、混悬剂(例如，贮库混悬剂)。在其他实施例中，TP受体拮抗剂可配制成局部剂型，例如但不限于贴剂、凝胶、糊剂、乳膏、乳剂、搽剂、香膏、洗剂和软膏。
优选实施例的详细描述
以下实例不旨在限制，并且代表本发明的某些实施例。
实例I
在本实例中，艾非曲班钠片用表1中列出的以下成分制备：
表1
使用合适的混合器将艾非曲班的钠盐、氧化镁、甘露醇、微晶纤维素和交聚维酮混合在一起约2至约10分钟。将所得混合物穿过#12至#40目大小的筛。此后，添加硬脂酸镁和胶体二氧化硅并继续混合约1至约3分钟。然后将所得均匀混合物压制成片剂，每片含有35mg艾非曲班钠盐。
实例II
在本实例中，1,000片每片含有400mg艾非曲班钠的片剂由表2中列出的以下成分制成：
表2
实例III
用表3中列出的以下成分制备艾非曲班钠注射液供静脉使用：
表3
将艾非曲班的钠盐、防腐剂和氯化钠溶解在3升注射用水中，然后将体积增加到5升。溶液通过无菌过滤器过滤并无菌填充到预先灭菌的小瓶中，然后用预先灭菌的橡胶塞封闭。每个小瓶含有75mg活性成分/150mL溶液的浓度。
参考文献
Ackermann,M.,S.E.Verleden,M.Kuehnel,A.Haverich,T.Welte,F.Laenger,A.Vanstapel,C.Werlein,H.Stark,A.Tzankov,W.W.Li,V.W.Li,S.J.Mentzer andD.Jonigk(2020)."Pulmonary Vascular Endothelialitis,Thrombosis,andAngiogenesis in Covid-19."N Engl J Med 383(2):120-128.
Acquaviva,A.,D.Vecchio,B.Arezzini,M.Comporti and C.Gardi(2013)."Signaling pathways involved in isoprostane-mediated fibrogenic effects in rathepatic stellate cells."Free Radic Biol Med 65:201-207.
Barrett,T.J.,A.H.Lee,Y.Xia,L.H.Lin,M.Black,P.Cotzia,J.Hochman andJ.S.Berger(2020)."Platelet and Vascular Biomarkers Associate With Thrombosisand Death in Coronavirus Disease."Circ Res 127(7):945-947.
Begley,C.J.,M.L.Ogletree,B.O.Meyrick and K.L.Brigham(1984)."Modification of pulmonary responses to endotoxemia in awake sheep bysteroidal and nonsteroidal anti-inflammatory agents."Am Rev Respir Dis 130(6):1140-1146.
Bertolino,F.,J.P.Valentin,M.Maffre,A.M.Bessac and G.W.John(1995)."TxA2 receptor activation elicits organ-specific increases in microvascularpermeability in the rat."Am J Physiol 268(2 Pt 2):R366-374.
Bilaloglu,S.,Y.Aphinyanaphongs,S.Jones,E.Iturrate,J.Hochman andJ.S.Berger(2020)."Thrombosis in Hospitalized Patients With COVID-19 in a NewYork City Health System."JAMA 324(8):799-801.
Bode,M.and N.Mackman(2014)."Regulation of tissue factor geneexpression in monocytes and endothelial cells:Thromboxane A2 as a newplayer."Vascul Pharmacol 62(2):57-62.
Brigham,K.L.,C.J.Begley,G.R.Bernard,A.A.Hutchison,J.E.Loyd,W.D.Lucht,B.Meyrick,J.H.Newman,M.E.Niedermeyer,M.L.Ogletree and et al.(1983)."Septicemia and lung injury."Clin Lab Med 3(4):719-744.
Caravita,S.,C.Baratto,F.Di Marco,A.Calabrese,G.Balestrieri,F.Russo,A.Faini,D.Soranna,G.B.Perego,L.P.Badano,L.Grazioli,F.L.Lorini,G.Parati andM.Senni(2020)."Haemodynamic characteristics of COVID-19 patients with acuterespiratory distress syndrome requiring mechanical ventilation.An invasiveassessment using right heart catheterization."Eur J Heart Fail 22(12):2228-2237.
Carpenter,C.T.,P.V.Price and B.W.Christman(1998)."Exhaled breathcondensate isoprostanes are elevated in patients with acute lung injury orARDS."Chest 114(6):1653-1659.
Cathcart,M.C.,R.Tamosiuniene,G.Chen,T.G.Neilan,A.Bradford,K.J.O'Byrne,D.J.Fitzgerald and G.P.Pidgeon(2008)."Cyclooxygenase-2-linkedattenuation of hypoxia-induced pulmonary hypertension and intravascularthrombosis."J Pharmacol Exp Ther 326(1):51-58.
Chow,J.H.,A.K.Khanna,S.Kethireddy,D.Yamane,A.Levine,A.M.Jackson,M.T.McCurdy,A.Tabatabai,G.Kumar,P.Park,I.Benjenk,J.Menaker,N.Ahmed,E.Glidewell,E.Presutto,S.Cain,N.Haridasa,W.Field,J.G.Fowler,D.Trinh,K.N.Johnson,A.Kaur,A.Lee,K.Sebastian,A.Ulrich,S.Pena,R.Carpenter,S.Sudhakar,P.Uppal,B.T.Fedeles,A.Sachs,L.Dahbour,W.Teeter,K.Tanaka,S.M.Galvagno,D.L.Herr,T.M.Scalea and M.A.Mazzeffi(2021)."Aspirin Use Is Associated WithDecreased Mechanical Ventilation,Intensive Care Unit Admission,and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019."Anesth Analg 132(4):930-941.
Collins,B.J.,M.G.Blum,R.E.Parker,A.C.Chang,K.S.Blair,G.L.Zorn,3rd,B.W.Christman and R.N.Pierson,3rd(2001)."Thromboxane mediates pulmonaryhypertension and lung inflammation during hyperacute lung rejection."J ApplPhysiol(1985)90(6):2257-2268.
Ganter,C.C.,S.M.Jakob and J.Takala(2006)."Pulmonary capillarypressure.A review."Minerva Anestesiol 72(1-2):21-36.
Gu,S.X.,T.Tyagi,K.Jain,V.W.Gu,S.H.Lee,J.M.Hwa,J.M.Kwan,D.S.Krause,A.I.Lee,S.Halene,K.A.Martin,H.J.Chun and J.Hwa(2021)."Thrombocytopathy andendotheliopathy:crucial contributors to COVID-19 thromboinflammation."Nat RevCardiol 18(3):194-209.
Gupta,A.,K.Kalantar-Zadeh and S.T.Reddy(2020)."Ramatroban as a NovelImmunotherapy for COVID-19."J Mol Genet Med 14(3).
Hasan,S.S.,T.Capstick,R.Ahmed,C.S.Kow,F.Mazhar,H.A.Merchant andS.T.R.Zaidi(2020)."Mortality in COVID-19 patients with acute respiratorydistress syndrome and corticosteroids use:a systematic review and meta-analysis."Expert Rev Respir Med 14(11):1149-1163.
Klausner,J.M.,I.S.Paterson,G.Goldman,L.Kobzik,C.R.Valeri,D.Shepro andH.B.Hechtman(1989)."Thromboxane A2 mediates increased pulmonary microvascularpermeability following limb ischemia."Circ Res 64(6):1178-1189.
Kobayashi,K.,D.Horikami,K.Omori,T.Nakamura,A.Yamazaki,S.Maeda andT.Murata(2016)."Thromboxane A2 exacerbates acute lung injury via promotingedema formation."Sci Rep 6:32109.
Kuhl,P.G.,J.M.Bolds,J.E.Loyd,J.R.Snapper and G.A.FitzGerald(1988)."Thromboxane receptor-mediated bronchial and hemodynamic responses in ovineendotoxemia."Am J Physiol 254(2 Pt 2):R310-319.
Li,Y.,J.Wu,S.Wang,X.Li,J.Zhou,B.Huang,D.Luo,Q.Cao,Y.Chen,S.Chen,L.Ma,L.Peng,H.Pan,W.D.Travis and X.Nie(2021)."Progression to fibrosing diffusealveolar damage in a series of 30 minimally invasive autopsies with COVID-19pneumonia in Wuhan,China."Histopathology 78(4):542-555.
Liu,Q.,N.Huang,A.Li,Y.Zhou,L.Liang,X.Song,Z.Yang and X.Zhou(2021)."Effect of low-dose aspirin on mortality and viral duration of thehospitalized adults with COVID-19."Medicine(Baltimore)100(6):e24544.
Majidi,S.,J.T.Fifi,T.R.Ladner,J.Lara-Reyna,K.A.Yaeger,B.Yim,N.Dangayach,T.J.Oxley,T.Shigematsu,B.R.Kummer,L.K.Stein,J.Weinberger,M.G.Fara,R.De Leacy,M.S.Dhamoon,S.Tuhrim and J.Mocco(2020)."Emergent LargeVessel Occlusion Stroke During New York City's COVID-19 Outbreak:ClinicalCharacteristics and Paraclinical Findings."Stroke 51(9):2656-2663.
Marshall,M.(2020)."The lasting misery of coronavirus long-haulers."Nature 585(7825):339-341.
McDonald,L.T.(2021)."Healing after COVID-19:are survivors at risk forpulmonary fibrosis？"Am J Physiol Lung Cell Mol Physiol 320(2):L257-L265.
Nakahata,N.(2008)."Thromboxane A2:physiology/pathophysiology,cellularsignal transduction and pharmacology."Pharmacol Ther 118(1):18-35.
Nanji,A.A.,E.C.Liong,J.Xiao and G.L.Tipoe(2013)."Thromboxaneinhibitors attenuate inflammatory and fibrotic changes in rat liver despitecontinued ethanol administrations."Alcohol Clin Exp Res 37(1):31-39.
Ogletree,M.L.,C.J.Begley,G.A.King and K.L.Brigham(1986)."Influence ofsteroidal and nonsteroidal anti-inflammatory agents on the accumulation ofarachidonic acid metabolites in plasma and lung lymph after endotoxemia inawake sheep.Measurements of prostacyclin and thromboxane metabolites and 12-HETE."Am Rev Respir Dis 133(1):55-61.
Ojo,A.S.,S.A.Balogun,O.T.Williams and O.S.Ojo(2020)."PulmonaryFibrosis in COVID-19 Survivors:Predictive Factors and Risk ReductionStrategies."Pulm Med 2020:6175964.
Pulley,J.M.,R.N.Jerome,M.L.Ogletree,G.R.Bernard,R.R.Lavieri,N.M.Zaleski,C.C.Hong,J.K.Shirey-Rice,C.L.Arteaga,I.A.Mayer,K.J.Holroyd andR.S.Cook(2018)."Motivation for Launching a Cancer Metastasis Inhibition(CMI)Program."Target Oncol 13(1):61-68.
Quinn,J.V.and G.J.Slotman(1999)."Platelet-activating factor andarachidonic acid metabolites mediate tumor necrosis factor and eicosanoidkinetics and cardiopulmonary dysfunction during bacteremic shock."Crit CareMed 27(11):2485-2494.
Sandberg,K.,K.E.Edberg,W.Fish,R.A.Parker,C.Hellerqvist and H.Sundell(1994)."Thromboxane receptor blockade(SQ 29,548)in group B streptococcaltoxin challenge in young lambs."Pediatr Res 35(5):571-579.
Schumacher,W.A.,H.D.Adams and M.L.Ogletree(1987)."Effect of thethromboxane A2-receptor antagonists,SQ 29,548 and SQ 28,668,on the pulmonaryhypertensive response to endotoxemia in swine."Pharmacology 34(6):301-308.
Schuster,D.P.,Kozlowski,J.,Brimioulle,S.(2001).Effect of thromboxanereceptor blockade on pulmonary capillary hypertension in acute lunginjury.American Thoracic Society.
Smith,W.J.,M.P.Murphy,R.F.Appleyard,R.J.Rizzo,L.Aklog,R.G.Laurenceand L.H.Cohn(1994)."Prevention of complement-induced pulmonary hypertensionand improvement of right ventricular function by selective thromboxanereceptor antagonism."J Thorac Cardiovasc Surg 107(3):800-806.
Suzuki,T.Kropski,J.Chen,J.Carrier,E.Chen,X.Sherrill,T.Polosukhin,V.Han,W.Rathinasabapathy,A.Gutor,S.Gulleman,P.Banovich,N.Tanjore,H.Freeman,M.Tada,Y.Young,L.Gokey,J.Blackwell,T.West,J.(2021).The F2-Isoprostane:Thromboxane-prostanoid receptor signaling axis drives persistent fibroblastactivation in pulmonary fibrosis.(Submitted for publication)
Tarantino,E.,P.Amadio,I.Squellerio,B.Porro,L.Sandrini,L.Turnu,V.Cavalca,E.Tremoli and S.S.Barbieri(2016)."Role of thromboxane-dependentplatelet activation in venous thrombosis:Aspirin effects in mouse model."Pharmacol Res 107:415-425.
Thies,S.D.,R.S.Corbin,C.D.Goff,O.A.Binns,S.A.Buchanan,K.S.Shockey,H.F.Frierson,Jr.,J.S.Young,C.G.Tribble and I.L.Kron(1996)."Thromboxanereceptor blockade improves oxygenation in an experimental model of acute lunginjury."Ann Thorac Surg 61(5):1453-1457.
Wakerlin,G.E.,Jr.,J.C.Finn,L.C.Siegel,G.V.Benson,T.F.Flavin andR.G.Pearl(1995)."Pulmonary capillary pressure measurement from pulmonaryartery occlusion pressure decay profile analysis in sheep."Anesth Analg 81(1):17-23.
Werfel,T.A.,D.J.Hicks,B.Rahman,W.E.Bindeman,M.T.Duvernay,J.G.Maeng,H.Hamm,R.R.Lavieri,M.M.Joly,J.M.Pulley,D.L.Elion,D.M.Brantley-Sieders andR.S.Cook(2020)."Repurposing of a thromboxane receptor inhibitor based on anovel role in metastasis identified by Phenome Wide Association Study."MolCancer Ther.
West,J.D.,C.L.Galindo,K.Kim,J.J.Shin,J.B.Atkinson,I.Macias-Perez,L.Pavliv,B.C.Knollmann,J.H.Soslow,L.W.Markham and E.J.Carrier(2019)."Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy forCardiomyopathy of Muscular Dystrophy."J Am Heart Assoc 8(21):e011902.
West,J.D.,B.M.Voss,L.Pavliv,M.de Caestecker,A.R.Hemnes andE.J.Carrier(2016)."Antagonism of the thromboxane-prostanoid receptor iscardioprotective against right ventricular pressure overload."Pulm Circ 6(2):211-223.
Yoshimura,K.,M.L.Tod,K.G.Pier and L.J.Rubin(1989)."Role ofvenoconstriction in thromboxane-induced pulmonary hypertension and edema inlambs."J Appl Physiol(1985)66(2):929-935.
虽然本发明已在其优选实施例中进行了描述，但应理解，所使用的词语是描述性词语而不是限制性词语，并且在其更广泛的方面，可以在所附权利要求的范围内进行改变而不背离本发明的真实的范围和精神。相反，可以在权利要求的等同物的范围(scope/range)内并且在不背离本发明的精神的情况下对细节进行各种修改。发明人进一步要求，授予其权利要求的范围符合在本申请提交日(以及本申请获得优先权的申请，如果有的话)存在的法律下可用的最广泛的可能解释，并且不允许由于法律随后的变化而缩小所附权利要求的范围，因为这种缩小将构成事后裁决，以及在没有正当程序或公正赔偿的情况下采取行动。
Claims (20)
1.一种治疗COVID-19的方法，该方法包括向患有SARS-CoV-2感染和/或COVID-19症状的患者施用治疗有效量的血栓素A2受体拮抗剂。
2.如权利要求1所述的方法，其中该COVID-19患者通过在门诊、住院和/或恢复期施用血栓素A2拮抗剂进行治疗。
3.如权利要求2所述的方法，其中该血栓素A2受体拮抗剂选自下组：3-[2-[[(1S,2R,3S,4R)-3-[4-(戊基氨基甲酰基)-1,3-噁唑-2-基]-7-氧杂双环[2.2.1]庚烷-2-基]甲基]苯基]丙酸(艾非曲班)或其一个或多于一个药学上可接受的盐的混合物。
4.如权利要求2所述的方法，其中该血栓素A2受体拮抗剂是3-[2-[[(1S,2R,3S,4R)-3-[4-(戊基氨基甲酰基)-1,3-噁唑-2-基]-7-氧杂双环[2.2.1]庚烷-2-基]甲基]苯基]丙酸单钠盐(艾非曲班钠)。
5.如权利要求1所述的方法，其中该血栓素A2受体拮抗剂通过口服、鼻内、吸入、直肠、***、舌下、口腔、肠胃外或经皮或其任何组合施用。
6.如权利要求2所述的方法，其中该血栓素A2受体拮抗剂在门诊或住院阶段预防性施用以防止呼吸衰竭的发展。
7.如权利要求2所述的方法，其中施用该血栓素A2受体拮抗剂以治疗和预防患者肺纤维化的进展。
8.如权利要求2所述的方法，其中该治疗有效量是从约10mg至约1,500mg/天。
9.如权利要求2所述的方法，其中该治疗有效量是从约10mg至约500mg/天，并且将该血栓素A2受体拮抗剂肠胃外施用。
10.如权利要求2所述的方法，其中该治疗有效量是从约50mg至约1,500mg/天，并且将该血栓素A2受体拮抗剂口服施用。
11.一种治疗患有COVID-19的人类患者的肺功能障碍的方法，该方法包括向该人类患者长期施用治疗有效量的血栓素A2受体拮抗剂。
12.如权利要求11所述的方法，其中该治疗有效量是从约10mg至约1,500mg/天。
13.如权利要求11所述的方法，其中该血栓素A2受体拮抗剂选自下组：3-[2-[[(1S,2R,3S,4R)-3-[4-(戊基氨基甲酰基)-1,3-噁唑-2-基]-7-氧杂双环[2.2.1]庚烷-2-基]甲基]苯基]丙酸(艾非曲班)或其一个或多于一个药学上可接受的盐的混合物。
14.如权利要求11所述的方法，其中该血栓素A2受体拮抗剂是3-[2-[[(1S,2R,3S,4R)-3-[4-(戊基氨基甲酰基)-1,3-噁唑-2-基]-7-氧杂双环[2.2.1]庚烷-2-基]甲基]苯基]丙酸单钠盐(艾非曲班钠)。
15.如权利要求13所述的方法，其中该治疗有效量是从约50mg至约250mg/天，并且将该艾非曲班口服施用。
16.如权利要求11所述的方法，其中该肺功能障碍是肺毛细血管高压。
17.如权利要求11所述的方法，其中该肺功能障碍是肺水肿。
18.如权利要求11所述的方法，其中该肺功能障碍是肺纤维化。
19.如权利要求11所述的方法，其中该肺功能障碍是血栓性微血管病。
20.如权利要求2所述的方法，其中COVID-19患者是年龄为60岁以下的人，没有血栓形成史，并被施用血栓素A2拮抗剂以预防或治疗大血管血栓性血管病。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US202063002511P | 2020-03-31 | 2020-03-31 | |
| US63/002,511 | 2020-03-31 | ||
| PCT/US2021/024760 WO2021202437A1 (en) | 2020-03-31 | 2021-03-30 | Methods and pharmaceutical compositions of thromboxane a2 receptor antagonist for the treatment of covid-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115666560A true CN115666560A (zh) | 2023-01-31 |
Family
ID=77929764
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180037977.9A Pending CN115666560A (zh) | 2020-03-31 | 2021-03-30 | 用于治疗covid-19的血栓素a2受体拮抗剂的方法和药物组合物 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20230129262A1 (zh) |
| EP (1) | EP4125882A4 (zh) |
| JP (1) | JP2023519674A (zh) |
| KR (1) | KR20220161394A (zh) |
| CN (1) | CN115666560A (zh) |
| AU (1) | AU2021246444A1 (zh) |
| CA (1) | CA3176619A1 (zh) |
| IL (1) | IL296771A (zh) |
| WO (1) | WO2021202437A1 (zh) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUE027546T2 (en) * | 2003-08-29 | 2016-10-28 | Brigham & Womens Hospital Inc | Hydantoin derivatives as cell necrosis inhibitors |
| CA2805110A1 (en) * | 2010-07-14 | 2012-01-19 | Cumberland Emerging Technologies, Inc. | Methods of treating hepatorenal syndrome and hepatic encephalopathy with thromboxane-a2 receptor antagonists |
| EP3142655B1 (en) * | 2014-05-16 | 2020-12-02 | Cumberland Pharmaceuticals Inc. | Compositions and methods of treating cardiac fibrosis with ifetroban |
| US20180050020A1 (en) * | 2016-08-22 | 2018-02-22 | Cumberland Pharmaceuticals, Inc. | Ifetroban treatment of portal hypertension |
-
2021
- 2021-03-30 US US17/915,608 patent/US20230129262A1/en active Pending
- 2021-03-30 WO PCT/US2021/024760 patent/WO2021202437A1/en unknown
- 2021-03-30 AU AU2021246444A patent/AU2021246444A1/en active Pending
- 2021-03-30 EP EP21779214.2A patent/EP4125882A4/en active Pending
- 2021-03-30 KR KR1020227037227A patent/KR20220161394A/ko active Search and Examination
- 2021-03-30 CA CA3176619A patent/CA3176619A1/en active Pending
- 2021-03-30 JP JP2022558130A patent/JP2023519674A/ja active Pending
- 2021-03-30 IL IL296771A patent/IL296771A/en unknown
- 2021-03-30 CN CN202180037977.9A patent/CN115666560A/zh active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CA3176619A1 (en) | 2021-10-07 |
| KR20220161394A (ko) | 2022-12-06 |
| EP4125882A4 (en) | 2024-03-27 |
| WO2021202437A1 (en) | 2021-10-07 |
| US20230129262A1 (en) | 2023-04-27 |
| JP2023519674A (ja) | 2023-05-12 |
| IL296771A (en) | 2022-11-01 |
| AU2021246444A1 (en) | 2022-10-20 |
| EP4125882A1 (en) | 2023-02-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Cortese et al. | Rosuvastatin: Beyond the cholesterol-lowering effect | |
| US10925860B2 (en) | Compositions and methods of treating cardiac fibrosis with ifetroban | |
| US20130096195A1 (en) | Therapeutic treatment | |
| US20060160896A1 (en) | Therapeutic treatment | |
| KR20100032854A (ko) | 아스피린 민감성 및 다른 군의 심혈관 질환 치료를 위한 ｔｐ 조절자의 용도 | |
| Bao et al. | Artemisinin and its derivate alleviate pulmonary hypertension and vasoconstriction in rodent models | |
| D Tortorella et al. | Desirable properties for 3rd generation cyclooxygenase-2 inhibitors | |
| DeMarco et al. | Rosuvastatin ameliorates the development of pulmonary arterial hypertension in the transgenic (mRen2) 27 rat | |
| WO2021181368A1 (en) | Methods of treating respiratory disease with deupirfenidone | |
| US20200155513A1 (en) | Thromboxane Receptor Antagonists in AERD/Asthma | |
| CN115666560A (zh) | 用于治疗covid-19的血栓素a2受体拮抗剂的方法和药物组合物 | |
| BRPI0711841A2 (pt) | uso de aminaftona | |
| Miyajima et al. | Disruption of elastic lamellae in aorta and dysfunction of vaso-regulation by rofecoxib in rats | |
| Hare | Differential HIF and NOS Responses to Acute Anemia: Defining Organ Specific Hemoglobin 2 Thresholds for Tissue Hypoxia. 3 | |
| AU9703601A (en) | Method for treating chronic obstructive pulmonary disease |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40085960 Country of ref document: HK |