CN114432281A - Application of compound (R) -TML104 in preparation of medicines for preventing and treating diseases related to vascular intimal hyperplasia - Google Patents
Application of compound (R) -TML104 in preparation of medicines for preventing and treating diseases related to vascular intimal hyperplasia Download PDFInfo
- Publication number
- CN114432281A CN114432281A CN202011198280.3A CN202011198280A CN114432281A CN 114432281 A CN114432281 A CN 114432281A CN 202011198280 A CN202011198280 A CN 202011198280A CN 114432281 A CN114432281 A CN 114432281A
- Authority
- CN
- China
- Prior art keywords
- tml104
- compound
- vsmc
- vascular
- atorvastatin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 55
- 206010020718 hyperplasia Diseases 0.000 title claims abstract description 41
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 230000002792 vascular Effects 0.000 title claims description 49
- 201000010099 disease Diseases 0.000 title claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title claims description 8
- 229940079593 drug Drugs 0.000 title abstract description 19
- 210000004509 vascular smooth muscle cell Anatomy 0.000 claims abstract description 95
- 230000009466 transformation Effects 0.000 claims abstract description 31
- 238000013508 migration Methods 0.000 claims abstract description 29
- 230000005012 migration Effects 0.000 claims abstract description 29
- 230000035755 proliferation Effects 0.000 claims abstract description 24
- 108010041191 Sirtuin 1 Proteins 0.000 claims abstract description 22
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 14
- 210000004204 blood vessel Anatomy 0.000 claims abstract description 12
- 230000000879 anti-atherosclerotic effect Effects 0.000 claims abstract description 3
- 102000000344 Sirtuin 1 Human genes 0.000 claims abstract 4
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 108010081589 Becaplermin Proteins 0.000 abstract description 35
- 230000000694 effects Effects 0.000 abstract description 10
- 230000006870 function Effects 0.000 abstract description 6
- 238000001727 in vivo Methods 0.000 abstract description 5
- 230000008602 contraction Effects 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 2
- 230000028327 secretion Effects 0.000 abstract description 2
- 208000024248 Vascular System injury Diseases 0.000 abstract 1
- 208000012339 Vascular injury Diseases 0.000 abstract 1
- 210000004026 tunica intima Anatomy 0.000 abstract 1
- 230000003827 upregulation Effects 0.000 abstract 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 54
- 229960005370 atorvastatin Drugs 0.000 description 54
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 52
- 241000700159 Rattus Species 0.000 description 25
- 230000006378 damage Effects 0.000 description 22
- 238000000034 method Methods 0.000 description 22
- 208000027418 Wounds and injury Diseases 0.000 description 20
- 208000014674 injury Diseases 0.000 description 20
- 102100031455 NAD-dependent protein deacetylase sirtuin-1 Human genes 0.000 description 18
- 108050006400 Cyclin Proteins 0.000 description 17
- 102100036691 Proliferating cell nuclear antigen Human genes 0.000 description 17
- 108010058546 Cyclin D1 Proteins 0.000 description 15
- 102000006311 Cyclin D1 Human genes 0.000 description 15
- 239000013641 positive control Substances 0.000 description 14
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 10
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 10
- 229940016667 resveratrol Drugs 0.000 description 10
- 235000021283 resveratrol Nutrition 0.000 description 10
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 9
- 229950004398 broxuridine Drugs 0.000 description 9
- 238000001262 western blot Methods 0.000 description 9
- 201000001320 Atherosclerosis Diseases 0.000 description 8
- 108091027967 Small hairpin RNA Proteins 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000004055 small Interfering RNA Substances 0.000 description 8
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 208000024172 Cardiovascular disease Diseases 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 230000004663 cell proliferation Effects 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 230000004936 stimulating effect Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 230000003248 secreting effect Effects 0.000 description 5
- 241000713666 Lentivirus Species 0.000 description 4
- 210000001168 carotid artery common Anatomy 0.000 description 4
- 210000000269 carotid artery external Anatomy 0.000 description 4
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 3
- 210000001367 artery Anatomy 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000010166 immunofluorescence Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 210000002460 smooth muscle Anatomy 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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
- 238000011047 acute toxicity test Methods 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- -1 atorvastatin compound Chemical class 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000001715 carotid artery Anatomy 0.000 description 2
- 210000004004 carotid artery internal Anatomy 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 230000002900 effect on cell Effects 0.000 description 2
- 230000030279 gene silencing Effects 0.000 description 2
- 238000003125 immunofluorescent labeling Methods 0.000 description 2
- 238000013227 male C57BL/6J mice Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000006748 scratching Methods 0.000 description 2
- 230000002393 scratching effect Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000036962 time dependent Effects 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OYJBHGSSAJNKJF-CQSZACIVSA-N (3R)-4,6-dimethoxy-3-(4-methoxyphenyl)-2,3-dihydroinden-1-one Chemical compound COC1=CC=C([C@@H](CC(C2=CC(OC)=C3)=O)C2=C3OC)C=C1 OYJBHGSSAJNKJF-CQSZACIVSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010060965 Arterial stenosis Diseases 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 102000008934 Muscle Proteins Human genes 0.000 description 1
- 108010074084 Muscle Proteins Proteins 0.000 description 1
- 102000005604 Myosin Heavy Chains Human genes 0.000 description 1
- 108010084498 Myosin Heavy Chains Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 102000003932 Transgelin Human genes 0.000 description 1
- 108090000333 Transgelin Proteins 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000008846 dynamic interplay Effects 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
- 230000002496 gastric effect Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 230000008069 intimal proliferation Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000037806 kidney injury Diseases 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000001617 migratory effect Effects 0.000 description 1
- 210000004237 neck muscle Anatomy 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000013077 scoring method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000002966 stenotic effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000006442 vascular tone Effects 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
Images
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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the field of medicines, relates to a novel medicinal application of a compound (R) -TML104 for up-regulating sirtuin-1 protein, and particularly relates to an application of the compound (R) -TML104 in medicines for up-regulating sirtuin-1 in vivo and in vitro to inhibit the transformation of Vascular Smooth Muscle Cells (VSMC) from a contraction type to a secretion type to play a role in inhibiting the proliferation of vascular intima. The result shows that the compound (R) -TML104 has the functions of obviously inhibiting PDGF-BB induced VSMC proliferation and migration activity, obviously reducing the thickness of intimal hyperplasia after vascular injury and being related to up-regulation of sirtuin-1 protein; the compound (R) -TML104 can be used for preparing a medicament for treating intimal hyperplasia of blood vessels and can also be used for preparing an anti-atherosclerosis medicament.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an application of a structurally optimized derivative (R) -TML104 of natural resveratrol sesquialter (±) -Isopauciflor F in mediating and up-regulating protein function of deacetylase sirtuin-1, in particular to an application of the derivative (R) -TML104 in preparing medicines for preventing and treating vascular intimal hyperplasia and atherosclerosis, wherein the function of the derivative can regulate and control Vascular Smooth Muscle Cells (VSMC).
Background
The prior art discloses that cardiovascular diseases (e.g. coronary heart disease, stroke, etc.) are among the most important diseases that endanger human life. The investigation shows that the cardiovascular disease and the mortality rate of China continuously rise, the death caused by the cardiovascular disease accounts for about 40 percent of the total death of the disease, is higher than the first death of tumors and other diseases, and is a great public health problem. Atherosclerosis is a common pathological basis for many cardiovascular diseases. Vascular intimal hyperplasia is one of the key factors in vascular atherosclerosis, angioplasty and vascular graft arterial stenosis, and the pathological process involves abnormal proliferation and shift of Vascular Smooth Muscle Cells (VSMCs). The maintenance of vascular homeostasis depends on dynamic interactions between local growth factors, vasoactive substances and hemodynamics.
VSMC are the major constituent cells of the media of arteries, normally exhibit a non-proliferative contractile phenotype, and express a series of contractile biomarkers, such as α -smooth muscle actin (α -SMA), smooth muscle 22 α (SM22 α), smooth muscle protein (smoothenin), and smooth muscle myosin heavy chain (SM-MHC), to maintain contraction and regulate vascular tone, vascular smooth muscle cell proliferation, migration ability, to ensure normal blood supply to tissues. VSMC are non-terminally differentiated cells with significant phenotypic plasticity, and when blood vessels are stimulated by external factors (e.g., cytokines, reactive oxygen species, lipids, etc.), the VSMC phenotype changes from contractile to secretory. VSMC phenotypic transformation and abnormal proliferation caused by the transformation are one of important markers and pathogenesis key links of the disease formation related to the vascular intimal hyperplasia. The key link for regulating and controlling the phenotypic transformation of the synthetic secretory VSMC provides a brand new idea for preventing and treating the occurrence and development of diseases related to intimal hyperplasia of blood vessels.
From 2012 to 2019, the number of new drugs on the market approved by the Food and Drug Administration (FDA) is realistic, the new drugs for cardiovascular diseases account for less than 10% of all indications, the mortality and morbidity of the cardiovascular diseases are high, but the research and development of the drugs are not satisfactory. Until now, the related diseases of the vascular intimal hyperplasia lack specific drugs clinically, and the commonly used statins can be used for preventing and improving the disease condition, but have obvious side effects, such as adverse reactions of liver and kidney injury, rhabdomyolysis, induced diabetes, accelerated aging, induced heart failure and the like, and limit the clinical application of the related diseases. The treatment method for life-threatening atherosclerotic stenosis patients mainly comprises surgical operations, including angioplasty, stent placement, stenotic vascular atherectomy and bypass surgery, drug-loaded stents such as paclitaxel and the like, and has high cost and high restenosis rate. Therefore, the clinical urgent need of new drugs and treatment strategies for specifically regulating and controlling intimal hyperplasia-related diseases is an urgent need to solve the global major public health problem.
The compound (R) -TML104 is a structurally optimized derivative of natural product resveratrol dyadic body (+/-) -Isopaucifloral F, the synthetic route of the compound is reported in the literature (chem. Eur. J.2016,22, 14535-14539), but the activity of the compound against diseases related to the vascular intimal hyperplasia is not reported. Based on the current state of the prior art, the inventor of the application intends to provide a new medicinal application of the compound (R) -TML104 in preparing medicines for preventing and treating intimal hyperplasia of blood vessels and atherosclerosis.
Disclosure of Invention
The invention aims to provide the application of a compound (R) -TML104 which has the functions of up-regulating sirtuin 1 protein and is used for inhibiting VSMC phenotypic transformation and preventing and treating diseases related to vascular intimal hyperplasia. In particular to application of a compound (R) -TML104 in preparing medicines for preventing and treating related diseases of intimal hyperplasia of blood vessels.
The invention provides an application of a compound (R) -TML104 in preparing a medicament for preventing and treating intimal hyperplasia and atherosclerosis, wherein the compound (R) -TML104 is a structurally optimized derivative of a half-fold (+/-) -Isopaucifloral F of a natural product resveratrol, and the structural formula of the derivative is as follows:
(R) -4, 6-dimethoxy-3- (4-methoxyphenyl) -2, 3-dihydro-1H-indanone molecular weight: 298, optical rotation value: [ alpha ] to]2 D 0＝-36(c＝0.14,CHCl3)。
In the invention, the compound (R) -TML104 is used for preparing the medicine for up-regulating sirtuin 1 protein.
In the invention, the compound (R) -TML104 is used for preparing a medicament for inhibiting the proliferation and migration of Vascular Smooth Muscle Cells (VSMC).
In the invention, the compound (R) -TML104 is used for preparing a medicament for inhibiting the phenotypic transformation of Vascular Smooth Muscle Cells (VSMC).
In the invention, the compound (R) -TML104 is used for preparing a medicament for inhibiting the vascular intimal hyperplasia.
In the invention, the compound (R) -TML104 is used for preparing the anti-atherosclerosis medicine.
The research of the invention at a cellular level discovers that (R) -TML104 can obviously inhibit PDGF-BB induced influence of phenotype transformation, proliferation and migration capacities of human VSMC and rat VSMC. Western blot results show that (R) -TML104 can remarkably inhibit PDGF-BB induced transformation of human VSMC and rat VSMC from a contractile type to a secretory type, and BrdU experiments, transwell experiments and scratch experiments show that (R) -TML104 can remarkably inhibit proliferation and migration of human VSMC and rat VSMC at the same time. The compound (R) -TML104 has better application prospect, and can be used for preparing drugs for VSMC cell phenotype transformation and VSMC proliferation and migration inhibition.
The invention discovers that the compound (R) -TML104 can obviously inhibit the vascular intimal hyperplasia caused by vascular intimal injury through in vivo level research, and simultaneously relieves the VSMC from contraction type to secretion type caused by the vascular intimal injury. In vivo immunofluorescence and immunohistochemical staining further show that inhibition of vascular intimal proliferation caused by vascular intimal injury by lentiviral silencing of sirtuin-1 protein (R) -TML104 disappears, while its effect of alleviating vascular intimal injury causes VSMC to switch from systolic to secretory disappears, demonstrating that it plays an important role in up-regulating sirtuin 1 protein. Therefore, the compound (R) -TML104 can be used for preparing the medicine for up-regulating sirtuin 1 protein.
The compound (R) -TML104 can play a critical role in the development and development of atherosclerosis due to the function of inhibiting the VSMC phenotype from being converted from a contractile type to a secretory type, particularly showing abnormal proliferation and migration and function change, so the compound (R) -TML104 can be used for preparing a medicine for resisting atherosclerosis.
The invention has the beneficial effects that:
(1) the atorvastatin compound has stronger effects of inhibiting VSMC phenotype transformation, proliferation and migration, and the equivalent dose of the atorvastatin compound is superior to that of a positive control drug in vivo and in vitro;
(2) the compound (R) -TML104 can regulate and control VSMC function and can be used for preparing medicines for preventing and treating diseases related to vascular intimal hyperplasia;
(3) the compound (R) -TML104 can better play a role of a medicament for preventing and treating diseases related to vascular intimal hyperplasia by up-regulating sirtuin-1 protein;
(4) the compound (R) -TML104 has better safety than atorvastatin in the preparation of medicaments for preventing and treating intimal hyperplasia of blood vessels and resisting atherosclerosis.
Drawings
FIG. 1 shows the effect of (R) -TML104 on cell viability of rat vascular smooth muscle cells, and the results show that VSMC incubation with (R) -TML104 (5-40. mu.M) for 24h had no effect on cell viability;
FIG. 2 shows the PDGF-BB-induced proliferation and migration activity of vascular smooth muscle cells in rats by (R) -TML104, and the results show that (R) -TML104 (1-10. mu.M) can dose-dependently inhibit PDGF-BB-induced phenotypic transformation of rat VSMCs; (R) -TML104(10 μ M) inhibited PDGF-BB-induced phenotypic transformation of rat VSMC (PCNA, # p <0.05), proliferation (# p <0.05) and migration (# p <0.05) better than positive control Atorvastatin (Atorvastatin,10 μ M);
FIG. 3 shows PDGF-BB-induced proliferation and migration activity of vascular smooth muscle cells of human origin in (R) -TML104, and results show that treatment of (R) -TML104 (10. mu.M) alone did not affect phenotypic transformation, proliferation and migration of VSMC of human origin; but (R) -TML104 (10. mu.M) significantly inhibited PDGF-BB-induced phenotypic transformation (cyclin D1, PCNA and alpha-SMA) of human VSMC, proliferation and migration; in addition, (R) -TML104(10 μ M) inhibited PDGF-BB-induced phenotypic transformation of human VSMC (cyclin D1, PCNA and α -SMA <0.05), proliferation (p <0.05), migration (p <0.05) better than positive control Atorvastatin (Atorvastatin,10 μ M);
FIG. 4 shows the effect of (R) -TML104 in inhibiting mouse intimal injury-induced intimal hyperplasia and VSMC phenotypic transformation (α -SMA, PCNA and Cyclin D1) and (R) -TML104(10mg/kg and 20mg/kg) in mice, while (R) -TML104(20mg/kg) was better than the positive control Atorvastatin (Atorvastatin,20mg/kg) in inhibiting intimal injury-induced intimal hyperplasia and VSMC phenotypic transformation (α -SMA, PCNA and Cyclin D1) (. xp < 0.05);
FIG. 5 shows that (R) -TML104 plays a role in inhibiting vascular intimal hyperplasia caused by vascular intimal injury by up-regulating sirtuin 1 protein, and the results show that both (R) -TML104(10 μ M) and Resveratrol (Resveratrol,10 μ M) can induce VSMC to express sirtuin-1 protein in a time-dependent manner, and that (R) -TML104(10 μ M) can induce sirtuin-1 expression better than Resveratrol (Resveratrol,10 μ M) at 24h (p < 0.05); the results show that (R) -TML104(20mg/kg) can obviously inhibit vascular intimal hyperplasia induced by vascular intimal injury and VSMC phenotypic transformation (alpha-SMA, PCNA and CyclinD1), while the vascular sirtuin-1 protein (R) -TML104(20mg/kg) can inhibit vascular intimal hyperplasia induced by vascular intimal injury and VSMC phenotypic transformation (alpha-SMA, PCNA and Cyclin D1) disappearance are silenced by lentiviral shRNA, and the control Scrambled shRNA (sh-Scr) lentivirus has no obvious influence on both vascular intimal hyperplasia and VSMC phenotypic transformation.
Detailed Description
The present invention is further illustrated below with reference to examples, which are not intended to describe the experimental procedures in great detail for the sake of brevity, and all parts not described in detail in the experiments are routine procedures well known to those skilled in the art, but the examples are by no means intended to limit the present invention.
The methods used in the following examples are conventional methods unless otherwise specified, and the reagents required in the following examples are commercially available unless otherwise specified
Data analysis in the examples One-WayANOVA multiple comparisons were performed using GraphpadPrism 8.0 statistical analysis software.
Example 1: effect of Compound (R) -TML104 on rat VSMC cell viability
As shown in FIG. 1, (R) -TML104 (5-100. mu.M) was used to treat rat Vascular Smooth Muscle Cells (VSMC) for 24h, and the cell viability was measured by the thiazole blue (MTT) method, which is briefly described as follows: adding the (R) -TML104 with the concentration into rat VSMC for 24h, adding MTT with 0.5mg/ml for incubation for 4h, and dissolving in DMSO at 490nm to measure absorbance; it was shown that (R) -TML104 (5-40. mu.M) treatment of VSMC for 24h had no effect on cell viability.
Example 2: compound (R) -TML104 inhibits PDGF-BB induced proliferation and migration of rat VSMC
(A) Pre-incubating rat VSMC for 4 hours (h) with compound (R) -TML104(1,5,10 μ M), stimulating with PDGF-BB for 24h, and analyzing cell proliferation marker molecules, cyclin D1(cyclin D1), Proliferating Cell Nuclear Antigen (PCNA) protein and contractile marker molecules, α -smooth muscle actin (α -SMA), with Western blot; the Westernblot method is briefly described as that, VSMC cell total protein is extracted and quantified, 30 μ g of the total protein is taken and separated by SDS-PAGE and transferred to a nitrocellulose membrane, 5% skim milk is sealed, the antibody is incubated overnight at 4 ℃, and a secondary antibody is incubated for 2h and then detected by a chemiluminescence reagent; the results show that (R) -TML104 (1-10 mu M) can inhibit PDGF-BB induced phenotypic transformation of rat VSMC in a dose-dependent manner;
(B) pre-incubating rat VSMC for 4 hours (h) with a compound (R) -TML104(10 μ M) and Atorvastatin (Atorvastatin,10 μ M), stimulating for 24h with PDGF-BB, and analyzing cell proliferation marker molecules cyclin D1, PCNA protein and contractile marker molecules alpha-SMA with Western blot; the Western blot procedure is as described above; the results showed that (R) -TML104(10 μ M) inhibited PDGF-BB-induced phenotypic transformation of rat VSMC better than positive control Atorvastatin (Atorvastatin,10 μ M) (PCNA,. xp < 0.05);
(C) pre-incubating rat VSMC for 4 hours (h) with compound (R) -TML104(10 μ M) and Atorvastatin (Atorvastatin,10 μ M), stimulating for 24h with PDGF-BB, and analyzing cell proliferation by staining with 5-bromodeoxyuridine (BrdU); proliferation assays were performed according to the BrdU proliferation kit instructions and are briefly described below: after the VSMC is treated, adding BrdU (10 mu mol/L) to incubate for 2h, staining cell nuclei by DAPI, and observing the number of BrdU positive cells under a fluorescence microscope (Zeiss LSM 880); the results showed that (R) -TML104(10 μ M) inhibited PDGF-BB-induced proliferation of rat VSMC better than the positive control Atorvastatin (Atorvastatin,10 μ M) (. sp < 0.05);
(D) pre-incubating rat VSMC4h with compound (R) -TML104(10 μ M) and Atorvastatin (Atorvastatin,10 μ M), stimulating for 18h by PDGF-BB, and measuring the migration capacity of rat VSMC by a Transwell method; the method is briefly described as follows: VSMC cells were seeded into a Transwell chamber, treated as described above, and migrated to the bottom of the chamber, fixed with paraformaldehyde, stained with crystal violet, and the number of migrated cells was observed under a microscope (Zeissaxio VertA 1). The results showed that (R) -TML104(10 μ M) inhibited PDGF-BB-induced rat VSMC migration better than the positive control Atorvastatin (Atorvastatin,10 μ M) (. sp < 0.05);
(E) VSMC were pretreated with compound (R) -TML104 (10. mu.M) and Atorvastatin (Atorvastatin, 10. mu.M) for 4h, stimulated with PDGF-BB for 24h, and the migration ability of rat VSMC was measured by cell-scratch method, which was briefly as follows: scratching a single layer of VSMC (dendritic cell culture) cells by adopting a 200 mu L micro pipette tip, taking a picture by using a 24h microscope (Zeissaxio VertA1) and then analyzing the migration distance of the cells; the results show that (R) -TML104(10 μ M) inhibits PDGF-BB-induced rat VSMC migration better than the positive control Atorvastatin (Atorvastatin,10 μ M) (. p <0.05), scale bar: 50 μm. Data are mean ± standard deviation, # p <0.05, # p < 0.01.
Example 3: compound (R) -TML104 inhibits PDGF-BB-induced proliferation and migration of human VSMC
To verify the species identity of (R) -TML104 on VSMC cell function regulation, phenotypic transformation of human aortic VSMC was induced with human PDGF-BB and the regulatory effect of (R) -TML104 on PDGF-BB-induced phenotypic transformation of human VSMC was observed:
(A) pre-incubation of human VSMC4 hours (h) with the compound (R) -TML104(10 μ M) and Atorvastatin (Atorvastatin,10 μ M), stimulation with PDGF-BB for 24h, Western blot analysis of cell proliferation marker molecules cyclin D1, PCNA protein and contractile marker molecule α -SMA; western blot analysis as described above, the results showed that treatment with (R) -TML104(10 μ M) alone did not affect VSMC phenotype, (R) -TML104(10 μ M) was able to significantly inhibit PDGF-BB-induced phenotypic transformation of human VSMC (cyclin D1, PCNA, and α -SMA) (. p <0.05), while (R) -TML104(10 μ M) inhibited PDGF-BB-induced phenotypic transformation of human VSMC better than the positive control Atorvastatin (Atorvastatin,10 μ M) (. p < 0.05);
(B) preincubating human VSMC for 4 hours (h) with compound (R) -TML104(10 μ M) and Atorvastatin (Atorvastatin,10 μ M), stimulating for 24h with PDGF-BB, and staining with 5-bromodeoxyuridine (BrdU) to analyze cell proliferation; BrdU-stained cell proliferation assays are described above; the results show that (R) -TML104(10 μ M) alone did not affect VSMC proliferation, (R) -TML104(10 μ M) was able to significantly inhibit PDGF-BB-induced human VSMC proliferation (p <0.05), while (R) -TML104(10 μ M) inhibited PDGF-BB-induced human VSMC proliferation better than Atorvastatin (10 μ M) as a positive control drug (Atorvastatin);
(C) pre-treating VSMC for 4h by using a compound (R) -TML104(10 mu M) and Atorvastatin (Atorvastatin,10 mu M), stimulating for 24h by using PDGF-BB, and determining the migration capacity of the VSMC of a rat by using a cell scratching method; cell scoring methods are described above; the results show that (R) -TML104(10 μ M) alone did not affect VSMC migration, (R) -TML104(10 μ M) was able to significantly inhibit PDGF-BB-induced human VSMC migration (p <0.05), while (R) -TML104(10 μ M) inhibited PDGF-BB-induced human VSMC migration better than Atorvastatin (10 μ M) which is a positive control drug (Atorvastatin);
(D) rat VSMC4h was preincubated with compound (R) -TML104 (10. mu.M) and Atorvastatin (Atorvastatin, 10. mu.M), and its migratory capacity was measured by Transwell method using PDGF-BB stimulation for 18 h. The Transwell method is as described above; the results show that (R) -TML104(10 μ M) alone did not affect VSMC migration, (R) -TML104(10 μ M) was able to significantly inhibit PDGF-BB-induced human VSMC migration ([ p ] 0.05), while (R) -TML104(10 μ M) inhibited PDGF-BB-induced human VSMC migration better than Atorvastatin (Atorvastatin,10 μ M) as a positive control drug ([ p ] 0.05); scale bar: 50 μm. Data are mean ± standard deviation, # p <0.05, # p < 0.01.
Example 4: compound (R) -TML104 inhibits mouse intimal injury-induced intimal hyperplasia
Male C57BL/6J mice weighing 21-24g were anesthetized by intraperitoneal injection with 1% sodium pentobarbital, fixed in supine position, and the median skin of the neck was opened with an incision of about 2 cm. Bluntly separating neck muscles, exposing a left common carotid artery, ligating an 8-0 silk thread at the Y-shaped bifurcation of an external carotid artery and an internal carotid artery to block blood flow, cutting the external carotid artery by scissors, damaging the intima of a blood vessel by a COOK guide wire (NO.C-SF-15-15, COOK, Bloomington) to cause intimal hyperplasia, and suturing neck skin after cleaning by sterile physiological saline; after the mice are clear-headed, feeding water and standard feed in cages; the operation of the sham operation group is the same as that of the model group except that the sham operation group does not need guide wire damage; gastric administration for 4 weeks, wherein after 28 days of continuous administration of (R) -TML104(10mg/kg/day), (R) -TML104(20mg/kg/day), and Atorvastatin (Atorvastatin,20 mg/kg/day), vascular tissue of about 1cm in length is taken from the position below the ligation site on the common carotid artery, and blood vessels of the same position and length are taken in a sham group; fixing with 4% paraformaldehyde, and embedding to obtain paraffin sections.
(A) Observing the mouse intimal hyperplasia area of artery by hematoxylin and eosin staining method and quantifying; the hematoxylin and eosin staining method is briefly described as follows: blood vessel sections were deparaffinized, stained with hematoxylin and eosin, photographed microscopically and areas of hyperplasia calculated using Image Pro Plus software (version 6.0, Media Cybernetics); the results show that (R) -TML104(10mg/kg,20mg/kg) can significantly inhibit vascular intimal injury-induced vascular intimal hyperplasia (. p <0.05,. p <0.01), while (R) -TML104(20mg/kg) inhibits vascular intimal injury-induced vascular intimal hyperplasia (. p <0.05) better than positive control Atorvastatin (Atorvastatin,20 mg/kg);
(B) the expression and the quantification of the mouse carotid artery alpha-SMA, PCNA and Cyclin D1 are observed by an immunofluorescence method, and the immunofluorescence method is briefly as follows: after frozen section of blood vessels, Triton-X100 transmembrane 5% goat serum was blocked, the antibodies were incubated overnight at 4 degrees, after 2h incubation at room temperature with fluorescent secondary antibody, DAPI stained nuclei, photographed by fluorescence microscope and analyzed for data using Image Pro Plus software (version 6.0, Media Cybernetics); the results show that (R) -TML104(10mg/kg,20mg/kg) can remarkably inhibit the transformation of VSMC phenotype induced by the intimal injury (alpha-SMA, PCNA and Cyclin D1) (. alpha.p <0.05,. alpha.p <0.01), and simultaneously (R) -TML104(20mg/kg) can better inhibit the transformation of VSMC phenotype induced by the intimal injury (alpha-SMA Cyclin D1) (. alpha.p <0.05) than the positive control drug Atorvastatin (Atorvastatin,20 mg/kg); scale bar: 50 μm. Data are mean ± standard deviation, # p <0.05, # p < 0.01.
Example 5: the compound (R) -TML104 plays a role in inhibiting vascular intimal hyperplasia caused by vascular intimal injury by up-regulating sirtuin 1 protein
(A) Rat VSMC was treated with (R) -TML104 (10. mu.M) and Resveratrol (Resveratro, 10. mu.M) for the different times shown in the figure and analyzed for sirtuin-1 expression using Western blot; westernblot analysis method As described above, the results showed that both (R) -TML104 (10. mu.M) and Resveratrol (Resveratro, 10. mu.M) were able to induce sirtuin-1 expression in a time-dependent manner (. p <0.05,. p <0.01), while (R) -TML104 (10. mu.M) was able to induce sirtuin-1 expression better than Resveratrol (Resveratro, 10. mu.M) at 24h (. p < 0.05);
(B) male C57BL/6J mice weighing 21-24g were anesthetized by intraperitoneal injection with 1% sodium pentobarbital, fixed in supine position, and the median skin of the neck was opened with an incision of about 2 cm. Blunt cervical muscle was isolated, left common carotid artery was exposed, blood flow was blocked by 8-0 silk ligation at the "Y-shaped" bifurcation of external and internal carotid arteries, dissected at the external carotid artery with scissors, and intimal hyperplasia was induced by injury of the intima of the vessels with COOK guide wire (NO.C-SF-15-15, Cook, Bloomington) while perfusing 50. mu.l sirtuin-1 shRNA and scambiled shRNA (1X 10 shRNA)9TU/mL) sterile saline was used to clean and suture the neck skin; after the mice are clear-headed, feeding water and standard feed in cages; the operation of the sham operation group is the same as that of the model group except that the sham operation group does not need guide wire damage; intragastric administration for 4 weeks at a dose of compound (R) -TML104(20mg/kg/day) for 28 consecutive days, and then collecting vascular tissue of about 1cm in length from below the ligation site on the common carotid artery, and collecting blood vessels of the same position and length in the sham group; fixing with 4% paraformaldehyde, and embedding to obtain paraffin sections.
(C) Observing the mouse intimal hyperplasia area of artery by hematoxylin and eosin staining method and carrying out quantitative analysis; hematoxylin and eosin staining methods are described above; the results show that (R) -TML104(20mg/kg) can obviously inhibit vascular intimal injury-induced vascular intimal hyperplasia (p is less than 0.01), while vascular sirtuin-1 protein (R) -TML104(20mg/kg) is silenced by lentiviral shRNA to inhibit disappearance of vascular intimal injury-induced vascular intimal hyperplasia, and the control Scrambled shRNA (sh-Scr) lentivirus has no obvious influence on vascular intimal hyperplasia;
(D) the expression and the quantification of the mouse carotid artery alpha-SMA, PCNA and Cyclin D1 are observed by an immunofluorescence method, and the immunofluorescence staining method is as described above; the results show that (R) -TML104(20mg/kg) can obviously inhibit VSMC phenotype transformation (alpha-SMA, PCNA and Cyclin D1) induced by vascular intimal injury (p is less than 0.01), while (R) -TML104(20mg/kg) inhibits vascular intimal injury-induced vascular intimal hyperplasia by silencing vascular sirtuin-1 protein through lentivirus shRNA, and the control sh-Scr lentivirus has no obvious influence on vascular VSMC phenotype transformation; scale bar: 50 μm. Data are mean ± standard deviation, # p <0.05, # p < 0.01.
Example 6: acute toxicity study of Compound (R) -TML104
An in vivo acute toxicity test study in mice was carried out on the compound (R) -TML104 and Atorvastatin (Atorvastatin). Kunming mice weighing 20 + -2 g healthy adults were divided into 12 groups of 10 mice each half male and female at random. Wherein, the compound comprises a compound (R) -TML1046 group and an Atorvastatin (Atorvastatin)6 group, namely a solvent blank group, a 500mg/kg group, a 400mg/kg group, a 300mg/kg group, a 250mg/kg group and a 150mg/kg group respectively; the administration was carried out daily by a single intraperitoneal injection, with an administration volume of 0.2mL/10 g. The behavioral status and death status of the mice were continuously observed and recorded for 14 days. The experimental data of mouse death is calculated by the SPSS software (IBM SPSS Statistics 19) by adopting the Bliss method, and the experimental result shows that (see Table 1): half-lethality LD of Compound (R) -TML10450A value of 401.12 mg/kg; and half-lethality LD of atorvastatin50The value was 245.25 mg/kg. The above data indicate that the compound (R) -TML104 is safer than atorvastatin and has acute toxicity 0.6 times lower than atorvastatin.
Table 1: acute toxicity test results of compound (R) -TML104 and atorvastatin
Claims (6)
1. The application of the compound (R) -TML104 in preparing the medicine for preventing and treating the diseases related to the vascular intimal hyperplasia is characterized in that: the structural formula is as follows:
2. the use according to claim 1, characterized in that the compound (R) -TML104 is used for the preparation of a medicament for upregulating the sirtuin 1 protein.
3. The use according to claim 1, characterized in that the compound (R) -TML104 is used for the preparation of a medicament for inhibiting the proliferation and migration of Vascular Smooth Muscle Cells (VSMC).
4. The use according to claim 1, characterized in that the compound (R) -TML104 is used for the preparation of a medicament for inhibiting the phenotypic transformation of Vascular Smooth Muscle Cells (VSMC).
5. The use according to claim 1, characterized in that the compound (R) -TML104 is used for the preparation of a medicament for the inhibition of intimal hyperplasia in blood vessels.
6. Use according to claim 1, characterized in that the compound (R) -TML104 is used for the preparation of an antiatherosclerotic medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011198280.3A CN114432281A (en) | 2020-10-31 | 2020-10-31 | Application of compound (R) -TML104 in preparation of medicines for preventing and treating diseases related to vascular intimal hyperplasia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011198280.3A CN114432281A (en) | 2020-10-31 | 2020-10-31 | Application of compound (R) -TML104 in preparation of medicines for preventing and treating diseases related to vascular intimal hyperplasia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114432281A true CN114432281A (en) | 2022-05-06 |
Family
ID=81358276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011198280.3A Pending CN114432281A (en) | 2020-10-31 | 2020-10-31 | Application of compound (R) -TML104 in preparation of medicines for preventing and treating diseases related to vascular intimal hyperplasia |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114432281A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022262597A1 (en) * | 2021-06-16 | 2022-12-22 | 复旦大学 | TNF-α SMALL MOLECULE INHIBITOR, PREPARATION METHOD THEREFOR, AND USE THEREOF |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107233346A (en) * | 2016-03-27 | 2017-10-10 | 复旦大学 | Purposes of the GSK J4 HCL in the medicine for preparing the related vascular diseases for the treatment of vascellum endometrial hyperplasia |
-
2020
- 2020-10-31 CN CN202011198280.3A patent/CN114432281A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107233346A (en) * | 2016-03-27 | 2017-10-10 | 复旦大学 | Purposes of the GSK J4 HCL in the medicine for preparing the related vascular diseases for the treatment of vascellum endometrial hyperplasia |
Non-Patent Citations (2)
| Title |
|---|
| MEI-LIN TANG等: "Sulfoxide-Based Enantioselective Nazarov Cyclization: Divergent Syntheses of (+)-Isopaucifloral F, (+)-Quadrangularin A, and (+)-Pallidol", CHEM. EUR. J., pages 14535 * |
| 韩吉来等: "白藜芦醇二聚体Quadrangularin A 和Pallidol 合成方法学研究", 有机化学, pages 1571 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022262597A1 (en) * | 2021-06-16 | 2022-12-22 | 复旦大学 | TNF-α SMALL MOLECULE INHIBITOR, PREPARATION METHOD THEREFOR, AND USE THEREOF |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zhang et al. | The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells | |
| Tsujii et al. | Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2 | |
| Yamashita et al. | Fasudil, a Rho kinase (ROCK) inhibitor, protects against ischemic neuronal damage in vitro and in vivo by acting directly on neurons | |
| RU2576512C2 (en) | Method and compositions for ageing suppression | |
| JPH08510451A (en) | Prevention and treatment of pathogenesis associated with hyperproliferative smooth muscle cells | |
| Wang et al. | Crocetin inhibits the proliferation, migration and TGF-β2-induced epithelial-mesenchymal transition of retinal pigment epithelial cells | |
| CN107095867B (en) | Application of HSP90 inhibitor in preparation of medicine for preventing and treating aortic disease | |
| Jiang et al. | Topotecan prevents hypoxia-induced pulmonary arterial hypertension and inhibits hypoxia-inducible factor-1α and TRPC channels | |
| Zhao et al. | LW-215, a newly synthesized flavonoid, exhibits potent anti-angiogenic activity in vitro and in vivo | |
| Cao et al. | Effects of tilianin on proliferation, migration and TGF‐β/smad signaling in rat vascular smooth muscle cells induced with angiotensin II | |
| Zhu et al. | Ginkgolide B targets and inhibits creatine kinase B to regulate the CCT/TRiC-SK1 axis and exerts pro-angiogenic activity in middle cerebral artery occlusion mice | |
| CN114432281A (en) | Application of compound (R) -TML104 in preparation of medicines for preventing and treating diseases related to vascular intimal hyperplasia | |
| Zhu et al. | Effect of sinomenine on vascular smooth muscle cell dedifferentiation and neointima formation after vascular injury in mice | |
| CN108096567A (en) | Applications of the histone methyltransferase EZH2 in the pharmaceutical preparation for preparing prevention or treatment arotic disease | |
| Wang et al. | Inhibition of vascular adventitial remodeling by netrin-1 in diabetic rats | |
| KR102501677B1 (en) | Vascular leakage blocking effect of primaquine diphosphate and its targets usp1 | |
| CN112618544A (en) | Use of apatinib as smooth muscle phenotype transformation inhibitor | |
| CN110974835A (en) | Application of tripterine in inhibiting tumor angiogenesis mimicry | |
| Yang et al. | Substance p inhibits the collagen synthesis of rat myocardial fibroblasts induced by Ang II | |
| CN111067895A (en) | Application of ITE in preparation of medicine for preventing and/or treating cardiopulmonary circulation system diseases | |
| Yin et al. | Role and mechanism of tissue plasminogen activator in venous wall fibrosis remodeling after deep venous thrombosis via the glycogen synthase kinase-3 beta signaling pathway | |
| CN115177608A (en) | Application of long-chain acyl carnitine compound in preparation of medicine for preventing and/or treating liver cancer | |
| US20110015410A1 (en) | Novel use of scoparone | |
| Robich et al. | Effects of selective cyclooxygenase-2 and nonselective cyclooxygenase inhibition on ischemic myocardium | |
| Yang et al. | Guanxintai exerts protective effects on ischemic cardiomyocytes by mitigating oxidative stress |
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 |