CN116270669A - Medicine for treating heart failure and application thereof - Google Patents
Medicine for treating heart failure and application thereof Download PDFInfo
- Publication number
- CN116270669A CN116270669A CN202310179133.9A CN202310179133A CN116270669A CN 116270669 A CN116270669 A CN 116270669A CN 202310179133 A CN202310179133 A CN 202310179133A CN 116270669 A CN116270669 A CN 116270669A
- Authority
- CN
- China
- Prior art keywords
- heart failure
- compound
- treating heart
- medicine
- vash
- 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
- 206010019280 Heart failures Diseases 0.000 title claims abstract description 59
- 239000003814 drug Substances 0.000 title claims abstract description 45
- 229940079593 drug Drugs 0.000 title abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 210000004688 microtubule Anatomy 0.000 claims abstract description 29
- 102000029749 Microtubule Human genes 0.000 claims abstract description 22
- 108091022875 Microtubule Proteins 0.000 claims abstract description 22
- 102100035027 Cytosolic carboxypeptidase 1 Human genes 0.000 claims abstract description 21
- 125000000524 functional group Chemical group 0.000 claims abstract description 7
- -1 patches Substances 0.000 claims description 29
- 108010008314 tyrosine-tubulin Proteins 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000000853 adhesive Substances 0.000 claims description 3
- 230000001070 adhesive effect Effects 0.000 claims description 3
- 239000000443 aerosol Substances 0.000 claims description 3
- 229940035676 analgesics Drugs 0.000 claims description 3
- 239000000730 antalgic agent Substances 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 238000013270 controlled release Methods 0.000 claims description 3
- 239000006071 cream Substances 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000003995 emulsifying agent Substances 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000007951 isotonicity adjuster Substances 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 3
- 239000000829 suppository Substances 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- 239000012730 sustained-release form Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims 1
- 235000013355 food flavoring agent Nutrition 0.000 claims 1
- 210000004413 cardiac myocyte Anatomy 0.000 abstract description 11
- 101000946505 Homo sapiens Cytosolic carboxypeptidase 1 Proteins 0.000 abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 42
- 230000002107 myocardial effect Effects 0.000 description 26
- 238000000034 method Methods 0.000 description 17
- 241000699670 Mus sp. Species 0.000 description 15
- 239000007928 intraperitoneal injection Substances 0.000 description 11
- 230000008602 contraction Effects 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000003032 molecular docking Methods 0.000 description 8
- 150000003384 small molecules Chemical class 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 206010016654 Fibrosis Diseases 0.000 description 6
- 230000004761 fibrosis Effects 0.000 description 6
- 230000004217 heart function Effects 0.000 description 6
- 230000010412 perfusion Effects 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 229930012538 Paclitaxel Natural products 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 229960001592 paclitaxel Drugs 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 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 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 210000002376 aorta thoracic Anatomy 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 239000003684 drug solvent Substances 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 206010007558 Cardiac failure chronic Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 210000000702 aorta abdominal Anatomy 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 210000002808 connective tissue Anatomy 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- QPHLRCUCFDXGLY-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)methanol Chemical compound COC1=CC(CO)=CC(OC)=C1OC QPHLRCUCFDXGLY-UHFFFAOYSA-N 0.000 description 2
- DSALCQNSJMUGOG-UHFFFAOYSA-N 1-dichlorophosphoryloxyhexane Chemical compound CCCCCCOP(Cl)(Cl)=O DSALCQNSJMUGOG-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 2
- 101100049052 Homo sapiens VASH1 gene Proteins 0.000 description 2
- 102000012214 Immunoproteins Human genes 0.000 description 2
- 108010036650 Immunoproteins Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 102100021163 Tubulinyl-Tyr carboxypeptidase 1 Human genes 0.000 description 2
- 102000003425 Tyrosinase Human genes 0.000 description 2
- 108060008724 Tyrosinase Proteins 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- PJANXHGTPQOBST-QXMHVHEDSA-N cis-stilbene Chemical compound C=1C=CC=CC=1/C=C\C1=CC=CC=C1 PJANXHGTPQOBST-QXMHVHEDSA-N 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003033 structure based virtual screening Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 230000002861 ventricular Effects 0.000 description 2
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 101100346154 Caenorhabditis elegans oma-1 gene Proteins 0.000 description 1
- 101100501181 Dictyostelium discoideum eif3d gene Proteins 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 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 1
- 101000668058 Infectious salmon anemia virus (isolate Atlantic salmon/Norway/810/9/99) RNA-directed RNA polymerase catalytic subunit Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 101100501193 Schizosaccharomyces pombe (strain 972 / ATCC 24843) moe1 gene Proteins 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108050001467 Tubulinyl-Tyr carboxypeptidase 1 Proteins 0.000 description 1
- 101150016807 VASH1 gene Proteins 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 206010002906 aortic stenosis Diseases 0.000 description 1
- 210000001765 aortic valve Anatomy 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000003708 edge detection Methods 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 210000002253 embryonic cardiomyocyte Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000008301 phosphite esters Chemical class 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 210000002254 renal artery Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- IRDFFAPCSABAGK-UHFFFAOYSA-N tert-butyl dihydrogen phosphate Chemical group CC(C)(C)OP(O)(O)=O IRDFFAPCSABAGK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 125000005023 xylyl group Chemical group 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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Cardiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to a medicine for treating heart failure and application thereof; a medicine for treating heart failure contains the compound shown in formula (I) as active component, and the application of said compound in preparing the medicine for treating heart failure is disclosed, which features that a special compound is used as chemical reagent to be combined with the functional group of microtubule tyrosine carboxypeptidase to block the biologic effect generated by the destyrosination of microtubule, and the excessive destyrosination of the microtubule of cardiac muscle cells in heart failure is reduced.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a medicine for treating heart failure and application thereof.
Background
Heart failure (HeartFailure, HF), heart failure is a complex clinical syndrome caused by any structural or functional impairment of ventricular filling or ejection of blood. In the past half century, the prevention, diagnosis and management of cerebrovascular diseases have advanced obviously, the mortality rate of developed countries is lowered by 2/3, the mortality rate of acute coronary syndrome, hypertension and arrhythmia is reduced obviously, and only the heart failure field is an exception. Current clinical regimens for treating heart failure are effective, but generally unsatisfactory. How to develop novel anti-heart failure drugs, improve the cure rate of patients and prolong the life span is still a scientific problem to be solved urgently.
Tubulin Tyrosine Carboxypeptidase (TCP) is a key enzyme for the destyrosination of microtubules in cardiomyocytes, which can cleave the tyrosine at the α -tubulin end to effect the destyration of microtubules. However, the composition of TCP has been a puzzle until scientists in the netherlands and france in 2017 find that TCP is composed of a vascular inhibitor protein-1 (vasohibin-1, VASH 1) and a small molecule protein SVBP (small molecule vascular inhibitor binding protein), and specifically knock out a myocardial cell VASH1 gene in vitro by a genetic means to destroy the activity of tubulin tyrosine carboxypeptidase, thereby reducing the level of destyrosination of a myocardial cell microtubule and improving the myocardial cell contraction force;
with the deep research of heart failure mechanism, new therapeutic targets are continuously emerging. The current ability of myocardial microtubule destyrosination to promote the onset and progression of heart failure has been demonstrated by many high-level studies, and the structure of key enzymes for myocardial microtubule destyrosination has been successfully resolved in 2019. The application combines structural bioinformatics with traditional biotechnology means, so as to find out a novel small molecular compound VASH-IN for inhibiting microtubule destyrosination, and is expected to become a new breakthrough point for treating heart failure.
Disclosure of Invention
The invention aims to provide a medicine for treating heart failure, which is used as an inhibitor to bind with the functional group of tubulin Tyrosine Carboxypeptidase (TCP) so as to block the effect of the inhibitor on the uncalcination of cell microtubules, thereby realizing the treatment of heart failure.
In order to achieve the above object, the present invention provides a medicament for treating heart failure, wherein the active ingredients comprise a compound shown as formula (I):
wherein, the dosage form of the medicine for treating heart failure is selected from one of various medical accepted aqueous solution injections, oral liquid preparations, tablets, emulsions, granules, powder injection, pills, powder, patches, suppositories, creams, gels, capsules, aerosols, sprays, powder mists, sustained release agents and controlled release agents.
The medicine for treating heart failure also comprises pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials are at least one selected from isotonic agents, buffer solutions, corrigents, excipients, fillers, adhesives, disintegrants, lubricants, emulsifying agents, solubilizers, bacteriostats, analgesics and antioxidants.
Wherein, the compound is used for preparing the medicine for treating heart failure.
Wherein, the compound is applied to preparing medicines for treating myocardial fibrosis.
Wherein the compound specifically binds to a tubulin tyrosine carboxypeptidase functional group to block the cleavage of tyrosine at the end of microtubules.
Wherein, the compound is used as an experimental inhibitor for inhibiting tubulin tyrosine carboxypeptidase.
Wherein, the compound is applied to preparing drugs for inhibiting cell microtubule from removing tyrosinase.
The invention relates to a medicine for treating heart failure and application thereof, which is used for preventing and treating heart failure by combining a special compound serving as a chemical reagent with a functional group of tubulin Tyrosine Carboxypeptidase (TCP) to block biological effects generated by microtubule destyrosination and reducing excessive destyrosination of microtubules of myocardial cells in heart failure.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a diagram showing the structural interfacing of a small molecule VASH-IN compound and a tubulin tyrosine carboxypeptidase VASH1-SVBP complex provided by a drug for treating heart failure according to the present invention.
FIG. 2 is an immunofluorescence of VASH-IN small molecule compounds inhibiting microtubule destyrosination of cardiomyocytes provided by a drug for treating heart failure according to the present invention.
FIG. 3 is a statistical chart of experimental data for inhibiting microtubule destyrosination of cardiomyocytes by VASH-IN small molecule compound provided by a drug for treating heart failure according to the present invention.
FIG. 4 is a representative picture of VASH-IN small molecule compounds provided by a drug for treating heart failure to improve the relaxation of myocardial cells and the contraction and relaxation of cells IN a contraction experiment.
FIG. 5 is a graph showing the improvement of myocardial cell contraction amplitude IN a myocardial cell relaxation and contraction experiment by VASH-IN small molecule compound provided by a drug for treating heart failure according to the present invention.
FIG. 6 shows the improvement of myocardial cell relaxation and time of relaxation IN a systolic experiment with VASH-IN small molecule compounds provided by a drug for treating heart failure according to the present invention.
FIG. 7 is a representative picture of experimental cardiac ultrasound IN which VASH-IN can improve cardiac function provided by a drug for treating heart failure according to the present invention.
FIG. 8 is a statistical plot of ejection fraction of an experiment IN which VASH-IN provided by a drug for treating heart failure can improve heart function according to the present invention.
FIG. 9 is a statistical graph of experimental data showing that VASH-IN provided by a drug for treating heart failure can improve the survival rate of an animal model of heart failure (aortic incomplete ligation model).
FIG. 10 is a representative picture of the effect of VASH-IN on alleviating myocardial tissue fibrosis IN an animal model of heart failure (aortic incomplete ligation model) provided by a drug for treating heart failure IN accordance with the present invention.
FIG. 11 is a statistical graph of experimental data showing that VASH-IN provided by a drug for treating heart failure can alleviate myocardial tissue fibrosis IN an animal model of heart failure (aortic incomplete ligation model).
FIG. 12 is a diagram of a process for synthesizing a compound provided by a drug for treating heart failure according to the present invention.
Detailed Description
Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to like or similar elements or elements having like or similar functions throughout. The embodiments described below by referring to the drawings are illustrative and intended to explain the present invention and should not be construed as limiting the invention.
The reagents involved in the examples of the present invention are commercially available and commercially available, and the other reagents used in the examples of the present invention were purchased from Sigma Aldrich (Sigma Aldrich), if not illustrated.
Referring to fig. 1 to 9, the present invention provides a medicament for treating heart failure, wherein the active ingredients include a compound shown as formula (I):
wherein, the dosage form of the medicine for treating heart failure is selected from one of various medical accepted aqueous solution injections, oral liquid preparations, tablets, emulsions, granules, powder injection, pills, powder, patches, suppositories, creams, gels, capsules, aerosols, sprays, powder mists, sustained release agents and controlled release agents.
The medicine for treating heart failure also comprises pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials are at least one selected from isotonic agents, buffer solutions, corrigents, excipients, fillers, adhesives, disintegrants, lubricants, emulsifying agents, solubilizers, bacteriostats, analgesics and antioxidants.
Wherein, the compound is used for preparing the medicine for treating heart failure.
Wherein the compound specifically binds to a tubulin tyrosine carboxypeptidase functional group to block the cleavage of tyrosine at the end of microtubules.
Wherein, the compound is used as an experimental inhibitor for inhibiting tubulin tyrosine carboxypeptidase.
Wherein, the compound is applied to preparing drugs for inhibiting cell microtubule from removing tyrosinase.
The preparation method of the compound comprises the following steps:
the reaction of 3,4, 5-trimethoxybenzyl alcohol (I) with LiBr/Me3SiCl gives benzyl bromide (II), which is further condensed with triphenylphosphine to give phosphonium salt (III), (III) with 4-methoxy-3- (xylyl dimethylsilyloxy) benzaldehyde, xylyl being the abbreviation for 1, 2-trimethylpropyl in this application, wittig of derivative (IV) gives cis-stilbene (V).
Subsequent desilication of (V) by tetrabutylammonium fluoride gives Kang Bu statin A4 (VI).
In the presence of dichloromethane and triethylamine, the phenolic hydroxyl group of (VI) and the dichlorophosphoric acid hexyl ester (VII) are subjected to phosphorylation reaction to obtain phosphite ester (VIII).
Finally, trifluoroacetic acid is used to cleave the tert-butyl phosphate group of the phosphite to provide the desired small molecule compound (IX), i.e., small molecule compound (VASH-IN) of this patent, the synthetic scheme of which is shown IN FIG. 12.
The specific scheme of the computer simulation screening is as follows:
the docking module in the MOE1 platform is used for structure-based virtual screening (SBVS). The Chemdiv compound library was selected as VS small molecule library. All compounds were prepared using the wash module in MOE 1. The structure of VASH2-VBP in the protein database (PDB code: 6J 4P) is defined as the receptor, with binding sites located around the natural ligand. Thereafter, all compounds were docked with the protein, ranked by high throughput rigid docking with the London dG score. Then, the top 1.5 ten thousand compounds were further selected to again dock with VASH2-SVBP, and ranked by flexibly docking with the "induced matching" method. Prior to docking, an implicit solvation model of AMBER12, force field and reaction field (R field) of EHT was selected. The proton state of the protein and the orientation of the hydrogen were optimized by the Quickprep module at PH 7 and temperature 300K. For flexible docking, the docking poses are first ranked by the London dG score, then force field optimized for the first 10 poses, and then the best ranked docking pose is selected for each compound using GBVI/WSA dG. After flexible docking, 1.5 ten thousand compounds were divided into structural clusters by fingerprint-based clustering (distance parameter between clusters set to 0.5), and the best ranked compound in each cluster was set as cluster center. The top 100 cluster centers were ultimately identified as potential compounds.
In vitro screening of organisms was performed:
the ability of the rat embryonic cardiomyocyte line H9C2 (which is derived from ATCC) to inhibit microtubule destyrosination was used as a primary screen for the first 100 compounds screened in the simulation.
The H9C2 cell line was plated in 6-well plates and incubated with DMEM+10% serum+1% diabody (with serum), 2mL of medium per well to a cell density of 70%. The final working concentrations per well were 0, 1nM, 10nM, 100nM, 1mM, 10mM, 100mM, respectively, with 2 microliters of paclitaxel (solvent: dimethyl sulfoxide (DMSO)) at different doses per well (0, 1nM, 10nM, 100nM, 1mM, 10mM, 100mM, respectively). Culturing was continued for 12 hours, cells were digested with RIPA, cellular proteins were extracted, and parallel immunoprotein electrophoresis was performed, and the optimal concentration of paclitaxel-induced microtubule-destyrosination was detected in H9C2 cells using microtubule-destyrosinating antibody (source abcam, cat. No. ab 48389) and background antibody (source CellSignaling technology, cat. No. 2144). The experiment was repeated three times independently.
The final working concentration of the experimental stimulus of the study was determined to be 1 μm.
The preparation method of the small molecule compound solution comprises the following steps:
small molecule compounds (initial concentration 10 mM) were dissolved in dimethyl sulfoxide (DMSO).
The method for intervention of H9C2 cells is as follows:
after plating the cells, when the cell growth density reaches 70%, 2. Mu.l of paclitaxel (working concentration 1. Mu.M) was added, and after 12 hours of culture, 2. Mu.l of a small molecule compound (working concentration 10. Mu.M) was added, and the culture was continued for 12 hours. Cells were digested by RIPA, cellular proteins were extracted, and immunoprotein electrophoresis was performed in parallel. Cell microtubule destyrosination levels of each group were detected using microtubule destyrosination antibodies and background antibodies thereof.
The experimental grouping scheme is as follows:
intervention group (cell culture environment is that compound is added into medium in DMEM+10% serum+1% double antibody containing taxol respectively;
negative control group (cell culture environment dmem+10% serum+1% medium in double antibody);
positive control group (cell culture environment is dmem+10% serum+1% medium in double antibody containing paclitaxel).
The candidate compounds with the most significant inhibition of H9C2 cell microtubule debluralization levels in the in vitro validation phase were identified by the codes in the Chemdiv compound library: 8020-5178, the structural formula of which is shown below, is named VASH-IN.
The structure butt joint of the VASH-IN small molecule compound and the tubulin tyrosine carboxypeptidase VASH1-SVBP complex is verified:
the binding model of the small molecular VASH-IN compound and the receptor VASH2-VBP is shown IN figure 1, the binding site of the VASH-IN and the receptor form proper spatial complementation, the oxygen atom of the phosphate group of the VASH-IN respectively forms two salt bridges with residues K157 and R211 IN the receptor, the benzene ring IN the VASH-IN forms pi-pi stacking with H192, and other residues around the receptor binding pocket, such as L159, K135, K247, H193, F191, L215 and the like, form van der Waals interactions with the VASH-IN. This demonstrates that small molecule compounds of VASH-IN form good binding to the tubulin tyrosine carboxypeptidase VASH1-SVBP complex.
The test that VASH-IN small molecule compound can effectively inhibit microtubule destyrosination level of cardiac muscle cells proves that:
method for separating myocardial cells:
mice were treated with 1% PentobaAfter anesthesia by intraperitoneal injection of sodium nitrosulfate (0.5 ml/100 g), the heart was rapidly removed by thoracotomy, the aortic arch was left long enough, and immediately after removal, the heart was placed in ice-cold table fluid. Cutting off all blood vessels, connective tissues and the above part of the aortic arch around the heart except the aorta, hanging the blood vessels, connective tissues and above part of the aortic arch on an isolated heart perfusion system, fastening the blood vessels, connective tissues and above part of the aortic arch by using wires, and simultaneously opening a constant flow pump; the procedure should be noted that the cannula insertion depth must not exceed the aortic valve, and the temperature around the heart and the temperature of the perfusion fluid are maintained at about 37 ℃ throughout the perfusion process, and the whole procedure is ensured to be as long as possible for 1 to 2 minutes. After the heart residual blood pump is clean, stopping the constant flow pump, changing the liquid inlet pipe into enzyme liquid from the table liquid, opening the constant flow pump and timing for 5 minutes. After 5 minutes, the enzyme solution was recovered and timing was started when the enzyme solution reached the heart suspension. During digestion, the hardness of the heart is noted, and when the heart becomes soft and hard and then becomes soft, and the effluent becomes viscous and can be drawn, the digestion process is ended. The heart is sheared, put into oxygen saturated KB liquid to wash out residual enzyme liquid, then put into new KB liquid, myocardial tissues except ventricles are sheared, the ventricular tissues are sheared into fragments of about 1mmX1mmX1mm in a 3 rd hole, the fragments are gently blown by a thick opening straw, the falling off of cells and cell clusters is visible, and the absorption supernatant is filtered by a nylon net of 200 meshes and is subjected to cell precipitation. Adding KB solution to re-suspend the myocardial cells, naturally settling, repeating for 3 times and 10 minutes each time, and standing the obtained cells at room temperature for 1 hour for later use. After cell counting, cells were seeded into 12-well plates with about 2X104 cells per well and placed in CO 2 Suspension culture in culture box at 37 deg.c, and serum-free DMEM culture liquid.
Cell grouping administration:
blank (Vehicle): the culture medium is serum-free DMEM culture solution
Administration group (VASH-IN): the culture medium is serum-free DMEM culture solution containing VASH-IN small molecular compound at 1uM concentration
The cell culture was placed in an incubator for 6 hours, fixed with 4% formalin, and incubated with microtubule destyrosinating antibody (origin abcam, cat. No. ab 48389) and its background antibody (origin cellsignaling technology, cat. No. 2144) and fluorescent secondary antibody. Photographs were taken with a confocal microscope and quantification of fluorescence intensity was performed with ImageJ software.
As shown IN the experimental results from FIG. 2 to FIG. 3, the VASH-IN small molecule compound can effectively inhibit the microtubule destyrosination level of myocardial cells. The results of the study showed that treatment of cardiomyocytes IN isolated adult C57/BL6 mice with a concentration of 1uM of the VASH-IN small molecule compound significantly reduced the level of destyrosination of cardiomyocytes relative to the control group (Vehicle).
Verification test that VASH-IN small molecule compounds can improve the diastole and systole functions of myocardial cells:
method for separating myocardial cells
The method of isolation of cardiomyocytes in this example was as before.
Measurement of myocyte contraction/relaxation function
Synchronously detecting the myocardial cell contraction/relaxation function by adopting an IonOptix single cell dynamic edge detection system; gradient recalcification of cardiomyocytes to [ Ca ] 2+ ]1.8mM, a drop of cardiomyocyte suspension was pipetted into a cell perfusion chamber on an inverted microscope stage and allowed to stand for 5 minutes to allow cardiomyocytes to settle to the bottom of the cell tank, and a peristaltic pump was used to remove 1.8mM [ Ca ] 2+ ]The pH was adjusted to 7.2 and the mixture was circulated into the cell tank by means of a bench top liquid perfusion (1 ml/min,37 ℃ C.). Electric field stimulation with wave width of 0.5HZ and 5ms is given (the stimulation is generated by platinum electrodes inlaid at two sides of the bottom of a perfusion cell through a stimulator), and cell contraction images are transmitted to a Myocam photographing system of IonOptix through a 40-time objective lens and are displayed on a computer monitor, and indexes such as myocardial cell contraction amplitude, diastole time (R90) and the like are acquired and recorded in real time by a computer.
Cell grouping administration:
blank (Vehicle): the culture medium is serum-free DMEM culture solution
Administration group (VASH-IN): the culture medium is serum-free DMEM culture solution containing VASH-IN small molecular compound at 1uM concentration
The cell incubator was left for 2 hours and assayed for myocardial cell contraction/relaxation function as described above. 15 cells were collected for each group.
As shown IN FIGS. 4 to 6, the myocardial cells of the isolated adult C57/BL6 mice were treated with VASH-IN small molecule compound at a concentration of 1uM to enhance their contractile capacity and shorten their time to relaxation, relative to the control group (Vehicle).
VASH-IN small molecule compounds significantly improve heart function IN mice of heart failure model group.
Establishment of a mouse model of chronic heart failure:
the experimental animals are male C57BL/6 mice which are 8-12 weeks old and have a weight of 20-25g, and are provided by the experimental animal center of the first people hospital in Shanghai city. A chronic heart failure model is established by an aortic stenosis method. The mice were anesthetized by intraperitoneal injection with 1% sodium pentobarbital (0.5 ml/100 g), fixed in the supine position, dehaired, sterilized, the skin and muscular layers were cut along the midline of the abdomen, the abdominal aorta was isolated, and the needle was carefully withdrawn after ligating the abdominal aorta with blunt 27 gauge probe over the renal artery. Penicillin is instilled in the abdominal cavity after operation, and the muscle layer and the skin are respectively sutured. The ligature retention continues to constrict the abdominal aorta, increasing afterload, gradually progressing to heart failure. The sham group was identical to the procedure described above, but without aortic ligation.
Animal modeling and group administration
The method comprises the steps of modeling according to the modeling method, randomly dividing the rats successfully modeled into 4 groups, setting normal control groups of 10 rats each, and feeding under standard environment. The modes of administration for each group are as follows:
normal group (Sham): intraperitoneal injection is carried out to administer the same volume of physiological saline;
model set (TAC): intraperitoneal injection is carried out to administer the same volume of physiological saline;
small molecule administration+normal group (sham+vash-IN): intraperitoneal injection of VASH-IN compound 5 mg/kg/day;
small molecule dosing + model group (TAC + vach-IN): intraperitoneal injection of VASH-IN compound 5 mg/kg/day;
each group was administered by intraperitoneal injection once a day for 60 consecutive days, and after the end of the administration, the heart function was measured as follows. The heart small animal ultrasonic examination is carried out by using a Vevo ultra-high resolution small animal ultrasonic imaging system and a high frequency probe through the chest 60 days after the operation. The cardiac ejection fraction (EF%) at 60 day time points was assessed for each group of mice.
The experimental results are shown in fig. 7 to 8. Compared with the normal group, the EF% of the model group is obviously reduced, and the model of the chronic heart failure is successfully modeled. The dosing group had an effect of increasing EF% compared to the model group, and had significant statistical differences. This shows that small molecule compound VASH-IN can be used for treating heart failure, and VASH-IN small molecule compound can obviously prolong survival time of mice IN heart failure model group
The method of molding and group administration of mice in this example was consistent with the cardiac function test. But the number of groups and the detection index are different. IN this example, 7 animals were treated IN the normal group (Sham), 11 animals were treated IN the model group (TAC), 6 animals were treated IN the small molecule administration+normal group (sham+VASH-IN), and 12 animals were treated IN the small molecule administration+model group (TAC+VASH-IN). Each group was given by intraperitoneal injection once a day for 60 consecutive days, and survival time was observed within 60 days of each group.
As shown IN the experimental results IN FIG. 9, compared with mice injected with the same volume of the drug solvent IN the intraperitoneal injection, the mice with the 5 mg/kg/day VASH-IN small molecular compound can effectively and remarkably prolong the survival time of the mice IN the heart failure model group. The survival rate of VASH-IN mice was 57.14% for 60 days. The treatment group of the drug solvent was 18.18%.
The method of molding and group administration of mice in this example was consistent with the cardiac function test. But the number of groups and the detection index are different. Each group was 4. The medicine is administrated by intraperitoneal injection, once daily, and continuously for 60 days. Anesthesia, chest opening, heart removal, paraffin fixation with 4% formalin, paraffin embedding, slicing, masson staining, and assessment of fibrosis of myocardial tissue of each group.
As shown IN fig. 10 to 11, the administration of the small molecular compound of VASH-IN at 5 mg/kg/day by intraperitoneal injection was effective IN significantly reducing myocardial tissue fibrosis IN mice of the heart failure model group, relative to mice injected intraperitoneally with an equal volume of the drug solvent. Mouse myocardial tissue fibrosis with VASH-IN was 7.72%. The treatment group of the drug solvent was 3.07%.
The invention relates to a medicine for treating heart failure and application thereof, which is characterized in that a special compound is used as a chemical reagent and is combined with a functional group of tubulin Tyrosine Carboxypeptidase (TCP) to block biological effects generated by microtubule destyrosination, and the medicine can be applied to medicines for preventing and treating heart failure by reducing the microtubule destyrosination of myocardial cells in heart failure and alleviating tissue fibrosis.
The above disclosure is only a preferred embodiment of the present invention, and it should be understood that the scope of the invention is not limited thereto, and those skilled in the art will appreciate that all or part of the procedures described above can be performed according to the equivalent changes of the claims, and still fall within the scope of the present invention.
Claims (7)
2. a medicament for the treatment of heart failure as claimed in claim 1,
the dosage form of the medicine for treating heart failure is selected from one of various medical accepted aqueous solution injections, oral liquid preparations, tablets, emulsions, granules, powder injection, pills, powder, patches, suppositories, creams, gels, capsules, aerosols, sprays, powder mists, sustained release agents and controlled release agents.
3. A medicament for the treatment of heart failure as claimed in claim 1,
the medicine for treating heart failure also comprises pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials are at least one selected from isotonic agents, buffer solutions, flavoring agents, excipients, fillers, adhesives, disintegrants, lubricants, emulsifying agents, solubilizers, bacteriostats, analgesics and antioxidants.
4. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of heart failure.
5. The use of a compound according to claim 1 in combination with a tubulin tyrosine carboxypeptidase functional group specifically to block the cleavage of tyrosine at the end of microtubules.
6. Use of a compound according to claim 1 as an experimental inhibitor for the inhibition of tubulin tyrosine carboxypeptidase.
7. Use of a compound according to claim 1 for the preparation of a medicament for inhibiting cell microtubule destyrosination.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310179133.9A CN116270669A (en) | 2023-02-27 | 2023-02-27 | Medicine for treating heart failure and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310179133.9A CN116270669A (en) | 2023-02-27 | 2023-02-27 | Medicine for treating heart failure and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116270669A true CN116270669A (en) | 2023-06-23 |
Family
ID=86829895
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310179133.9A Pending CN116270669A (en) | 2023-02-27 | 2023-02-27 | Medicine for treating heart failure and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116270669A (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090012325A1 (en) * | 2007-02-22 | 2009-01-08 | Ajith Manage | Methods for preparing phosphoric acids of combrestastatin and derivatives thereof |
US20180326022A1 (en) * | 2017-04-21 | 2018-11-15 | The Trustees Of The University Of Pennsylvania | Compositions and methods for improving heart function and treating heart failure |
CN111329867A (en) * | 2020-03-31 | 2020-06-26 | 江苏大学附属医院 | 1,25- (OH)2D3Application in preparing medicine for treating heart failure |
US20200407726A1 (en) * | 2017-10-26 | 2020-12-31 | Les Laboratoires Servier | Methods and pharmaceutical compositions for treating tubulin carboxypeptidases associated diseases |
-
2023
- 2023-02-27 CN CN202310179133.9A patent/CN116270669A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090012325A1 (en) * | 2007-02-22 | 2009-01-08 | Ajith Manage | Methods for preparing phosphoric acids of combrestastatin and derivatives thereof |
US20180326022A1 (en) * | 2017-04-21 | 2018-11-15 | The Trustees Of The University Of Pennsylvania | Compositions and methods for improving heart function and treating heart failure |
US20200407726A1 (en) * | 2017-10-26 | 2020-12-31 | Les Laboratoires Servier | Methods and pharmaceutical compositions for treating tubulin carboxypeptidases associated diseases |
CN111329867A (en) * | 2020-03-31 | 2020-06-26 | 江苏大学附属医院 | 1,25- (OH)2D3Application in preparing medicine for treating heart failure |
Non-Patent Citations (2)
Title |
---|
"CAS:519060-00-5", STN REGISTRY DATABASE, 22 May 2003 (2003-05-22) * |
HADIMANI MB ET.AL: "Synthesis, in vitro, and in vivo evaluation of phosphate ester derivatives of combretastatin A-4", BIOORG MED CHEM LETT., vol. 13, no. 9, 5 May 2003 (2003-05-05), pages 1505 - 1508, XP002478872, DOI: 10.1016/S0960-894X(03)00206-3 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1759834B (en) | Application of berberine or associated with Simvastatin in preparing product for preventing or curing disease or symptom related to blood fat | |
CN104220057B (en) | Pharmaceutical composition and method | |
AU2015393357A1 (en) | Peptide having anti-diabetic and anti-obesity effects, and use thereof | |
US20120232142A1 (en) | Novel use of dimethylfumarate | |
CN105636596A (en) | Treating inflammation using LLP2A-bisphosphonate conjugates and mesenchymal stem cells | |
CA3149833A1 (en) | Regenerating functions and phenotypes of connective tissue through npas2 suppression | |
CN113456645A (en) | Application of DMXAA in preparing medicine for preventing and treating osteoporosis | |
CN1649645A (en) | Depsipeptide for therapy of kidney cancer | |
WO2019055064A1 (en) | Compositions and methods for preventing and treating heterotopic ossification and pathologic calcification | |
Borbély et al. | Impact of two neuronal Sigma-1 receptor modulators, PRE084 and DMT, on neurogenesis and neuroinflammation in an Aβ1–42-injected, wild-type mouse model of AD | |
CN1149822A (en) | Therapeutical homeopathic dilutions of growth factors and methods of their use | |
JP2005501823A (en) | Use of angiotensin I derivatives as medicaments for the treatment and prevention of infarct-related heart injuries and disorders | |
CN116270669A (en) | Medicine for treating heart failure and application thereof | |
CN101244258B (en) | Use of TAT-N25 polypeptide in treating cell growth exception dermatosis such as psoriasis | |
JP2006515276A (en) | Furan derivative having preventive and therapeutic effects on osteoporosis and pharmaceutical composition containing the same | |
CN109562097A (en) | The carry out form of andrographolide treatment multiple sclerosis | |
RU2299741C1 (en) | Peptide normalizing metabolism in osseous and cartilage tissue, pharmaceutical composition based on thereof and method for its using | |
CN114053298A (en) | Medicine for inhibiting myocardial hypertrophy and construction method of model | |
CN112274642A (en) | Application of CK2 inhibitor in preparation of medicine for treating rheumatoid arthritis | |
CN111671756A (en) | Application of TGF-beta Smad signal pathway inhibitor in preparation of medicine for treating liver capsule type hydatid | |
CN1839922A (en) | Traditional Chinese medicine preparation for treating leukoderma, psoriasis and its preparation method | |
CN107124883A (en) | Peptide with osteoclast differentiation and activity suppression ability and application thereof | |
CN116850180B (en) | Application of cork xanthoxylin in preparing medicament for treating rheumatoid arthritis | |
CN104922106B (en) | Application of the Artesunate in anti-osteoclast differentiation class medicine is prepared | |
CN114209703B (en) | Application of AMPK inhibitor Compound C in preparation of medicine for treating cystic echinococcosis |
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 |