CN112587530B - Novel pharmaceutical application of Baricitinib - Google Patents
Novel pharmaceutical application of Baricitinib Download PDFInfo
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- CN112587530B CN112587530B CN202011516743.6A CN202011516743A CN112587530B CN 112587530 B CN112587530 B CN 112587530B CN 202011516743 A CN202011516743 A CN 202011516743A CN 112587530 B CN112587530 B CN 112587530B
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Abstract
The invention discloses a pharmaceutical application of Baricitinib. The application is the application of Baricitinib (Baricitinib) or pharmaceutically acceptable salts and esters thereof in preparing medicines for promoting myocardial cell proliferation. Experiments prove that the barrectin benzoate can promote the rat myocardial cell proliferation. Therefore, the Baricitinib can be used for preparing related fields such as medicines for promoting the proliferation of myocardial cells and medicines for treating or preventing heart diseases, and provides a new medicine and a new treatment idea for treating or preventing heart diseases such as myocardial infarction.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a new application of a ba Ruiktinib medicine.
Background
Cardiovascular diseases have become the first killer threatening human health currently, and 4000 million heart failure patients worldwide have become the main cause of human death. It has been found that in mammals, cardiomyocytes gradually lose proliferative capacity after adult life, and once myocardial infarction occurs, the loss of cardiomyocytes cannot be reversed. About 20-40 million myocardial cells exist in adults, about 25% of myocardial cells are lost within hours after the occurrence of myocardial infarction, the proliferation capacity of the remaining myocardial cells is very limited and is not enough to recover the systolic function of the heart, and finally, the heart failure of patients dies. To solve this problem, besides surgery, basic transformation studies mainly include finding cardiac stem cells or precursor cells, transplanting the cells to the myocardial infarction area by induced differentiation, but lack of sufficient molecular markers and low transplantation efficiency limit the use of this technology; the fibroblasts are transdifferentiated into cardiomyocytes using reprogramming techniques, or supplemented to the missing myocardium by means of promoting endogenous cardiomyocyte proliferation. The existing research shows that the heart of lower vertebrates such as zebra fish, salamander and the like has strong regeneration capacity, and newborn suckling mice also have certain regeneration capacity, and the regeneration capacity is mainly realized through myocardial cell proliferation induced by injury, and the capacity disappears after the adult. Adult hearts have not been considered to regenerate in the past, but extensive evidence suggests that there is a slow renewal of mammalian cardiomyocytes, and studies have found that neonatal cardiomyocytes are derived from existing myocardium. Therefore, an increasing number of scientists are interested in a strategy that induces the proliferation of endogenous cardiomyocytes. Therefore, the search for drugs capable of inducing the proliferation of endogenous cardiac muscle cells is of great significance for the treatment of cardiovascular diseases of human beings.
Baricitinib is a selective irreversible inhibitor of Janus kinase 1(JAK1) and Janus kinase 2(JAK 2). Baricitinib obtains European drug administration (EMA) approval for marketing at 2017, 2 and 13 days, and then obtains Japanese pharmaceutical and medical device integration agency (PMDA) approval for marketing at 2017, 7 and 3 days, the product is initially developed by Incyte, later authorized for marketing and is sold by the Incyte
Approved for the treatment of mild to moderate rheumatoid arthritis in adult patients who are inadequately responsive or intolerant to other anti-arthritic drugs. However, no reports on the induction of endogenous cardiomyocyte proliferation by barrectin.
Disclosure of Invention
The invention aims to provide a new application of Baricitinib or pharmaceutically acceptable salts and esters thereof.
The Baricitinib (Baricitinib) CAS No.1187594-09-7 has a structural formula shown in formula I:
the pharmaceutically acceptable salt of the brigatinib can be phosphate.
The new application of the Baricitinib or the pharmaceutically acceptable salt and ester thereof provided by the invention is the application of the Baricitinib or the pharmaceutically acceptable salt and ester thereof in preparing products for promoting the proliferation of myocardial cells.
The cardiomyocytes can be human or mammalian cardiomyocytes. The product may be a pharmaceutical product.
The invention also aims to provide application of Baricitinib (Baricitinib) or pharmaceutically acceptable salts and esters thereof in preparing products for preventing and/or treating cardiovascular diseases. The product may be a pharmaceutical product.
Further, in some embodiments of the invention, the cardiovascular disease may be a heart disease resulting from loss, injury or death of cardiomyocytes.
Further, in some embodiments of the present invention, the above-mentioned heart diseases include, but are not limited to, myocardial infarction, heart failure, and other cardiomyopathies resulting from loss, injury, or death of cardiomyocytes, and the like.
Products prepared from Baricitinib (Baricitinib) or pharmaceutically acceptable salts and esters thereof for promoting myocardial cell proliferation and products prepared for preventing and/or treating cardiovascular diseases are also in the protection scope of the invention.
When necessary, one or more pharmaceutically acceptable carriers can be added into the medicine; the carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field.
The above medicine can be made into various forms such as injection, tablet, powder, granule, capsule, oral liquid, paste, cream, etc.; the medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
The above drugs can be introduced into body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method; or mixed or coated with other materials and introduced into body.
It is still another object of the present invention to provide a method for culturing cardiomyocytes in vitro.
The method for culturing the myocardial cells in vitro comprises the step of adding Barrictinib (Baricitinib) or pharmaceutically acceptable salts and esters thereof into a culture medium containing the myocardial cells.
The final concentration of the barrecetinic acid (Baricitinib) or the pharmaceutically acceptable salt and ester thereof in the culture medium is 0.5-4 mu mol/L. The cardiomyocytes can be human or mammalian cardiomyocytes.
The invention also provides a method for promoting the proliferation of the myocardial cells in vitro.
The method for promoting the proliferation of the myocardial cells in vitro comprises the step of treating the myocardial cells with Barrictinib (Baricitinib) or pharmaceutically acceptable salts and esters thereof.
The concentration of the Baricitinib (Baricitinib) or the pharmaceutically acceptable salt and ester thereof in the treatment system is 0.5-4 mu mol/L. The cardiomyocytes can be mammalian cardiomyocytes.
Experiments prove that Baricitinib (Baricitinib) can promote the proliferation of rat myocardial cells. Therefore, Baricitinib (Baricitinib) can be used for preparing medicines for promoting myocardial cell proliferation, medicines for treating or preventing heart diseases and other related fields, and provides a new medicine and treatment idea for treating or preventing heart diseases such as myocardial infarction.
Drawings
FIG. 1 is a graph showing the effect of Baricitinib (Baricitinib) on the proliferation of cardiomyocytes in newborn rats.
FIG. 2 is a graph showing the effect of Baricitinib (Baricitinib) in promoting entry of neonatal rat cardiomyocytes into the cell cycle (pH 3 is used as a cell cycle activity marker);
FIG. 3 is a graph showing the effect of Baricitinib (Baricitinib) in promoting the entry of neonatal rat cardiomyocytes into the cell cycle (Ki 67 is used as a cell cycle activity marker).
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Baricitinib (Baricitinib) used in the examples below was a DMSO solution of Baricitinib (Baricitinib). Baricitinib, manufacturer TargetMol, Cat number: t2485.
In the following examples "FBS" is fetal bovine serum.
The cTnT-mAG-hGeminin (1/110) virus used in the following examples was constructed as follows:
the cTnT myocardial specific promoter (shown as a sequence 1 in a sequence table) and mAG-hGeminin (1/110) (GenBank: NM-015895) are assembled and cloned on a pShuttle vector (Addgene 16402) by pEASY-Uni Seamless Cloning and Assembly Kit (all-type gold CU101-01), and then are subjected to enzyme digestion by a restriction enzyme PmeI to collect a linear plasmid; the linearized plasmid was co-transformed with pAdEasy1 DNA (Addgene 16400) to BJ5183 competent, recombinant plasmid was selected and amplified, and 293A cells were transfected with the recombinant plasmid (7.5X 10 cells were transfected the day before transfection)5293A cells were plated in a 60mm dish and cultured in DMEM medium containing 5% fetal bovine serum until the cell count reached 1.0-1.5X 106Then, transfecting the cells with the recombinant plasmid by using a calcium phosphate coprecipitation method, removing a culture solution containing coprecipitation particles the next day after transfection, washing with a PBS buffer solution, subpackaging the cells into a 6-hole plate (3 ml of DMEM culture solution containing 5% fetal calf serum is added into each hole), and standing for 6 hours to allow the cells to adhere to the wall; covering the agarose after 6 hours for the formation of viral plaques (plaques should form within 10-21 days, adding agarose/DMEM mixture every 4-5 days or when the medium turns yellow); after obtaining the initial virus, the adenovirus is purified by 2-3 rounds of amplification and cesium chloride density gradient centrifugation.
The Goat anti-Rabbit IgG (H + L) Highly Cross-Adsorbed Secondary Antibody used in the examples described below was a Secondary Antibody manufactured by Invitrogen having the trade name of A32731, available under the trade name Goat anti-Rabbit IgG (H + L) high hly Cross-Adsorbed Secondary Antibody, Alexa Fluor Plus 488.
The Goat anti-Mouse IgG (H + L) Highly Cross-Adsorbed Secondary Antibody used in the examples described below was a Secondary Antibody manufactured by Life technologies under the trade designation A21424 under the trade name Goat anti-Mouse IgG (H + L) high hly Cross-Adsorbed Secondary Antibody, Alexa Fluor 555.
Anti- α -Actinin used in the following examples is a first antibody manufactured by Sigma under the trade name A7811
The Phospho-Histone H3(Ser10) used in the examples described below was a primary antibody manufactured by CST Inc. under the designation 9701S
The Anti-Ki67 antibody used in the following examples is a first antibody manufactured by abcam, Inc. under the designation ab15580
Example 1 in vitro test for Barrictinib (Baricitinib) on the promotion of cardiomyocyte proliferation in rats
(1) Culture of cardiac muscle cells of SD rat
Cardiomyocytes from 3-day-old SD rats were isolated and cultured in DMEM high-sugar medium (Hyclone) + 5% horse serum (GIBCO) in a 37-degree, 5% carbon dioxide incubator.
(2) Experimental grouping and processing
The myocardial cells of SD rats were isolated, and 5% horse serum (GIBCO) + DMEM high-sugar medium culture (Hyclone) was added, cytarabine (final concentration 20umol/L) was added to suppress the growth of non-myocardial cells, cells were infected with cTnT-mAG-hGeminin (1/110) virus (MOI value of virus infection: 100) after 48 hours of attachment, and then changed to DMEM containing 0.5% FBS after 24 hours, and the cells were subjected to the divided-dose treatment, as follows:
a. experimental groups: calibrutinib treatment (final concentration in medium 4. mu. mol/L) for 24 hours.
b. Blank control group: the same amount of DMSO as in the a experiment group was added.
(3) Test method
After the above 2 groups were treated for 24 hours, nuclei were stained with hoechst fluorescent dye, and then photographed with a high content living cell analyzer (Molecular Device), and mAG-hGeminin (1/110) positive cardiomyocytes and total cell numbers were analyzed.
(4) Results
The test results are shown in FIG. 1. As can be seen in FIG. 1, mAG-hGeminin (1/110) positive cardiomyocytes increased 2.5-fold after Baricitinib treatment compared to the blank control (0.5% FBS + DMSO). Mean ± SEM; p < 0.01.
Example 2 in vitro assay for Barrictinib (Baricitinib) to promote entry of neonatal rat cardiomyocytes into the cell cycle
Rat cardiomyocytes born 3 days were isolated, Barbicitinib (Baricitinib) (final concentration in the medium was 2. mu. mol/l), DMEM + DMSO as control (control), 48H later three washes with PBS, 4% PFA (paraformaldehyde) fixed at room temperature for 15min, PBS three washes, 1% BSA/PBS/0.1% Triton blocked at room temperature for 1H, 1H later primary antibodies Anti- α -Actinin (1:300, sigma, mouse, A7811), Phospho-Histone H3(Ser10) antibody (1:300, CST, rabbit,9701S), Anti-Ki67(1:300, abcam, rabbit, ab 80) overnight at 4 ℃, 1% BSA/PBS 1554 washes with 1.02% Tween, secondary antibodies: goat anti-rabbit IgG (H + L) highly cross-adsorbed secondary antibody (1:500, Invitrogen, a32731), goat anti-mouse IgG (H + L) highly cross-adsorbed secondary antibody (1:500, Life technologies, a21424), left at room temperature for 1H, washed 3 times with PBS/0.02% Tween, stained nuclei with DAPI, photographed with a confocal microscope, and statistically analyzed for the proportion of cardiomyocytes positive for PH3 and positive for Ki 67.
The test results are shown in fig. 2 and 3. As can be seen from fig. 2 and 3, PH 3-positive cardiomyocytes and Ki 67-positive cardiomyocytes in the barrertinib (barcitinib) -treated group were significantly increased compared to the control group. Mean ± SEM; p < 0.05.
SEQUENCE LISTING
<110> Xin you kang pharmaceutical technology (Nanjing) Limited
New pharmaceutical application of <120> Baricitinib
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 836
<212> DNA
<213> Artificial sequence
<400> 1
tgtagttaat gattaacccg ccatgctact tatctaccag ggtaatgggg atcctctaga 60
actatagcta gaattcgccc ttacgggccc cccctcgagg tcgggataaa agcagtctgg 120
gctttcacat gacagcatct ggggctgcgg cagagggtcg ggtccgaagc gctgccttat 180
cagcgtcccc agccctggga ggtgacagct ggctggcttg tgtcagcccc tcgggcactc 240
acgtatctcc gtccgacggg tttaaaatag caaaactctg aggccacaca atagcttggg 300
cttatatggg ctcctgtggg ggaaggggga gcacggaggg ggccggggcc gctgctgcca 360
aaatagcagc tcacaagtgt tgcattcctc tctgggcgcc gggcacattc ctgctggctc 420
tgcccgcccc ggggtgggcg ccggggggac cttaaagcct ctgcccccca aggagccctt 480
cccagacagc cgccggcacc caccgctccg tgggacgatc cccgaagctc tagagcttta 540
ttgcggtagt ttatcacagt taaattgcta acgcagtcag tgcttctgac acaacagtct 600
cgaacttaag ctgcagaagt tggtcgtgag gcactgggca ggtaagtatc aaggttacaa 660
gacaggttta aggagaccaa tagaaactgg gcttgtcgag acagagaaga ctcttgcgtt 720
tctgataggc acctattggt cttactgaca tccactttgc ctttctctcc acaggtgtcc 780
actcccagtt caattacagc tcttaaggct agagtactta atacgactca ctatag 836
Claims (9)
1. The application of the barrectin benzoate or the pharmaceutically acceptable salt thereof in preparing the medicaments for preventing and/or treating the cardiovascular diseases;
the cardiovascular disease is heart disease caused by myocardial cell loss, damage or death due to various reasons; the heart disease is myocardial infarction;
the structural formula of the barrectin benzoate is shown as a formula I:
(formula I).
2. A method for culturing cardiomyocytes in vitro, comprising adding baricitinib or a pharmaceutically acceptable salt thereof to a culture medium containing cardiomyocytes.
3. The method of claim 2, wherein: the final concentration of the barrectin benzoate or the pharmaceutically acceptable salt thereof in the culture medium is 0.5-4 mmol/L.
4. A method according to claim 2 or 3, characterized in that: the cardiomyocyte is a human cardiomyocyte.
5. A method according to claim 2 or 3, characterized in that: the cardiac muscle cell is a cardiac muscle cell of a mammal.
6. A method of promoting cardiomyocyte proliferation in vitro comprising treating cardiomyocytes with ba reicherinib or a pharmaceutically acceptable salt thereof.
7. The method of claim 6, wherein: the concentration of the barrectin benzoate or the pharmaceutically acceptable salt thereof in the treatment system is 0.5-4 mmol/L.
8. The method according to claim 6 or 7, characterized in that: the cardiomyocyte is a human cardiomyocyte.
9. The method according to claim 6 or 7, characterized in that: the cardiac muscle cell is a cardiac muscle cell of a mammal.
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