CN106902347A - The purposes of close cyclosporine inhibitor - Google Patents
The purposes of close cyclosporine inhibitor Download PDFInfo
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- CN106902347A CN106902347A CN201510992309.8A CN201510992309A CN106902347A CN 106902347 A CN106902347 A CN 106902347A CN 201510992309 A CN201510992309 A CN 201510992309A CN 106902347 A CN106902347 A CN 106902347A
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- Prior art keywords
- cyclosporin
- cyclosporine
- carbon atoms
- hepatitis
- hydroxymethylleucine
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to the purposes of close cyclosporine inhibitor, the purposes of close cyclosporine inhibitor or its pharmaceutically acceptable salt or solvate in medicine is prepared is specifically provided, the medicine is used to treat and/or prevent the hepatitis b virus infected disease for causing.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to application of a cyclophilin inhibitor.
Background
Hepatitis B (Hepatitis B) is an infectious disease caused by infection with Hepatitis B virus (Hepatitis B virus), and there are approximately 3 million people worldwide infected with Hepatitis B virus, of which there are 1 million people in china. Acute hepatitis B virus infection is often converted into chronic infection, even liver cirrhosis, liver dysfunction, liver cancer and the like. Liver cancer caused by chronic hepatitis B accounts for 60% -80% of the total incidence of liver cancer worldwide, and chronic hepatitis B has become a disease seriously threatening human health.
HBV belongs to the hepadnaviridae family, and its genome is 3.2kb incompletely closed double-stranded circular DNA. The complete viral particle consists of a nucleocapsid and an envelope. The nucleocapsid is mainly composed of DNA wrapped by virus core antigen protein, reverse transcriptase and terminal protein of the virus, and the main components of the envelope are the same as those of the cell membrane of the host. Hepatitis B virus is mainly transmitted by mother and infant, sexually transmitted and blood.
The replication process of HBV in host cells can be simply divided into three phases: (1) the viral particles enter the cell, releasing the RC-DNA comprising the nucleocapsid into the cytoplasm, which is subsequently transported into the nucleus, forming cccDNA. (2) Different genomic and subgenomic RNAs are transcribed by RNA polymerase II, where pgRNA is selectively used as a new template and synthesized into the nucleocapsid protein and viral DNA polymerase. (3) The synthesized viral genome and viral protein are combined and packaged to form progeny virus particles, enter a Golgi apparatus to form envelopes, and are released outside cells through budding to carry out the next round of infection and replication.
The life cycle of HBV in a host is mainly expressed in four stages. The first stage is the immune tolerance phase. In healthy adults, this latency period is typically two to four weeks, while in neonates, the latency period can be as long as several decades. In the second phase, the immune response of the body begins or increases, stimulating the production of large amounts of cytokines and inflammatory factors. The infected at this stage had a decrease in HBV DNA in the serum, but secreted HBeAg. In acute patients with HBV infection, this stage usually lasts for about 4 weeks, but in chronic infected patients, the second stage lasts for a long time and may lead to cirrhosis and complications. When the host's immunocompetence is triggered, the ability to substantially reduce or eliminate infected cells, the replication of the virus is diminished to the point of disappearance, which means the beginning of the third phase. In stage three, the infection has been eliminated and the transaminase levels in the organism returned to normal levels, however, HBsAg remains positive, probably due to integration of the S gene into the host genome. The fourth phase is called the immunization phase. The physiological characteristic of most infected individuals at this stage is positive for hepatitis B surface antigen antibodies and negative for hepatitis B surface antigen. At this stage, the presence of HBV DNA is not detected. Many factors influence the progress of these four stages, such as genetic susceptibility of the host, the presence of other viruses, the emergence of HBV mutants, sex, treatment with immunosuppressive agents, and the like.
At present, the medicines for patients with hepatitis B are mainly divided into several categories including liver protection, enzyme reduction, virus resistance, hepatic fibrosis resistance, immunity regulation and the like, and the medicines are still in the aspect of antiviral medicine treatment research. The current treatment scheme for the viral hepatitis B can only achieve the aim of inhibiting HBV replication and secondary infection, and cannot directly damage virosomes or even eliminate viruses. There are two classes of drugs used for the treatment of chronic hepatitis: one is by direct interference with HBV replication and one is by modulation of HBV-specific immune responses. The former are mainly nucleotide or nucleoside analogues, such as lamivudine, adefovir, entecavir, and the like, which inhibit virus replication by directly inhibiting the activity of reverse transcriptase. The latter are mainly interferon and pegylated interferon-2 a, which have strong immunomodulatory effects. However, interferon treatment is easy to cause serious adverse reactions, so that a lot of patients can not tolerate the treatment and quit the treatment; nucleoside analog treatment is prone to viral variation and drug resistance, and rebound often occurs after drug withdrawal. In recent years, a series of novel antiviral drugs acting on the replication cycle of HBV viruses are emerging, and among them, cyclosporin (CyP) inhibitors targeting host factors are also receiving more and more attention.
Cyclosporin A (CyPA) was originally discovered as a protein receptor for cyclosporin A (CsA), an immunosuppressant useful for antifungal, antiparasitic, anti-inflammatory and anti-HIV activity. Cyclosporin a and certain derivatives thereof have been reported to have anti-HCV activity. Recent studies have shown that cyclosporin a inhibits the transport activity of sodium-taurocholic acid transport polypeptide (NTCP) and blocks the binding of NTCP to HBV capsid proteins in vitro, thereby blocking HBV entry into host cells. Cyclosporin A related complexes (SCYX618806, Alisporivir, etc.) have stronger anti-HBV potential than cyclosporin A. Cyclosporin treatment, however, causes severe nephrotoxicity, manifested as severe renal vasoconstriction, leading to the development of irreversible renal structural and functional impairment. There is therefore a need for effective methods and compositions for treating or preventing viral hepatitis.
The problem of complications arising from cyclosporin treatment was subsequently solved, since it was surprisingly found that certain 3-substituted cyclosporin derivatives have anti-HCV activity and unexpectedly good toxicological properties. Current studies indicate that immuno-deficient analogues of cyclophilins, such as NIM811, SCY-635 and Alisporivir, hold promise for replacing cyclophilins as anti-hepatitis C chemotherapeutic drugs.
Today, it is known that treatment with interferon alone or in combination with Ribavirin (Ribavirin) is effective in eradicating HCV but still has major limitations, and thus researchers have variously studied anti-HCV drugs instead of or in combination with interferon. The major breakthrough among them was antiviral studies on the cyclosporin derivative SCY-635. The cyclosporine derivative SCY-635 induces the in-vivo immune response of a hepatitis C patient, promotes host cells to produce I/II/III type interferon, and has more excellent anti-HCV effect when being used together with the interferon.
However, hepatitis b caused by HBV infection is still very difficult to cure so far, and the current treatment scheme for hepatitis b can only achieve the aim of inhibiting HBV replication and secondary infection, but cannot completely eliminate hepatitis b virus, which is a difficult point of hepatitis b treatment relative to hepatitis c treatment. The immunomodulatory role played by SCY-635 in hepatitis c virus-related diseases gives us a reasonable conjecture that the drug is not only suitable for anti-RNA virus, but may also have inhibitory effect on DNA virus. Moreover, until now, no reports about the inhibition of hepatitis B virus infection by cyclosporine derivative SCY-635 exist. However, it is also clear that drugs which can treat diseases associated with hepatitis C virus are not necessarily also capable of treating diseases associated with hepatitis B virus. Although interferon with broad-spectrum antiviral effect can resist hepatitis C virus and hepatitis B virus, other drugs for treating diseases related to two viruses have different action mechanisms and different curative effects. Most of anti-hepatitis B virus nucleoside drugs can play a role in resisting hepatitis B virus by being converted into triphosphate form in vivo, and the nucleoside drugs can inhibit the activities of virus DNA polymerase and reverse transcriptase, competitively permeate into a virus DNA chain with deoxycytidine to terminate the extension and synthesis of the DNA chain, so that the replication of the virus is inhibited to play a role in resisting the DNA virus. The lamivudine in the form of triphosphate can be inserted into a hepatitis B virus DNA chain being synthesized to block the synthesis of HBV DNA; adefovir inhibits HBV DNA polymerization by acting as a terminator for the DNA chain. Nucleoside drugs are ineffective against hepatitis C virus, and effective clearance of hepatitis C virus is only possible when long-acting interferon is used in combination with the broad-spectrum antiviral drug ribavirin. The anti-hepatitis C virus mechanism of ribavirin is to inhibit RNA polymerase activity after phosphorylation by intracellular kinase, and inhibit the formation of a 5' end cap structure playing a key role in the replication process of hepatitis C virus, and the phosphorylated ribavirin can be an inhibitor of inosine monophosphate (IAmp) deoxyenzyme to block the synthesis of guanylic acid, so that the replication of hepatitis C virus is inhibited, and the anti-hepatitis C virus effect is played. However, the curative effect of ribavirin on hepatitis B virus is weaker and far less than the inhibitory effect of nucleoside drugs on hepatitis B virus, so that ribavirin is gradually withdrawn from the hepatitis B virus treatment market. The novel medicine for directly resisting hepatitis C virus directly targets HCV non-structural protein and specifically inhibits NS3/4A protease, NS5A protein and NS5B RNA polymerase. The NS3/4A inhibitor Simeprevir and the NS5B inhibitor Sofosbuvir have recently been approved for sale. Since anti-hepatitis C virus drugs are not universal with anti-hepatitis B virus drugs, our study of SCY-635 on the efficacy of treatment of hepatitis B virus related diseases is still very significant and valuable.
Disclosure of Invention
The present invention aims to solve at least one of the above technical problems to at least some extent or to at least provide a useful commercial choice. Therefore, an object of the present invention is to provide a drug effective for the treatment or prevention of hepatitis B.
According to a particular discovery of the present invention, the following embodiments are provided:
the present invention relates to a medicament and a method for preventing and/or treating diseases caused by hepatitis B virus infection. Therefore, the compound of the invention can also be used for preparing medicines and medicaments for treating diseases caused by hepatitis B virus infection. In particular aspects, such drugs and medicaments comprise a therapeutically effective dose of a cyclosporin inhibitor and a pharmaceutically acceptable carrier.
According to an embodiment of the invention, the use of a cyclosporin inhibitor having the structure shown in formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment and/or prevention of a disease caused by infection with hepatitis b virus:
wherein,
a is a residue of formula IIa or IIb:
b is ethyl, 1-hydroxyethyl, isopropyl or n-propyl;
r1 is:
straight-chain or branched alkyl containing from one to six carbon atoms, optionally substituted by one or more identical or different radicals R3Substitution;
a straight or branched alkenyl group containing two to six carbon atoms, which is optionally substituted with one or more same or different groups selected from halogen, hydroxyl, amino, monoalkylamino and dialkylamino;
straight or branched alkynyl containing two to six carbon atoms, optionally substituted with one or more identical or different groups selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
cycloalkyl containing three to six carbon atoms, optionally substituted with one or more identical or different groups selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; or
A straight or branched chain alkoxycarbonyl group containing one to six carbon atoms;
r2 represents isobutyl or 2-hydroxyisobutyl;
x is sulfur, -S (O)n-or oxygen;
R3selected from halogen, hydroxy, carboxy, alkoxycarbonyl, -NR4R5and-NR6(CH2)mNR4R5；
R4And R5Independently from each other:
hydrogen;
straight-chain or branched alkyl containing from one to six carbon atoms, optionally substituted by one or more identical or different radicals R7Substitution;
straight or branched alkenyl or alkynyl groups comprising two to four carbon atoms;
cycloalkyl containing three to six carbon atoms, optionally substituted with a straight or branched chain alkyl containing one to six carbon atoms;
substituted phenyl optionally substituted with one to five identical or different groups selected from halogen, alkoxy, alkoxycarbonyl, amino, alkylamino and dialkylamino;
a saturated or unsaturated heterocyclic ring containing five or six ring atoms and one to three identical or different heteroatoms selected from nitrogen, sulfur and oxygen;
or R4And R5Together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing four to six ring atoms, which ring may optionally contain another heteroatom selected from nitrogen, oxygen and sulfur, which ring may optionally be substituted with one to four identical or different groups selected from alkyl, phenyl and benzyl;
R6represents hydrogen or a linear or branched alkyl group containing from one to six carbon atoms;
R7is selected from the group consisting of halogen, hydroxy, carboxy, alkoxycarbonyl and-NR8R9At least one of (a);
R8and R9Each independently hydrogen or a straight or branched alkyl group containing from one to six carbon atoms;
n is 1 or 2;
m is 2, 3 or 4;
halogen is fluorine, chlorine, bromine or iodine.
According to an embodiment of the invention, in the cyclosporin inhibitor a is a residue having formula IIa and B is ethyl.
According to an embodiment of the invention, R1 in the cyclophilin inhibitor is 2-aminoethyl, 2-aminopropyl, 2-monoalkylaminoethyl, 2-monoalkylaminopropyl, 2-dialkylaminoethyl, 2-dialkylaminopropyl, 2-monocycloalkylaminoethyl, 2-monocycloalkylaminopropyl, 2-dicycloalkylaminoethyl or 2-dialkylaminopropyl, wherein alkyl is a straight or branched chain comprising from one to four carbon atoms and cycloalkyl comprises from three to six carbon atoms.
According to an embodiment of the invention, X in the cyclophilin inhibitor is oxygen or sulfur; according to a particular embodiment of the invention, when X is sulfur in the cyclosporin inhibitor, R1 is selected from dimethylaminoethyl, diethylaminoethyl, methyl-tert-butylaminoethyl and ethyl-tert-butylaminoethyl.
According to an embodiment of the invention, the pharmaceutically acceptable salt is a phosphate, citrate, acetate, hydrochloride, mesylate or propionate salt.
According to an embodiment of the invention, the cyclosporin inhibitor is one of the following structures or a pharmaceutically acceptable salt of one of the following:
3-methoxy cyclosporin;
3- (2-aminoethoxy) cyclosporine;
3(2-N, N-dimethylaminoethoxy) cyclosporine;
3- (isopropoxy) cyclosporine;
3- (2-ethylbutoxy) cyclosporin;
3- (2, 2-dimethylpropoxy) cyclosporin;
3- (2-hydroxyethoxy) cyclosporine;
3- (3-hydroxypropoxy) cyclosporine;
3- [2- (N-methylamino) ethoxy ] cyclosporine;
3- [2- (N-methyl-N-isopropylamino) ethoxy ] cyclosporin;
3- [2- (piperidin-1-yl) ethoxy ] cyclosporine;
3- [2- (N-morpholine) ethoxy) cyclosporine;
3-ethoxy cyclosporin;
3- (2-methoxyethylsulfanyl) -4- (γ -hydroxymethylleucine) cyclosporine;
3- [ (R) -2- (N, N-dimethylamino) ethylsulfanyl-Sar ] -4- (γ -hydroxymethylleucine) cyclosporine;
3-ethylsulfanyl cyclosporin;
3-propenyl thio cyclosporin;
3- [ (2-methoxy) ethylthio ] cyclosporin;
3- (methylthio) 4- (γ -hydroxymethylleucine) cyclosporine;
3- (methoxy) -4- (γ -hydroxymethylleucine) cyclosporin;
3- (prop-2-en-1-oxy) -4- (γ -hydroxymethylleucine) cyclosporine;
3- (isopropoxy) -4- (γ -hydroxymethylleucine) cyclosporine;
3- (ethoxy) -4- (γ -hydroxymethylleucine) cyclosporin;
3- [2- (methoxy) ethoxy ] -4- (γ -hydroxymethylleucine) cyclosporine;
3- [3- (methoxy) propoxy ] -4- (gamma-hydroxymethylleucine) cyclosporine.
According to an embodiment of the present invention, the disease caused by hepatitis b virus infection is at least one selected from the group consisting of acute hepatitis b, chronic hepatitis b, liver fibrosis, liver cirrhosis, and liver cancer.
According to an embodiment of the invention, the cyclosporin inhibitor is administered orally or parenterally.
According to an embodiment of the invention, the dosage of the administration is 1-1000 mg/day, preferably 50-500 mg/day, most preferably 100 mg/day. According to a specific embodiment of the present invention, the dose administered to mice, which are a model of hepatitis B infection, is 10mg/kg Bid, and if the bioavailability of mice and humans does not differ much, the dose administered to adults is 10mgx60 × 2/12-100 mg/day.
According to an embodiment of the present invention, 3- [ (R) -2- (N, N-dimethylamino) ethylthio-Sar ] -4- (γ -hydroxymethylleucine) cyclosporine (SCY-635), or a pharmaceutically acceptable salt or solvate thereof, is used for the preparation of a medicament for the prevention and/or treatment of chronic hepatitis b virus infection.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 shows a graph of the effect of SCY-635 on HBsAg, HBeAg expression, according to example 4 of the present invention;
FIG. 2 shows a graph of the effect of SCY-635 on HBV DNA copy number, according to example 4 of the present invention;
FIG. 3 shows a graph of the effect of SCY-635 on HBsAg, HBeAg expression, according to example 5 of the present invention;
FIG. 4 shows a graph of the effect of SCY-635 on HBV DNA copy number, according to example 5 of the present invention;
FIG. 5 shows a graph of the effect of SCY-635 on HBsAb expression according to example 5 of the present invention;
FIG. 6 shows a map of the effect of SCY-635 on IFN-a secretion by PBMC cells according to example 6 of the present invention.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 preparation of 3-methoxy Cyclosporin
A solution of 3- (mercaptobenzothiazol-2-ylthio) cyclosporin (0.4g, 0.28mmol) and camphorsulfonic acid (0.7g, 3mmol) in dry tetrahydrofuran and dry methanol was heated at 50 ℃ for 2 h. The mixture was cooled to room temperature and saturated sodium bicarbonate, ether and water were added. The layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. Chromatography was repeated on silica gel eluting with a mixture of dichloromethane and ethyl acetate to give 120mg of 3-methoxycyclosporin.
EXAMPLE 2 preparation of 3- (2-methoxyethylthio) -4- (gamma-hydroxymethylleucine) cyclosporin
Liquid ammonia (30mL) was concentrated under nitrogen. Sodium amide (1.0g) was added followed by a solution of 4- (γ -hydroxymethylleucine) -cyclosporin (1.22g,1.0mmol) in tert-butyl methyl ether (20 mL). The mixture was stirred at-35 ℃ for 90 minutes. 2-methoxyethyl disulfide (5.9g) was added and stirring was continued at-35 ℃ for another 2 hours. Ammonium chloride (1.5g) was added as a solid and the mixture was stirred at-33 ℃ for 10 minutes. After returning to room temperature, the mixture was diluted with tert-butyl methyl ether, washed with water, brine and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified using silica gel column chromatography, eluting first with ethyl acetate/heptane and then with methanol/ethyl acetate, to give 500mg of 3- (2-methoxyethylthio) -4- (γ -hydroxymethylleucine) cyclosporine.
EXAMPLE 3 preparation of 3- [ (R) -2- (N, N-dimethylamino) ethylthio-Sar ] -4- (gamma-hydroxymethylleucine) cyclosporin
A solution of 4- (gamma-hydroxymethylleucine) cyclosporin (1.22g,1.0mmol) in dry tetrahydrofuran was added dropwise to a solution of Lithium Diisopropylamide (LDA) in dry tetrahydrofuran under an inert atmosphere at low temperature. The mixture was stirred at-35 ℃ for 90 minutes. 2- (N, N-dimethylamino) ethyl disulfide (4.6g) was added and stirring was continued at-35 ℃ for another 2 hours. Ammonium chloride (1.5g) was added as a solid and the mixture was stirred at-33 ℃ for 10 minutes. After returning to room temperature, the mixture was diluted with tert-butyl methyl ether, washed with water, brine and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel, eluting first with ethyl acetate/heptane and then with methanol/ethyl acetate, to give 260mg of 3- [ (R) -2- (N, N-dimethylamino) ethylthio-Sar ] -4- (γ -hydroxymethylleucine) cyclosporin.
EXAMPLE 4 preparation of a salt of 3- [ (R) -2- (N, N-dimethylamino) ethylthio-Sar ] -4- (gamma-hydroxymethylleucine) cyclosporin
3- [ (R) -2- (N, N-dimethylamino) ethylthio-Sar ] -4- (gamma-hydroxymethylleucine) cyclosporin was dissolved in 10ml of diethyl ether, the corresponding acid was added, stirred at 25 ℃ for 2 hours, and the precipitate was collected by filtration, washed with cold ether, and dried in vacuo. Thereby obtaining the phosphate, citrate, acetate, hydrochloride, methanesulfonate and propionate of 3- [ (R) -2- (N, N-dimethylamino) ethylthio-Sar ] -4- (gamma-hydroxymethylleucine) cyclosporine, respectively.
Example 5 Effect of SCY-635 on hepatitis B Virus HBsAg, HBeAg levels and HBV DNA copy number
1. Experimental Material
HepG and Huh7 liver cancer cells: provided by the Wuhan university Collection (HepG2 collection with the number GDC024, Huh7 collection with the number GDC 134);
fetal bovine serum: purchased from Gibco corporation, USA;
DMEM medium: purchased from Gibco corporation, USA;
lipo2000 transfection reagent: purchased from Life corporation, usa;
HBsAg/HBeAg detection kit: purchased from Shanghai Kowa bioengineering, Inc.;
hepatitis B Virus (HBV) nucleic acid amplification (PCR) fluorescent quantitative detection kit: purchased from Shanghai Kowa bioengineering, Inc.
2. Cell culture conditions
HepG2, Huh7 cells in DMEM medium containing 10% Fetal Bovine Serum (FBS) at a volume fraction of 5% CO2The culture was carried out at 37 ℃ under saturated humidity.
3. Experiment grouping
Blank control group: adding no cell and medicament, and only adding an equal volume of DMEM culture solution containing 10% FBS;
negative control group: adding the cells without drugs, adding equal amount of dimethyl sulfoxide (DMSO), and adding equal volume of DMEM medium containing 10% FBS;
different concentration groups of SCY-635 (drug group for short): adding cells and SCY-635 solutions with different concentrations, wherein the SCY-635 is prepared by dimethyl sulfoxide (DMSO), the final concentrations of the SCY-635 are respectively 0.5 mu mol/L, 1 mu mol/L and 2 mu mol/L, and adding an equal volume of DMEM medium containing 10% FBS.
4. Experimental methods
Taking HepG2 cells or Huh7 cells in logarithmic growth phase as 4 × 105The density of each well is inoculated into 24-well plate, each well is 0.5ml, and the plate is placed in 5% CO2Culturing at 37 deg.C under saturated humidity for 6 hr to make the cells adhere to the wall and grow well, sucking off the culture medium in the culture plate, and adding fresh culture medium. Cells were transfected with 0.8. mu.g of HBV whole genome plasmid (pBlue-HBV1.3) per well as follows: mu.g of plasmid and 2. mu.L of Lipo2000 transfection reagent were added to 100. mu.L of Opti-MEM serum-free medium, mixed well, left for 20min, and the mixture was added to the cultured cells. Culturing for 12 hr, discarding culture medium, adding culture solution or medicinal solution into corresponding holes according to the above experiment groups, each group having 3 multiple holes with 5% CO2And culturing at 37 ℃ for 48 hours under saturation humidity, collecting cell culture solution, centrifuging for 5 minutes, taking supernatant to detect the HBsAg level and the HBeAg level, collecting cells to extract HBV DNA (replication intermediate closed circular DNA, cccDNA) at the same time, performing fluorescence quantitative PCR detection, measuring the HBsAg level and the HBeAg level in the supernatant by using an ELISA detection kit, measuring an OD value by using an enzyme-linked immunosorbent assay (the detection wavelength is 450nm and the reference wavelength is 630nm), and determining the inhibition percentage (5) ═ × 100% (negative control group OD value-drug group OD value)/(negative control group OD value-blank control group OD value).
5. Results of the experiment
The experimental results are shown in the attached drawings 1-2:
among them, FIG. 1 shows the effect of SCY-635 on the expression of HBsAg, HBeAg: the results show that: as shown in the data of Table 1, SCY-635 can inhibit secretion of HBsAg and HBeAg by the hepatoma cell lines HepG2 and Huh7 cells transiently transfected with HBV genome plasmid, and has dose-dependence. Particularly, the inhibition effect of the high-dose group of SCY-635 on HBsAg/HBeAg is very obvious, and the inhibition rate is as high as 58%. It is suggested that SCY-635 has certain inhibition effect on hepatitis B virus and certain potential for treating hepatitis B virus related diseases.
The effect of SCY-635 on HBsAg, HBeAg expression in Huh7 cells is shown in Table 1:
TABLE 1 Effect of SCY-635 on HBsAg, HBeAg expression in Huh7 cells
In HepG2 cells, the effect of SCY-635 on the expression of HBsAg and HBeAg is shown in Table 2:
TABLE 2 influence of SCY-635 on HBsAg, HBeAg expression in HepG2 cells
FIG. 2 shows the effect of SCY-635 on HBV DNA copy number, and the results show that: as shown in the data in Table 2, SCY-635 has a strong inhibitory effect on the replication of hepatitis B virus DNA and shows a dose-dependent relationship, especially, the inhibitory rate on the replication activity of HBV DNA is as high as 80-90% at a higher dose (2. mu. mol/L). It is suggested that SCY-635 has better inhibition effect on the replication of hepatitis B virus.
The effect of SCY-635 on HBsAg, HBeAg expression in Huh7 cells is shown in Table 3:
TABLE 3 influence of SCY-635 on HBsAg, HBeAg expression in Huh7 cells
In HepG2 cells, the effect of SCY-635 on the expression of HBsAg and HBeAg is shown in Table 4:
TABLE 4 influence of SCY-635 on HBsAg, HBeAg expression in HepG2 cells
Example 6 Effect of SCY-635 on HBV DNA and HBeAg/HBsAg/HBsAb expression in mouse model
1. Experimental Material
BALB/C mice: SPF grade, female, purchased from Beijing Wittiaxle laboratory animal technologies, Inc.;
HBsAg/HBeAg detection kit: purchased from Shanghai Kowa bioengineering, Inc.;
hepatitis B Virus (HBV) nucleic acid amplification (PCR) fluorescent quantitative detection kit: purchased from Shanghai Kowa bioengineering, Inc.;
HBsAb detection kit: purchased from Shanghai Kowa bioengineering, Inc.;
lamivudine (3 TC): purchased from the Puerarin Stecke pharmaceutical (Suzhou) Co.
2. Establishment of experimental animal model
HBV1.3 ploid whole genome plasmid (paav-HBV1.3) constructed by lentiviral vector is injected into tail vein under high pressure to infect BALB/c mouse. The model mice were injected with paav-HBV1.3 plasmid at 0.08X body weight (g)/ml, tail vein injection was completed within 5s, and the plasmid concentration was 6.5. mu.g/ml (PBS dilution). After the mice are injected with plasmids, the expression of hepatitis B virus HBeAg, HBsAg and HBV DNA can be continuously detected. The drug is administrated by gastric lavage, tail vein blood is taken to detect the amount of HBsAg, HBeAg and virus nucleic acid in the blood of the mouse, and the therapeutic effect of the drug on the mouse infected by the hepatitis B virus is evaluated.
3. Experiment grouping
Blank control group: BALB/C mice that do not express the HBV full genome;
negative control group: BALB/C mice expressing HBV whole genome, orally taking the same dose of physiological saline;
positive control group: BALB/C mice expressing HBV whole genome orally taking lamivudine of 3mg/kg or 1 mg/kg;
different concentration groups of SCY-635 (drug group for short): BALB/C mice expressing HBV whole genome, orally administering different concentrations (10mg/kg and 3.3mg/kg) of SCY-635;
4 results of the experiment
The experimental results are shown in the attached figures 3-4.
In particular, fig. 3 shows that SCY-635 has an enhanced inhibitory effect on HBsAg and HBeAg with an increase in concentration and duration of action, and particularly has a significant inhibitory effect on HBsAg. The HBsAg expression level in the blood of the mice continuously decreased during 15 days of administration of the positive control lamivudine. The expression level of HBsAg in the blood of the mice rapidly decreases during the period of 2-6 days after the administration of high concentration SCY-635, and the HBsAg still maintains a low expression level 7-15 days later. The inhibitory effect of SCY-635 on the HBsAg expression level in mouse blood seems to be slightly better than that of lamivudine.
FIG. 4 shows that SCY-635 is beneficial for reducing HBV DNA copy number with increasing concentration and duration of action. The continuous increase of the HBV DNA expression in blood 6 days before the administration of the mouse is mainly influenced by the expression of the transfection plasmid, and the inhibition effect of the drug group on the HBV DNA begins to be shown in 2-6 days after the administration. After 2-15 days of administration, the positive control lamivudine continuously and efficiently inhibits HBV DNA level, and the high concentration SCY-635 has stronger HBV DNA inhibiting capability than the low concentration SCY-635. Although the ability of SCY-635 to inhibit HBV DNA is not as strong as that of lamivudine, compared with the control group, SCY-635 has obvious effect of inhibiting HBV DNA.
FIG. 5 shows that oral administration of SCY-635 favors seroconversion of HBsAb. Mice were treated with drug for 15 days and HBsAb expression levels were measured 3 days after drug administration was stopped. HBsAb is a protective antibody generated by host immune regulation on hepatitis B virus, and the expression quantity of HBsAb reflects the regulation and control effect of host immune system on virus. When mice are infected with HBV by high-pressure intravenous injection of HBV genome lentiviral vector plasmid and then treated for 15 days, the expression level of HBsAb in positive control lamivudine group and SCY-635 high concentration group is detected to be increased, but the method has limited virus infection time, so the detected expression level of HBsAb is low. The results suggest that SCY-635 may regulate the host immune response, thereby achieving the effect of inhibiting hepatitis B virus.
Example 7 SCY-635 Regulation of IFN-a secretion by PBMC cells of hepatitis B patients
1. Experimental Material
Blood of hepatitis B patients: is from the clinical laboratory of people hospital in Wuhan City;
lymphocyte separation solution: purchased from Beijing Biyuntian Biotechnology Ltd;
RPMI-1640 medium: purchased from Gibco corporation, USA;
human IFN-a detection kit: purchased from Beijing Dake as Biotechnology, Inc.
2. Isolation of PBMC cells
Diluting fresh patient blood with serum-free RPMI-1640 medium in equal volume, slowly adding lymphocyte separation liquid in equal volume along the tube wall, mixing, and centrifuging at room temperature of 2000rpm for 15 min. After centrifugation, the mixture is divided into four layers from the bottom of the tube to the liquid level, namely a red blood cell and granulocyte layer, a layered liquid layer, a mononuclear cell layer and a plasma layer. The atomized mononuclear cell layer is carefully sucked into a new centrifugal tube, 3 times of volume of RPMI-1640 culture medium is added for washing for 3 times, each time, the centrifugation is carried out at 2000rpm for 10 minutes, and finally, the mononuclear lymphocytes are obtained. The obtained PBMC cells were plated in 12-well cell culture plates on average.
3. Experiment grouping
Blank control group: adding the RPMI-1640 culture solution containing 10% FBS in the same volume without adding cells and medicines;
negative control group: adding the cells without drugs, adding equal amount of dimethyl sulfoxide (DMSO), and adding equal volume of RPMI-1640 culture solution containing 10% FBS;
different concentration groups of SCY-635 (drug group for short): adding cells and SCY-635 solutions with different concentrations, preparing SCY-635 by using dimethyl sulfoxide (DMSO), and adding equal volume of RPMI-1640 culture solution containing 10% FBS into the SCY-635 solutions with final concentrations of 0.5 mu mol/L, 1 mu mol/L and 2 mu mol/L respectively.
4. Results of the experiment
The experimental results are shown in figure 6.
FIG. 6 shows the effect of SCY-635 on the amount of IFN-a secreted by PBMC cells from hepatitis B patients. The results showed that different doses of SCY-635 (0.5. mu. mol/L, 1. mu. mol/L and 2. mu. mol/L) stimulated IFN-a secretion from PBMC cells of hepatitis B patients in amounts of 1.55pg/ml, 10.85pg/ml and 32.5pg/ml, respectively, suggesting that SCY-635 can reactivate the immune response of hepatitis B patients and that the immune effect is enhanced with increasing concentration of SCY-635.
The activity assays of the salt form and the solvate were performed with reference to SCY-635. It is shown that the salts or solvates of the cyclosporin inhibitor of the present invention can also treat and/or prevent diseases caused by infection with hepatitis B virus.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. Use of a cyclosporin inhibitor having the structure shown in formula I or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment and/or prevention of a disease caused by infection with hepatitis b virus:
wherein,
a is a residue of formula IIa or IIb:
b is ethyl, 1-hydroxyethyl, isopropyl or n-propyl;
r1 is:
straight-chain or branched alkyl containing from one to six carbon atoms, optionally substituted by one or more identical or different radicals R3Substitution;
a straight or branched alkenyl group containing two to six carbon atoms, which is optionally substituted with one or more same or different groups selected from halogen, hydroxyl, amino, monoalkylamino and dialkylamino;
straight or branched alkynyl containing two to six carbon atoms, optionally substituted with one or more identical or different groups selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino;
cycloalkyl containing three to six carbon atoms, optionally substituted with one or more identical or different groups selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; or
A straight or branched chain alkoxycarbonyl group containing one to six carbon atoms;
r2 is isobutyl or 2-hydroxyisobutyl;
x is-S (O)n-, sulfur or oxygen;
R3selected from halogen, hydroxy, carboxy, alkoxycarbonyl, -NR4R5and-NR6(CH2)mNR4R5；
R4And R5Independently from each other:
hydrogen;
straight-chain or branched alkyl containing from one to six carbon atoms, optionally substituted by one or more identical or different radicals R7Substitution;
straight or branched alkenyl or alkynyl groups comprising two to four carbon atoms;
cycloalkyl containing three to six carbon atoms, optionally substituted with a straight or branched chain alkyl containing one to six carbon atoms;
substituted phenyl optionally substituted with one to five identical or different groups selected from halogen, alkoxy, alkoxycarbonyl, amino, alkylamino and dialkylamino;
a saturated or unsaturated heterocyclic ring containing five or six ring atoms and one to three identical or different heteroatoms selected from nitrogen, sulfur and oxygen;
or R4And R5Together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing four to six ring atoms, which may optionally contain another heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one to four identical or different groups selected from alkyl, phenyl and benzyl;
R6is hydrogen or a straight or branched alkyl group containing from one to six carbon atoms;
R7is selected from the group consisting of halogen, hydroxy, carboxy, alkoxycarbonyl and-NR8R9At least one of (a);
R8and R9Each independently hydrogen or a straight or branched alkyl group containing from one to six carbon atoms;
n is 1 or 2;
m is 2, 3 or 4;
halogen is fluorine, chlorine, bromine or iodine.
2. The use according to claim 1, wherein in the cyclosporin inhibitor a is a residue of formula IIa and B is ethyl.
3. Use according to claim 1, wherein R1 in the cyclophilin inhibitor is 2-aminoethyl, 2-aminopropyl, 2-monoalkylaminoethyl, 2-monoalkylaminopropyl, 2-dialkylaminoethyl, 2-dialkylaminopropyl, 2-monocycloalkylaminoethyl, 2-monocycloalkylaminopropyl, 2-dicycloalkylaminoethyl or 2-dialkylaminopropyl, wherein alkyl is a straight or branched chain comprising from one to four carbon atoms and cycloalkyl comprises from three to six carbon atoms.
4. Use according to claim 1, wherein in the cyclosporin inhibitor X is oxygen or sulphur;
optionally, when X is sulfur, R1 is selected from the group consisting of dimethylaminoethyl, diethylaminoethyl, methyl-tert-butylaminoethyl and ethyl-tert-butylaminoethyl.
5. Use according to claim 1, characterized in that the pharmaceutically acceptable salt is a phosphate, citrate, acetate, hydrochloride, mesylate or propionate salt.
6. Use according to claim 1, wherein the cyclosporin inhibitor is one of the following or a pharmaceutically acceptable salt of one of the following:
3-methoxy cyclosporin;
3- (2-aminoethoxy) cyclosporine;
3(2-N, N-dimethylaminoethoxy) cyclosporine;
3- (isopropoxy) cyclosporine;
3- (2-ethylbutoxy) cyclosporin;
3- (2, 2-dimethylpropoxy) cyclosporin;
3- (2-hydroxyethoxy) cyclosporine;
3- (3-hydroxypropoxy) cyclosporine;
3- [2- (N-methylamino) ethoxy ] cyclosporine;
3- [2- (N-methyl-N-isopropylamino) ethoxy ] cyclosporin;
3- [2- (piperidin-1-yl) ethoxy ] cyclosporine;
3- [2- (N-morpholine) ethoxy) cyclosporine;
3-ethoxy cyclosporin;
3- (2-methoxyethylsulfanyl) -4- (γ -hydroxymethylleucine) cyclosporine;
3- [ (R) -2- (N, N-dimethylamino) ethylsulfanyl-Sar ] -4- (γ -hydroxymethylleucine) cyclosporine;
3-ethylsulfanyl cyclosporin;
3-propenyl thio cyclosporin;
3- [ (2-methoxy) ethylthio ] cyclosporin;
3- (methylthio) 4- (γ -hydroxymethylleucine) cyclosporine;
3- (methoxy) -4- (γ -hydroxymethylleucine) cyclosporin;
3- (prop-2-en-1-oxy) -4- (γ -hydroxymethylleucine) cyclosporine;
3- (isopropoxy) -4- (γ -hydroxymethylleucine) cyclosporine;
3- (ethoxy) -4- (γ -hydroxymethylleucine) cyclosporin;
3- [2- (methoxy) ethoxy ] -4- (γ -hydroxymethylleucine) cyclosporine;
3- [3- (methoxy) propoxy ] -4- (gamma-hydroxymethylleucine) cyclosporine.
7. The use according to claim 1, wherein the disease caused by hepatitis B virus infection is at least one selected from the group consisting of acute hepatitis B, chronic hepatitis B, liver fibrosis, liver cirrhosis, and liver cancer.
8. Use according to claim 1, characterized in that the cyclosporin inhibitor is administered orally or parenterally.
9. Use according to claim 8, wherein the dose is 1-1000 mg/day, preferably 50-500 mg/day, most preferably 100 mg/day.
10. Use according to claim 1, wherein the cyclosporin inhibitor is 3- [ (R) -2- (N, N-dimethylamino) ethylsulfanyl-Sar ] -4- (γ -hydroxymethylleucine) cyclosporin.
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| US12060440B2 (en) | 2020-03-26 | 2024-08-13 | Farsight Medical Technology (Shanghai) Co., Ltd. | Cyclophilin inhibitors and uses thereof |
| CN113694177A (en) * | 2020-04-15 | 2021-11-26 | 睿诺医疗科技（上海）有限公司 | Prevention and treatment of organ damage |
| WO2021209003A1 (en) * | 2020-04-15 | 2021-10-21 | Farsight Medical Technology (Shanghai) Co., Ltd. | Prevention and treatment of organ injuries |
| WO2023102847A1 (en) | 2021-12-09 | 2023-06-15 | Waterstone Pharmaceuticals (Wuhan) Co., Ltd. | Ws635 uses thereof in medicine |
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