Use of adenosine receptor inhibitors for the preparation of a medicament for the treatment of hyperlipidemia and cardiovascular and cerebrovascular diseases

Abstract

The application provides application of an adenosine receptor inhibitor in preparation of a drug for treating hyperlipidemia and cardiovascular and cerebrovascular diseases. GPR146 is a GPCR orphan receptor for regulating blood lipid metabolism which is discovered by the inventors in the prior art. In the process of screening an endogenous ligand of GPR146, the inventors accidentally find that GPR146 can form a functional complex with another GPCR family member A2AR to jointly respond to the activation of adenosine. The adenosine inhibitor can achieve a significant blood lipid-lowering effect, and lays a key theoretical foundation for developing a blood lipid-lowering drug targeting GPCR. The application will be widely applied in the treatment of hyperlipidemia and related cardiovascular and cerebrovascular diseases.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to the application of adenosine receptor inhibitors in the preparation of drugs for the treatment of hyperlipidemia and cardiovascular and cerebrovascular diseases. Background Technology

[0002] Hyperlipidemia, especially hypercholesterolemia, is a major cause of a series of metabolic diseases, including atherosclerosis, coronary heart disease, fatty liver, and type 2 diabetes. Recent studies have also found that hyperlipidemia plays an important role in neurodegenerative diseases. Currently marketed small-molecule lipid-lowering drugs mainly target cholesterol synthesis and absorption pathways; however, these drugs have limited cholesterol-lowering effects and certain side effects. Inhibitors targeting the secretory proteins PCSK9 and ANGPTL3, which have been marketed in recent years, have shown good lipid-lowering effects, but these drugs are expensive and require long-term injections (Table 1). Therefore, inexpensive, convenient, and highly effective small-molecule lipid-lowering drugs have always been an important research and development direction for major pharmaceutical companies (Chen LG, et al. SciChina Life Sci. 2019).

[0003] Table 1: Major Cholesterol-Lowering Drugs Available on the Market

[0004]

[0005] G protein-coupled receptors (GPCRs) are a class of membrane protein receptors with seven transmembrane domains. They transmit extracellular signals into the cell through interactions with intracellular G proteins. The human genome encodes thousands of GPCR family members, which participate in various aspects of bodily and cellular life activities. Importantly, more than one-third of currently marketed small molecule drugs target the GPCR family, playing a crucial role in drug development and disease treatment.

[0006] Hyperlipidemia has a significant genetic component. The applicant previously conducted population cohort genetic analysis and functional experiments, discovering that the orphan GPCR receptor GPR146 responds to activation of serum contents, and inhibiting its expression significantly reduces serum cholesterol levels without other side effects (F. Han et al., Hypercholesterolemia risk-associated GPR146 is an orphan G-protein coupled receptor that regulates blood cholesterol levels in humans and mice. Cell Res 30, 363-365 (2020)). This result was also reported around the same time by Dr. Cowan's laboratory at Harvard Medical School (H. Yu et al., GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis. Cell, 1276-1288e1214 (2019)). GPR146 is the first GPCR reported to directly regulate serum cholesterol levels, and has become an important new target for the development of lipid-lowering drugs, attracting widespread attention (Rom O, et al, Curr Opin Lipidol, 2021). Currently, the structure of GPR146 is unclear, and its ligands, related agonists, and inhibitors have not been reported, becoming a major bottleneck in the development of drugs targeting GPR146.

[0007] Therefore, it is necessary to develop a drug targeting GPR146 for the treatment of hyperlipidemia and cardiovascular and cerebrovascular diseases. Summary of the Invention

[0008] The purpose of this invention is to provide the application of adenosine receptor inhibitors in the preparation of drugs for the treatment of hyperlipidemia and cardiovascular and cerebrovascular diseases. This application has found that adenosine inhibitors have significant lipid-lowering effects and have important application prospects in lowering blood lipids and treating cardiovascular diseases.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] In a first aspect of the invention, the use of adenosine receptor inhibitors in the preparation of medicaments for treating hyperlipidemia and cardiovascular and cerebrovascular diseases is provided.

[0011] Further, the adenosine receptor inhibitor includes at least one of Istradefylline (KW6002), CSC, SCH 58261, SCH 442416, ZM241,385, VER 6947, VER 7835, Schering compound, preladenant (SCH420814), and SYN115, specifically as follows: Figure 1 As shown.

[0012] Furthermore, the drug also includes pharmaceutically acceptable excipients and carriers.

[0013] Furthermore, the excipients include at least one of fillers, disintegrants, binders, excipients, diluents, lubricants, sweeteners, or colorants.

[0014] Furthermore, the dosage form of the drug includes at least one of granules, tablets, pills, capsules, injections, or dispersants.

[0015] Furthermore, the medications used to treat hyperlipidemia and cardiovascular diseases include medications for lowering cholesterol.

[0016] In a second aspect of the invention, the use of an inhibitor of the GPR146-adenosine receptor A2AR complex in the preparation of a medicament for the treatment of hyperlipidemia and cardiovascular and cerebrovascular diseases is provided.

[0017] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0018] This invention relates to the application of adenosine receptor inhibitors in the preparation of drugs for treating hyperlipidemia and cardiovascular diseases. In screening endogenous ligands for the cholesterol-regulating receptor GPR146, we unexpectedly discovered that GPR146 can form a functional complex with A2AR, jointly responding to adenosine activation, indicating that the adenosine receptor A2AR is a key receptor regulating cholesterol metabolism. Simultaneously, the inventors of this application found that adenosine receptor inhibitors have significant lipid-lowering effects. This suggests that adenosine receptor inhibitors have important application prospects in the preparation of drugs for lowering blood lipids and treating cardiovascular diseases. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0020] Figure 1 This is the structural formula for various adenosine receptor inhibitors.

[0021] Figure 2 Adenosine specifically activates downstream signaling pathways of GPR146. Left: Adenosine can dose-dependently activate GPR146 and its downstream cAMP-PKA-CRE signaling pathway; Right: The effect of gene silencing GPR146 on inhibiting adenosine activation. A: Adenosine.

[0022] Figure 3 Among nucleoside analogues, only adenosine can activate GPR146 and its downstream cAMP-PKA-CRE signaling pathway.

[0023] Figure 4 The activation of adenosine depends on A2AR. Left: Gene silencing of A2AR inhibits the activation of adenosine; Right: A2AR-specific inhibitors inhibit the activation of adenosine. A: Adenosine;

[0024] Figure 5 This demonstrates a specific interaction between A2AR and GPR146. IP: Immunoprecipitation;

[0025] Figure 6 Knocking out the liver Gpr146 gene significantly reduced serum cholesterol levels in mice. NC: normal diet; HFHC: high-fat, high-cholesterol diet.

[0026] Figure 7 KW6002, an A2AR-specific inhibitor, significantly reduced serum cholesterol levels in mice.

[0027] Figure 8 GPR146 protein expression was induced by doxycycline. GPR146 and the internal control Vinculin were detected by Western blotting using their specific antibodies.

[0028] Figure 9 This is a plasmid map of the TETON lentiviral expression vector. Detailed Implementation

[0029] The present invention will be described in detail below with reference to specific embodiments and examples, thereby making the advantages and various effects of the present invention more clearly apparent. Those skilled in the art should understand that these specific embodiments and examples are for illustrative purposes only and are not intended to limit the present invention.

[0030] Throughout this specification, unless otherwise specified, the terminology used herein should be understood as having the meaning commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the event of any conflict, this specification shall prevail.

[0031] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be obtained by purchasing them from the market or by existing methods.

[0032] The technical solution of this application embodiment is to solve the above-mentioned technical problems, and the general idea is as follows:

[0033] GPR146 can respond to the activation of serum contents, and inhibiting its expression significantly reduces serum cholesterol levels.

[0034] The inventors of this application first discovered that adenosine activation of the cAMP-PKA signaling pathway depends on GPR146. In screening endogenous ligands for GPR146, we unexpectedly discovered that GPR146 can form a functional complex with A2AR, co-responding to adenosine activation. This indicates that the adenosine receptor A2AR is a key receptor regulating cholesterol metabolism, and that adenosine can activate the cAMP-PKA pathway through adenosine-A2AR. 2A The R pathway regulates blood lipid levels. Therefore, it can be inferred that adenosine receptor inhibitors could be used to develop drugs that lower cholesterol.

[0035] Extracellular adenosine exerts its physiological functions by binding to adenosine receptors on the cell membrane, inducing conformational changes in the receptors, and subsequently activating downstream G proteins and their downstream signal transduction pathways. The adenosine receptor family is currently mainly divided into four types: A1R, A... 2A R, A 2B R, A3R, where A1R, A 2A R and A3R receptors have a high affinity for adenosine; A 2B R is a low-affinity receptor, requiring a high concentration of adenosine to activate A. 2B R. A1R and A3R are associated with G protein subtypes G. i and G o Coupled, it inhibits the activity of adenylate cyclase, reducing intracellular cAMP concentration; A 2A R and A 2B R then interacts with the activated G protein G. s Coupled, it activates adenylate cyclase, thereby increasing the concentration of cyclic adenosine monophosphate (cAMP) and activating downstream protein kinase A (PKA). 2A R is mainly expressed in the liver, heart, lungs, brown adipose tissue, immune system (spleen, thymus, immune cells and platelets), and central nervous system.

[0036] Adenosine-A 2A The R pathway has been found to play an important role in various diseases in the human body, such as cancer and Parkinson's disease. Adenosine-A 2AThe R pathway has been found to play an important role in various diseases in the human body, such as cancer and Parkinson's disease, making the development of effective and highly selective A pathways feasible. 2A R-blockers have become an attractive area of ​​research. Currently, adenosine receptor A... 2A R-blockers can be broadly classified into two categories: xanthine derivatives and azacyclic polycyclic systems. Natural xanthine binds to all adenosine receptors at micromolar concentrations (15-80 μM) without any selectivity. Researchers have screened for A-blockers by randomly substituting groups on the xanthine ring. 2A R exhibits high selectivity, while small molecules with low affinity for other adenosine receptors, such as DMPX and KF17837, are less effective. However, due to the poor water solubility and photoisomerism of xanthine derivatives, small molecule compounds with nitrogen-containing heterocyclic structures have been developed, which have high affinity for A. 2A R also possesses specific affinity, such as SCH 58261, SCH 63390, and ZM241385. Currently, various A2AR antagonists, including Istradefylline (KW6002), CSC, SCH 58261, SCH 442416, ZM241385, VER6947, VER 7835, Schering compound, preladenant (SCH 420814), and SYN115, have entered clinical trials for use in cancer immunotherapy, treatment of neurological diseases, and other applications.

[0037] KW6002, officially named (E)1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine, belongs to the styrylxanthine class of compounds. KW6002 exhibits high selectivity for A2AR: its affinity for A2AR in rats is 60 times that of A1R, and in humans, it is 800 times that of A1R. The equilibrium dissociation constant (Ki value) between KW6002 and A2AR is 2.2 nM. The elimination half-life of KW6002 in humans is approximately 47 hours, making it the longest-lived A2A receptor antagonist currently available. It readily crosses the blood-brain barrier after oral administration. KW6002 has shown positive effects in the treatment of Parkinson's disease and is currently undergoing Phase III clinical trials in multiple regions worldwide. It has been approved for clinical use in Japan.

[0038] Therefore, the inventors of this application selected KW6002 as a representative adenosine receptor inhibitor for research, and we found that feeding KW6002 can significantly reduce serum cholesterol levels. Figure 8(Left). Serum cholesterol is mainly divided into low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL). LDL is a major contributing factor to cardiovascular diseases such as atherosclerosis, while HDL is considered to have a protective effect on the cardiovascular system. We found that KW6002 primarily lowers LDL cholesterol levels, with no significant effect on HDL cholesterol. Figure 8 (Right) indicates that KW6002 has important application prospects in the treatment of hypercholesterolemia and cardiovascular and cerebrovascular diseases.

[0039] The application of the adenosine receptor inhibitor of this application in the preparation of drugs for treating hyperlipidemia and cardiovascular and cerebrovascular diseases will be described in detail below with reference to embodiments and experimental data.

[0040] Example 1: GPR146 and A2AR form a functional complex, jointly responding to adenosine activation.

[0041] I. Adenosine activation of the cAMP-PKA signaling pathway depends on GPR146

[0042] In our previous work, we discovered that the downstream signaling pathway regulated by GPR146 is cAMP-PKA-CRE (F. Han et al., Hypercholesterolemia risk-associated GPR146 is an orphan G-protein coupled receptor that regulates blood cholesterol levels in humans and mice. Cell Res 30, 363-365 (2020)). To find an endogenous ligand for GPR146, we co-expressed GPR146 and the CRE luciferase reporter system in HEK293T cells. The specific steps were as follows:

[0043] 1. Establishment of the GPR146 TETON-induced expression system

[0044] GPR146 has a seven-transmembrane structure, which can easily lead to folding errors under overexpression. Rho-guided peptides effectively assist in the folding and accurate intracellular localization of GPCR family proteins and are widely used in GPCR research. In this study, we overexpressed GPR146 by constructing a Rho-GPR146 fusion expression plasmid. The TET ON induction expression system can precisely control protein expression levels, so we chose this system for our GPR146 overexpression study. Using standard molecular cloning techniques, we inserted the Rho-GPR146 gene fragment (SEQ ID NO.1) into the TET ON lentiviral expression vector (provided from a gift, image shown). Figure 9 As shown in SEQ ID NO.2, the original sequence of the TETON lentiviral expression vector is located at the FseI and AgeI sites. After co-transfection with helper plasmids PSPAX and PMD2G, it was packaged into lentiviral particles in 293T cells. Subsequently, we used this virus to infect HEK293 cells, and selected stable TETON-induced expression cell lines expressing Rho-GPR146 using the blastidin resistance gene carried by the expression vector. Figure 2 As shown, different concentrations of doxycycline (Dox) can induce Rho-GPR146 expression in a dose-dependent manner, indicating that the cell line was successfully constructed. Subsequent experiments used 2 μg / ml doxycycline for expression induction.

[0045] 2. Screening for GPR146 ligands using the CRE-Luciferase luciferase reporter system.

[0046] On day 1, the Rho-GPR146 stably expressing cell line with good growth was passaged at a cell density of 4 × 10⁶ cells / year. 6 / 10cm dish.

[0047] On the second day, when the cells reached a density of 60%-80%, luciferase reporter plasmids were transfected using liposomes. The transfection plasmids included the CRE-Luciferase reporter plasmid (Promega) and the hRenilla internal control plasmid (Promega). CRE is a regulatory element responding to the transcription factor Creb and is widely used in studies of cAMP-PKA-Creb signaling pathway activity.

[0048] On the third day, 24 hours after transfection, the cells were digested with trypsin and seeded into 96-well plates, and doxycycline was added to induce the expression of GPR146.

[0049] On the fourth day, the cell culture medium was changed to DMEM containing 0.1% BSA.

[0050] On the fifth day, different concentrations of adenosine, guanosine, thymidine, uridine, cytidine, and inosine were added, and luciferase activity was detected 6 hours later.

[0051] Through screening over 1000 small molecule metabolites, we discovered that adenosine can specifically activate GPR146 activity and its downstream cAMP-PKA-Cre signaling pathway. Figure 3 (Left), and gene silencing GPR146 can block this activation effect, indicating that the activation effect of adenosine is GPR146-dependent. Figure 3(Right). The siRNA sequences used for gene silencing were predicted using the siRNA gene silencing sequence prediction software on the Merck official website. The three siRNA sequences with the highest scores were selected for synthesis. siRNA synthesis was performed by Shanghai Gemma. The synthesized siRNAs were directly transfected into cells using Lipofectamine RNAiMAX (Thermofi sher, catalog number 13778030), and the transfection process was performed strictly according to the official instructions. Two of the siRNAs with good gene silencing effects were used in the current experiment. The siRNA sequences are shown in Table 2.

[0052] Adenosine, along with guanosine, thymidine, uridine, cytidine, and inosine, are all nucleotide metabolites. We found that among these nucleoside small molecules, only adenosine can activate GPR146, indicating that adenosine is a specific small molecule that activates GPR146. Figure 4 ).

[0053] Table 2

[0054]

[0055] II. Adenosine activation of the cAMP-PKA signaling pathway depends on A2AR

[0056] A2AR is a known adenosine receptor (JFChen, HKEltzschig, BBFredholm, Adenosine receptors as drug targets -- what are the challenges Nat Rev Drug Discov 12, 265-286 (2013)). The discovery that GPR146 specifically responds to adenosine stimulation prompted us to investigate whether A2AR plays a role in this activation process.

[0057] 1. Gene silencing A2AR inhibits the activation of GPR146 by adenosine.

[0058] (a) First, we used the shRNA gene silencing sequence prediction software on the Merck official website to predict and select the three shRNA sequences with the highest scores. The shRNA target sequences were synthesized by Beijing Qingke Biotechnology Co., Ltd. During synthesis, the shRNA sequences contained AgeI and EcoRI restriction sites at both ends. Subsequently, the sequences were cloned into the lentiviral expression vector pLKO.1-TRC (from Addgene, catalog number 179360) through the AgeI and EcoRI restriction sites to construct the pLKO.1-shRNA plasmid. Lentiviral virus was packaged in 293T cells using the same method as in Example 1.

[0059] (b) Validation of the gene silencing efficiency of the three shRNAs in 293T cells. The specific implementation was as follows: Day 1, 293T cells were seeded in six-well plates; Day 2, lentivirus infection was performed; Day 3, the culture medium was replaced with fresh medium according to the cell condition; Day 4, the cells were harvested, and the A2AR gene silencing efficiency was detected using real-time PCR.

[0060] Two shRNAs with good gene silencing efficiency were selected for subsequent experiments and named sh-A2AR-1 and shA2AR-2, respectively (sequences are shown in Table 3).

[0061] Table 3

[0062]

[0063] (c) In TETON-induced GPR146 expression cell lines, A2AR gene silencing experiments were performed, with specific experimental procedures as shown in b). The transfection conditions for the luciferase reporter plasmid and the adenosine treatment conditions were the same as in Example 1.

[0064] 2. The A2AR inhibitor KW6002 inhibits the activation of GPR146 by adenosine.

[0065] Referring to Example 1, the activation ability of adenosine on GPR146 under KW6002 (1 μM) conditions was simultaneously detected in a TET ON-induced GPR146 expression cell line. Figure 5 As shown on the right, KW6002 can significantly inhibit the activation of GPR146 by adenosine, indicating that the activation of GPR146 by adenosine depends on A2AR, and that A2AR inhibitors can inhibit the activity of GPR146.

[0066] III. A2AR and GPR146 form a complex

[0067] On day 1, the 293T cells in good growth condition were passaged at a density of 2.1 × 10⁻⁶. 6 / 10cm dish.

[0068] On the second day, when the cell density reached 60%-80%, the corresponding expression plasmid was transfected. The transfection reagent was LPEI, and the ratio of LPEI to plasmid was 2 μl: 1 μg. After 8 hours, the culture medium was replaced with fresh medium.

[0069] On day four, 48 hours after transfection, cells were collected and cell lysates were prepared. Part of the cell lysate was retained as input, and the rest was used for immunoprecipitation (using Anti-Flag M2 agarose gel beads). The input and immunoprecipitated samples were analyzed by Western blotting to determine changes in the levels of GPR146 and A2AR. Using biochemical methods such as co-immunoprecipitation, we found that GPR146 can interact with A2AR. Figure 6 Therefore, inhibitors of the GPR146-adenosine receptor A2AR complex can be used in the preparation of drugs for the treatment of hyperlipidemia and cardiovascular and cerebrovascular diseases. These inhibitors can inhibit GPR146 or adenosine receptor A2AR alone, or they can inhibit both GPR146 and adenosine receptor A2AR simultaneously.

[0070] IV. Gene knockout of Gpr146 reduces serum cholesterol levels in mice

[0071] Previous studies have shown a significant association between GPR146 gene mutations and hypercholesterolemia in the population. By creating tissue-specific gene knockout mice, we discovered that liver Gpr146 is a crucial receptor for regulating serum cholesterol. Liver-specific gpr146 gene knockout mice (Li-gpr146- / -) exhibited lower serum cholesterol levels. Figure 7 It also helps to combat hypercholesterolemia caused by a high-fat, high-cholesterol diet. The specific experimental procedure is as follows:

[0072] Liver-specific gpr146 gene knockout mice were obtained using the Cre-LoxP system. First, using gene targeting technology, the F lox site was inserted flanking the gpr146 gene. Then, these F lox / F lox mice were mated with liver-specific Cre-expressing mice (Albumin-Cre) to obtain liver-specific gpr146 gene knockout mice (Li-gpr146) using Cre-LoxP. - / - In all experiments, littermates of F lox / F lox mice that did not express Cre served as the control group. All genotypes were validated by PCR gene amplification analysis. After the mice reached adulthood, we analyzed Li-gpr146... - / - Mice were fed a normal diet, or a high-fat, high-cholesterol diet for two weeks, and the total cholesterol levels in the serum of mice were further measured after overnight starvation.

[0073] Example 2: Adenosine receptor inhibitors reduce serum cholesterol levels in mice

[0074] 1. Preparation of a high-cholesterol mouse model

[0075] Wild-type mice have much lower cholesterol levels, especially low-density lipoprotein cholesterol (LDL-C), compared to humans. To better mimic human serum LDL-C levels, we used adeno-associated virus to overexpress the LDL receptor blocker PCSK9 in mouse liver, thereby increasing serum LDL-C levels. This method is also widely used in mouse cholesterol metabolism studies (J. Keeter WC, Carter NM, Nadler JL, Galkina EV., The AAV-PCSK9 murine model of atherosclerosis and metabolic dysfunction. Eur Heart J Open. 2022 Apr 20;2(3):oeac028.doi:10.1093 / ehjopen / oeac028). The specific method is as follows:

[0076] Step 1: Preparation of PCSK9-expressing adeno-associated virus

[0077] Adeno-associated virus (AAV) is a well-established method for in vivo gene delivery and has been used in clinical gene therapy. In this protocol, the PCSK9 gene fragment was first cloned into an AAV expression vector using standard molecular cloning methods. This was further co-expressed with helper plasmids (all plasmids were derived from Addgene), followed by isolation and purification to obtain AAV particles. Specific experimental procedures can be found at (F. Han et al., Hypercholesterolemia risk-associated GPR146 is anorphan G-protein coupled receptor that regulates blood cholesterol levels in humans and mice. Cell Res30, 363-365 (2020)).

[0078] Step 2: Use PCSK9 adeno-associated virus to prepare a high-cholesterol mouse model

[0079] The isolated and purified PCSK9 adeno-associated virus particles were injected into mice via tail vein injection (5*10). 11 Particles / mouse), and after 14 days, blood was drawn from the tail vein to test serum cholesterol levels, and further in vivo experiments with KW6002 were carried out.

[0080] 2. In vivo experiments of the A2AR inhibitor KW6002

[0081] The hypercholesterolemia mouse model prepared above was randomly divided into two groups. KW6002 was dissolved in corn oil. One group was administered corn oil as a blank by gavage, while the other group was administered the A2AR inhibitor KW6002 (10 mg / kg) by gavage once daily. All gavage procedures were performed under anesthesia to minimize interference with the mice. After four consecutive days of gavage, the mice were starved for four hours, then anesthetized and sacrificed. Blood was collected from the eyeballs to analyze serum total cholesterol levels. Simultaneously, high-performance liquid chromatography (FPLC) was used to analyze changes in cholesterol content in different lipoprotein components.

[0082] The results are as follows Figure 8 As shown, gavage administration of KW6002 significantly reduced serum total cholesterol levels. Serum cholesterol is mainly divided into low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), with LDL-C being the most significant risk factor for cardiovascular and cerebrovascular diseases such as atherosclerosis. We found that feeding KW6002 primarily reduced LDL-C (LDL-C...). Figure 8 (Right) It has no significant effect on high-density lipoprotein cholesterol, indicating that KW6002 can be used to treat hypercholesterolemia and cardiovascular and cerebrovascular diseases.

[0083] Finally, it should be noted that the terms “comprising,” “including,” or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0084] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0085] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. The use of an adenosine receptor inhibitor in the preparation of a medicament for the treatment of hypercholesterolemia, wherein the adenosine receptor inhibitor is Istradefylline (KW-6002).

2. The application according to claim 1, characterized in that, The drug also includes pharmaceutically acceptable excipients and carriers.

3. The application according to claim 2, characterized in that, The excipients include at least one of fillers, disintegrants, binders, diluents, lubricants, sweeteners, and colorants.

4. The application according to claim 1, characterized in that, The dosage form of the drug includes at least one of granules, tablets, pills, capsules, injections, or dispersants.

5. The application according to claim 1, characterized in that, The medications used to treat hypercholesterolemia include medications used to lower cholesterol.

6. The use of an inhibitor of the GPR146-adenosine receptor A2AR complex in the preparation of a medicament for the treatment of hypercholesterolemia, said inhibitor being Istradefylline (KW-6002).

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