Application of 4-deoxy-4-arylthio-N-pyranoside compound

Abstract

The invention provides application of 4-deoxy-4-arylthio-N-pyranoside compounds, the compounds have the agonistic activity of peroxisome proliferator activated receptors (PPAR) alpha and gamma, and nine compounds have the agonistic activity on the PPAR alpha by participating in expression of related genes such as glycometabolism, lipid metabolism and inflammatory reaction; 11 compounds have agonistic activity on PPAR (peroxisome proliferator activated receptor) gamma; the eight compounds have the activity of double excitation of PPAR alpha and PPAR gamma. The compound can be used for preventing and treating type 2 diabetes mellitus, hyperlipidemia, non-alcoholic hepatitis and neurodegenerative diseases, and has an important application prospect.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to the use of 4-deoxy-4-arylthio-N-pyranoside compounds and optical isomers thereof or pharmaceutically acceptable salts thereof in the preparation of drugs targeting peroxisome proliferator-activated receptors (PPAR) α and γ, in particular to the use of 4-deoxy-4-arylthio-N-pyranoside compounds in drugs targeting PPAR α and γ for preventing and treating type 2 diabetes, hyperlipidemia, non-alcoholic hepatitis and neurodegenerative diseases. Background Art

[0002] Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and are a type of ligand-activated transcription factor that is mainly involved in the expression of genes related to glucose and lipid metabolism and inflammatory response, and is associated with a variety of diseases, such as type 2 diabetes, obesity, hyperlipidemia, cancer, and neurodegenerative diseases. Therefore, PPARs are important research targets for drug development and design in the fields of inflammatory regulation, cell differentiation, glucose metabolism, and lipid metabolism.

[0003] Peroxisome proliferator-activated receptors (PPARs) are divided into three subtypes based on their structure and function, namely PPARα, PPARβ / δ and PPARγ. Each subtype has structural homology with other members of the nuclear receptor family and has specific functions and tissue distribution. PPARα is the earliest cloned member of the PPAR family and is mainly found in lipid-related tissues, such as the liver, skeletal muscle, myocardium, and kidney tissue. It can promote the catabolism of fatty acids and lipoprotein metabolism, reduce triglycerides, and increase high-density lipoprotein levels. At present, the fibrate PPARα agonists used in clinical practice, such as bezafibrate and fenofibrate, are mainly used as lipid-lowering drugs for the treatment of hypertriglyceridemia. PPARγ has multiple biological functions and plays an important role in regulating metabolism, controlling inflammation, improving atherosclerosis, inhibiting tumors, and regulating immunity. It is reported that PPARγ can regulate the body's glucose and lipid metabolism homeostasis. Currently, PPARγ has become an important target for type 2 diabetes. PPARγ agonists can increase tissue sensitivity to insulin, improve insulin resistance, lower blood sugar, promote adipocyte differentiation and reduce lipid deposition. PPARγ agonists are the most studied of the three subtypes, and the representative drugs are oral hypoglycemic drugs thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone.

[0004] Nonalcoholic fatty liver disease is an acquired metabolic disease closely related to insulin resistance and genetic susceptibility. As a pathological stage of the development of simple fatty liver to liver fibrosis, it is one of the important causes of cryptogenic cirrhosis and is common in patients with metabolic syndromes such as obesity, type 2 diabetes, and hyperlipidemia. Studies have shown that PPAR pan-agonists may have synergistic therapeutic advantages and can improve nonalcoholic fatty liver disease by inhibiting lipogenesis and enhancing liver fatty acid metabolism related to β-oxidation, thus achieving a more ideal therapeutic effect. Therefore, the development of multiple agonists has become a cutting-edge hotspot. Summary of the invention

[0005] The purpose of the present invention is to provide the application of 4-deoxy-4-arylthio-N-pyranoside compounds, which have agonist activity on peroxisome proliferator-activated receptors (PPAR) α and γ, and participate in the expression of genes related to sugar metabolism, lipid metabolism, inflammatory response, etc. Nine compounds have agonist activity on PPARα; 11 compounds have agonist activity on PPARγ, and can be used for the prevention and treatment of type 2 diabetes, hyperlipidemia, non-alcoholic hepatitis and neurodegenerative diseases, and have important application prospects.

[0006] The application of a 4-deoxy-4-arylthio-N-pyranoside compound described in the present invention, and the application of the 4-deoxy-4-arylthio-N-pyranoside compound in the preparation of a peroxisome proliferator-activated receptor agonist drug, has the structural formula:

[0007]

[0008] The 4-deoxy-4-arylthio-N-pyranoside compound is used in the preparation of drugs for preventing and treating type 2 diabetes, hyperlipidemia, non-alcoholic hepatitis and neurodegenerative diseases by targeting peroxisome proliferator-activated receptors α and γ.

[0009] Among the 4-deoxy-4-arylthio-N-pyranoside compounds, nine compounds, DCZ8266, DCZ8269, DCZ8271, DCZ8284, DCZ8232, DCZ8307, DCZ8273 and DCZ8241, have agonist activity on PPARα; among them, compound DCZ8283 exhibits strong PPARγ agonist activity;

[0010] Eleven compounds have agonist effects on PPARγ, namely DCZ8262, DCZ8266, DCZ8269, DCZ8271, DCZ8283, DCZ8284, DCZ8232, DCZ8307, DCZ8273, DCZ8241, and DCZ8272, among which DCZ8283 has a more significant agonist activity on PPARγ;

[0011] Compounds DCZ8232, DCZ8307, DCZ8241, DCZ8269, DCZ8271, DCZ8284, DCZ8266 and DCZ8273 have dual agonist activity of PPARα and PPARγ.

[0012] The present invention provides a 4-deoxy-4-arylthio-N-pyranoside compound, the structural formula of which is

[0013]

[0014] in:

[0015] is a double bond or a single bond;

[0016] R is selected from unsubstituted or substituted aryl or heteroaryl, wherein the heteroaryl has one or more heteroatoms selected from the group consisting of O, N or S.

[0017] M is unsubstituted, carbonyl, hydroxyl, OAc, OTf or OBz;

[0018] Y is -CH2-, methyl or none;

[0019] W is OAc;

[0020] X is S, O,

[0021] L is unsubstituted or substituted n is 0, 1, 2, 3, 4, 5 or 6.

[0022] Z is hydrogen, hydroxy, carboxyl, alkyl, tert-butyloxycarbonyl, C3-C8 cycloalkyl, unsubstituted or substituted C6 aryl or C3 heteroaryl, wherein the heteroaryl has one or more heteroatoms selected from the group consisting of O, N or S.

[0023] Each of the substitutions in R and Z refers to being independently substituted by one or more substituents selected from the following: halogen (F, Cl, Br), C l -C6 alkyl, C3-C8 cycloalkyl, C l -C6 alkoxy, halogenated C l -C6 alkyl, carbonyl, carboxyl, aminomethyl, or pharmaceutically acceptable salts and stereoisomers thereof.

[0024] In an embodiment, the synthesis of the specific 4-deoxy-4-arylthio-N-pyranoside compound represented by formula (1) can be found in patent 202410264469X.

[0025] The application of the 4-deoxy-4-arylthio-N-pyranoside compounds of the present invention is the application of the 4-deoxy-4-arylthio-N-pyranoside compounds in the preparation of drugs targeting peroxisome proliferator-activated receptors (PPAR) α and γ.

[0026] Experimental studies have shown that this type of compound can effectively activate the activity of peroxisome proliferator-activated receptors (PPAR) α and γ, and can act as a peroxisome proliferator-activated receptor (PPAR) α and γ agonist. It has the potential to be developed into a drug for the prevention and treatment of glucose and lipid metabolism disorders, inflammation and other related diseases.

[0027] Specifically, the 4-deoxy-4-arylthio-N-pyranoside compound, as a peroxisome proliferator-activated receptor (PPAR) α and γ agonist, can be used to prevent and treat diseases related to glucose metabolism disorders, especially type 2 diabetes, including the prevention of sequelae related thereto, with particular mention of: hyperglycemia, improving insulin tolerance, improving glucose tolerance, protecting pancreatic β cells, and preventing microvascular diseases.

[0028] Specifically, the 4-deoxy-4-arylthio-N-pyranoside compound, as a peroxisome proliferator-activated receptor (PPAR) α and γ agonist, can be used to prevent and treat diseases related to dyslipidemia and its sequelae, including but not limited to atherosclerosis, coronary heart disease, cerebrovascular disease, etc., especially these diseases characterized by one or more of the following factors: high plasma triglyceride concentration, low HDL cholesterol concentration, low ApoA lipoprotein concentration, high LDL cholesterol concentration, and high ApoB lipoprotein concentration.

[0029] Specifically, the 4-deoxy-4-arylthio-N-pyranoside compound, as a peroxisome proliferator-activated receptor (PPAR) α and γ agonist, can be used to prevent and treat diseases related to dyslipidemia and its sequelae, including but not limited to atherosclerosis, coronary heart disease, cerebrovascular disease, etc., especially these diseases characterized by one or more of the following factors: high plasma triglyceride concentration, low HDL cholesterol concentration, low ApoA lipoprotein concentration, high LDL cholesterol concentration, and high ApoB lipoprotein concentration.

[0030] Specifically, the 4-deoxy-4-arylthio-N-pyranoside compound, as a peroxisome proliferator-activated receptor (PPAR) α and γ agonist, can be used to prevent and treat diseases related to metabolic syndrome, including but not limited to obesity (overweight), central obesity, hypertension, heart failure, and hypertensive heart disease.

[0031] Specifically, the 4-deoxy-4-arylthio-N-pyranoside compound is a peroxisome proliferator-activated receptor (PPAR) α and γ agonist and can be used to prevent and treat non-alcoholic hepatitis.

[0032] Specifically, the 4-deoxy-4-arylthio-N-pyranoside compound is a peroxisome proliferator-activated receptor (PPAR) α and γ agonist and can be used to prevent and treat neurodegenerative diseases.

[0033] The present invention provides a compound with a single concentration of 5 μM or 10 μM for the agonist effect on peroxisome proliferator-activated receptor (PPAR) α and PPARγ, and the determination results are shown in Figure 1 , Figure 2 and Figure 3 ; Some of the compounds exhibit PPARγ activity, or PPARα and PPARγ dual agonist activity.

[0034] The beneficial effects of the application of the 4-deoxy-4-arylthio-N-pyranoside compounds described in the present invention are mainly reflected in:

[0035] (1) The present invention provides a class of 4-deoxy-4-arylthio-N-pyranoside compounds with a novel core skeleton, which can be used as PPARα and PPARγ agonists.

[0036] (2) The 4-deoxy-4-arylthio-N-pyranoside compounds provided by the present invention have different selectivities for PPARα and PPARγ. The preliminary activity screening results show that the compound DCZ8283 exhibits strong PPARγ agonist activity, but no PPARα agonist activity, and is a selective PPARγ agonist. DCZ8232, DCZ8307, DCZ8241, DCZ8269, DCZ8271, DCZ8284, DCZ8266 and DCZ8273 have dual agonist activity for PPARα and PPARγ.

[0037] (3) The present invention selected compounds DCZ8232, DCZ8307 and DCZ8283 for computational simulation with PPARα / γ proteins to further study the ligand-protein interaction pattern. The results showed that the selected compounds had higher docking scores than the positive compound Lanilanol, indicating that the selected compounds had better binding with PPARα / γ proteins, which was basically consistent with the activity data results. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The present invention is to evaluate the PPARα agonist activity of 4-deoxy-4-arylthio-N-pyranoside compounds. A, PPARα agonist activity evaluation of 9 compounds including DCZ8245, DCZ8246, DCZ8247, DCZ8251, DCZ8255, DCZ8256, DCZ8257, DCZ8262 and DCZ8263. B, PPARα agonist activity evaluation of 9 compounds including DCZ8264, DCZ8265, DCZ8267, DCZ8268, DCZ8269, DCZ8270, DCZ8271, DCZ8284 and DCZ8285. C, DCZ8280, DCZ8282, DCZ8283, DCZ8290, DCZ8293, DCZ8294, DCZ8295, DCZ8321, evaluation of PPARα agonist activity of 8 compounds, D, DCZ8254, DCZ8232, DCZ8307, DCZ8266, DCZ8273, DCZ8277, DCZ8318, DCZ8319, DCZ8320, DCZ8241, evaluation of PPARα agonist activity of 10 compounds. E, DCZ8272, DCZ8275, DCZ8276, DCZ8278, DCZ8279, DCZ8286, DCZ8287, DCZ8288, DCZ8298, evaluation of PPARα agonist activity of 9 compounds. With Lanilanol as the positive control and DMSO as the negative control, 46 compounds were divided into 5 groups for testing, the positive control concentration was 30 μM, the compound concentration was 5 μM or 10 μM, and the luciferase activity (vertical axis) was detected to reflect the activation effect of the compound on PPARα. The calculated value was greater than 120% and had a significant difference, which was considered to have a transcriptional activation effect.

[0039] Figure 2 The agonist activity of 4-deoxy-4-arylthio-N-pyranoside compounds of the present invention on PPARγ is evaluated. Figure 1A, PPARα agonist activity evaluation of 9 compounds including DCZ8245, DCZ8246, DCZ8247, DCZ8251, DCZ8255, DCZ8256, DCZ8257, DCZ8262 and DCZ8263. B, PPARγ agonist activity evaluation of 9 compounds including DCZ8264, DCZ8265, DCZ8267, DCZ8268, DCZ8269, DCZ8270, DCZ8271, DCZ8284 and DCZ8285. C, DCZ8280, DCZ8282, DCZ8283, DCZ8290, DCZ8293, DCZ8294, DCZ8295, DCZ8321, evaluation of PPARγ agonist activity of 8 compounds, D, DCZ8254, DCZ8232, DCZ8307, DCZ8266, DCZ8273, DCZ8277, DCZ8318, DCZ8319, DCZ8320, DCZ8241, evaluation of PPARγ agonist activity of 10 compounds. E, DCZ8272, DCZ8275, DCZ8276, DCZ8278, DCZ8279, DCZ8286, DCZ8287, DCZ8288, DCZ8298, evaluation of PPARγ agonist activity of 9 compounds.

[0040] Figure 3 The PPARα and PPARγ agonist activities of 9 compounds of the present invention, namely DCZ8232, DCZ8241, DCZ8307, DCZ8269, DCZ8271, DCZ8283, DCZ8284, DCZ8266 and DCZ8273, are compared.

[0041] Figure 4 This is the molecular docking of the compounds DCZ8232, DCZ8307 and the positive drug Lanilanol of the present invention with PPARα; the crystal structure of PPARα is PDBID: 3g8i, the purple arrows represent hydrogen bonds, and the green arrows represent π-π interactions.

[0042] Figure 5 The molecular docking of the compounds DCZ8232, DCZ8307, DCZ8283 and the positive drug lanilanol with PPARγ; the crystal structure of PPARγ is PDBID: 4prg, the purple arrows indicate hydrogen bonds, the green arrows indicate π-π interactions, and the red arrows indicate π-cation interactions. DETAILED DESCRIPTION

[0043] The present invention is further described below in conjunction with specific embodiments, but the scope of the present invention is not limited thereto.

[0044] Example 1

[0045] The use of the 4-deoxy-4-arylthio-N-pyranoside compound in the preparation of a peroxisome proliferator-activated receptor agonist drug has the structural formula:

[0046]

[0047] The 4-deoxy-4-arylthio-N-pyranoside compound is used in the preparation of drugs for preventing and treating type 2 diabetes, hyperlipidemia, non-alcoholic hepatitis and neurodegenerative diseases by targeting peroxisome proliferator-activated receptors α and γ.

[0048] Among the 4-deoxy-4-arylthio-N-pyranoside compounds, nine compounds, DCZ8266, DCZ8269, DCZ8271, DCZ8284, DCZ8232, DCZ8307, DCZ8273 and DCZ8241, have agonist activity on PPARα; among them, compound DCZ8283 exhibits strong PPARγ agonist activity;

[0049] Eleven compounds have agonist effects on PPARγ, namely DCZ8262, DCZ8266, DCZ8269, DCZ8271, DCZ8283, DCZ8284, DCZ8232, DCZ8307, DCZ8273, DCZ8241, and DCZ8272, among which DCZ8283 has a more significant agonist activity on PPARγ;

[0050] Compounds DCZ8232, DCZ8307, DCZ8241, DCZ8269, DCZ8271, DCZ8284, DCZ8266 and DCZ8273 have dual agonist activity of PPARα and PPARγ.

[0051] Example 2

[0052] Evaluation of PPARα and PPARγ agonist activity of 4-deoxy-4-arylthio-N-pyranoside compounds

[0053] 1. Instrument: EnVisionTM (PE)

[0054] 2. Materials:

[0055] DMEM-HG medium (1967442, Gibco), Gibco, USA;

[0056] FBS (10091-148, Hyclone), Hyclone, USA;

[0057] HKT293T cells, Thermo Fisher, USA;

[0058] PPRE X3-TK-luc (P10619, Miaoling Biotechnology), Wuhan Miaoling Biotechnology Co., Ltd.;

[0059] pEnCMV-PPARA(human)-3×HA-SV40-Neo (P29901, Miaoling Biotechnology Co., Ltd., Wuhan Miaoling Biotechnology Co., Ltd.);

[0060] pEnCMV-PPARG(human)-3×FLAG (P18448, Miaoling Biotechnology Co., Ltd., Wuhan Miaoling Biotechnology Co., Ltd.);

[0061] CellTiter-Blue-G808B (200399; Promega), Promega Corporation, USA;

[0062] Steady-Glo Luciferase (31479901, Promega), Promega Corporation, USA;

[0063] CulturPlateTM-96-well cell plate (3917, Corning), Corning, USA;

[0064] 15mL centrifuge tube (430828, Corning), Corning, USA.

[0065] 3. Experimental methods:

[0066] 3.1. Sample processing:

[0067] The samples were dissolved in DMSO and stored at low temperature, and the concentration of DMSO in the final system was controlled within the range that did not affect the detection activity;

[0068] 3.2 Experimental steps:

[0069] (1) Transfection: HEK293T cells were transfected with PPARα (PPARγ) and PPRE plasmids and cultured in a 37°C, 5% CO2 incubator for 8 h. The culture medium was replaced with new medium. 24 h after transfection, the cells were digested and collected, and plated on a CulturPlateTM-96-well cell plate at a density of 25 w / mL and stabilized overnight.

[0070] (2) Compound stimulation: cells were co-treated with compounds at 5 or 10 μM for 12 h (the negative control group was complete culture medium containing the same concentration of DMSO as the compound group);

[0071] (3) Detection: Add 20 μL CellTiter-Blue Reagent to each well (no need to aspirate the original culture medium), incubate for 2 hours under culture conditions, and use the Envision instrument reading (560Ex / 590Em) to detect the cytotoxicity of the compound (the liquid volume in each well is now 120 μL); aspirate 90 μL of liquid from each well, add 20 μL of luciferase substrate, incubate at room temperature in the dark for 5 minutes, and use the Envision instrument reading (full wavelength detection of fluorescence intensity) to detect luciferase activity;

[0072] (4) Data processing: The luciferase / cell title blue ratio of each compound well is calculated, with the control group (DMSO) as 100%. If the ratio is greater than 120% and has a significant difference, it is considered to have a transcriptional activation effect. Each sample is set up with duplicate wells (n ≥ 3) in the test, and the results are expressed as the standard error of mean (SEM);

[0073] The PPARγ agonist activity evaluation method and data processing method of 4-deoxy-4-arylthio-N-pyranoside compounds are the same as above.

[0074] 4. Experimental results and discussion:

[0075] The in vitro activation activity of 46 synthesized 4-deoxy-4-arylthio-N-pyranoside compounds on PPARα and γ was investigated, Lanifibranor was used as a positive control, the compound administration concentration was 5μM or 10μM, and all compounds were divided into 5 groups for detection. The results are as follows Figure 1 and 2 As shown;

[0076] Figure 1 The results showed that at a concentration of 5 μM or 10 μM, 9 of the 46 compounds had agonist effects on PPARα, namely, compounds DCZ8266, DCZ8269, DCZ8271, DCZ8284, DCZ8232, DCZ8307, DCZ8273 and DCZ8241;

[0077] Figure 2 The results showed that 11 of the 46 compounds had agonist effects on PPARγ, namely DCZ8262, DCZ8266, DCZ8269, DCZ8271, DCZ8283, DCZ8284, DCZ8232, DCZ8307, DCZ8273, DCZ8241, and DCZ8272. Among them, DCZ8283 had a significant agonist activity on PPARγ, 2.5μM ( Figure 2 The agonist activity of 10 μM and 10 μM on PPARγ was 240% and 221%, respectively;

[0078] like Figure 3 As shown in the figure, 8 out of 46 compounds have PPARα / γ dual agonist effects, while compound DCZ8283 has significant PPARγ agonist activity, but no PPARα agonist activity, and may be a selective PPARγ agonist. Compounds DCZ8282 and DCZ8298 have no PPARα and PPARγ activity. It can be seen from the structure that the introduction of a large ester group at the C-2 position of the sugar ring of 4-deoxy-4-arylthio-N-pyranoside compounds is beneficial to improving the selectivity of PPARγ.

[0079] Example 3

[0080] Molecular docking of 4-deoxy-4-arylthio-N-pyranoside compounds with PPARα / γ protein:

[0081] The present invention selected compounds DCZ8232, DCZ8307 and DCZ8283 with relatively strong PPARα / γ agonist activity to perform molecular docking simulation on the crystal structures reported in the literature (PDBID: 3g8i and 4prg), and further studied the action mode of 4-deoxy-4-arylthio-N-pyranoside compounds with PPARα / γ;

[0082] The single crystal structures of PPARα (PDBID: 3g8i) and PPARγ (PDBID: 4prg) were downloaded from the PDB database and molecular docking was performed using the Schrödinger 2020 software GLIDE module to study protein-ligand interactions. The 2D interaction results are shown in Figure 4 and 5 As shown; Figure 4 The docking results showed that DCZ8232 and DCZ8307 had good binding with PPARα (PDBID: 3g8i), with docking scores of -10.57 kcal / mol and -9.79 kcal / mol, respectively, which were better than the positive drug lanilanol (-8.39 kcal / mol); among them, for lanilanol, the carboxyl group formed a hydrogen bond with TYR334 of PPARα, which was the key binding site. The acetyl group and methylenedioxybenzene ring of DCZ8232 had hydrogen bonding and π-π interactions with TYR334. In addition, the carbonyl group on the amide bond formed a hydrogen bond with CYS275; and DCZ8307 also had a similar interaction site; therefore, DCZ8232 and DCZ8307 had better binding with PPARα than lanilanol.

[0083] like Figure 5As shown in the figure, the docking scores of DCZ8232, DCZ8307 and DCZ8283 with PPARγ (PDBID: 4prg) were -9.33 kcal / mol, -10.62 kcal / mol and -9.28 kcal / mol, respectively, which were better than the positive drug lanilanol (-8.74 kcal / mol), indicating better binding with PPARα. For lanilanol, the carboxyl group and Cl atom are its key binding sites. The action sites of DCZ8232, DCZ8307 and DCZ8283 with PPARγ have their own characteristics. In addition, hydrophobic interaction is also a key influencing factor.

Claims

1. An application of 4-deoxy-4-arylthio-N-pyranoside compounds, characterized in that The use of the 4-deoxy-4-arylthio-N-pyranoside compound in the preparation of a peroxisome proliferator-activated receptor agonist drug has the structural formula:

2. The use according to claim 1, characterized in that The 4-deoxy-4-arylthio-N-pyranoside compound is used in the preparation of drugs for preventing and treating type 2 diabetes, hyperlipidemia, non-alcoholic hepatitis and neurodegenerative diseases by targeting peroxisome proliferator-activated receptors α and γ.

3. The use according to claims 1 and 2, characterized in that Among the 4-deoxy-4-arylthio-N-pyranoside compounds, nine compounds, DCZ8266, DCZ8269, DCZ8271, DCZ8284, DCZ8232, DCZ8307, DCZ8273 and DCZ8241, have agonist activity on PPARα; among them, compound DCZ8283 exhibits strong PPARγ agonist activity; Eleven compounds have agonist activity on PPARγ, namely, DCZ8262, DCZ8266, DCZ8269, DCZ8271, DCZ8283, DCZ8284, DCZ8232, DCZ8307, DCZ8273, DCZ8241, and DCZ8272, among which DCZ8283 has a more significant agonist activity on PPARγ; Compounds DCZ8232, DCZ8307, DCZ8241, DCZ8269, DCZ8271, DCZ8284, DCZ8266 and DCZ8273 have dual agonist activity of PPARα and PPARγ.

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