JP5725491B2 - Insulin resistance improving action by retinoic acid receptor ligand - Google Patents

Description

  The present invention relates to a novel drug containing a retinoid.

  Insulin resistance is a basic condition of various diseases including metabolic syndrome, and has been pointed out to be associated with hypertension, obesity, hyperlipidemia and the like. Nonalcoholic fatty liver disease (NAFLD) is also known to have a high frequency of insulin resistance. NAFLD is a disease concept that includes simple fatty liver and its severe form of nonalcoholic steatohepatitis (NASH). In recent years, the number of patients who develop liver cancer from NASH has increased. It has been demanded. Insulin resistance increases the risk of various cancer types including liver cancer, and hyperinsulinemia increases the growth rate of liver cancer. It is suggested to be involved in carcinogenesis / progress. Therefore, improvement of insulin resistance is very important not only for treatment of NAFLD but also for preventing hepatocarcinogenesis.

  On the other hand, the relationship between liver diseases and retinoids is described in several documents. Retinoid is a general term for compounds including retinol, retinal, retinoic acid (RA), and derivatives thereof. Non-Patent Document 1 describes that RAR-E transgenic mice (RAR-E Tg) in which RA signals are specifically suppressed in the liver frequently develop liver cancer. Non-Patent Document 2 shows that acyclic retinoid significantly reduces the recurrence of hepatocellular carcinoma (HCC, hepatocellular carcinoma) after surgical resection or ethanol injection therapy, and Non-Patent Document 3 shows that retinoid is a liver tumor. It is described that it acts in an inhibitory manner. Non-patent document 4 lacks detailed data and the specific values are unknown, but ATRA was administered to db / db mice (leptin receptor-deficient mice expressed only in the pituitary gland). Then, it is described that the blood sugar level decreased.

Yanagitani A, Yamada S, Yasui S, Shimomura T, Murai R, Murawaki Y, Hashiguchi K, Kanbe T, Saeki T, Ichibe M, Tanabe Y, Yoshida Y, Morino S, Kurimasa A, Usuda N, Yamazaki H, Kunisada T , Ito H, Murawaki Y, Shiota G. Retinoic acid receptor α dominant negative form causes steatohepatisis and liver tumors in transgenic mice.Hepatology 2004; 40: 366-375. Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, Tanaka T, Tsurumi K, Okuno M, Tomita E, Nakamura T, Kojima T. Prevention of second primary tumors by an acyclic retinoid, polyrenoic acid, in patiens with hepatocellular carcinoma. N Engl J Med 1996; 334: 1561-1567. Nakamura N, Shidoji Y, Yamada Y, Hatakeyama H, Moriwaki H, Muto Y. Induction of apoptosis by acyclic retinoid in the human hepatoma-derived cell line, HuH-7. Biochem Biophys Res Commun 1995; 207: 382-388. Morita at al., Diabetes Frontier Vol.19 No.6 (December 2008) (823) Medical Review.

However, the prior art described in the above literature has room for improvement in the following points.
Although the mechanisms of insulin resistance and liver disease have been gradually elucidated in the above documents, this is not sufficient, and further mechanism elucidation is necessary for planning new drugs or treatment strategies. .

  In addition, many unclear points remained regarding the effects when retinoids were administered to living bodies. The db / db mouse described in Non-Patent Document 4 is a special mouse deficient in leptin, and therefore, when a retinoid is administered, it may exhibit a pharmacological effect different from that of a mouse that has developed a disease in the natural environment. Is expensive. It is probably due to the retinoin mechanism. Therefore, the mechanism for evaluating the administration effect of retinoids on organisms is incomplete.

  This invention is made | formed in view of the said situation, and it aims at providing the novel chemical | medical agent containing a retinoid based on the function of the retinoid which was not demonstrated until now.

  According to the present invention, an insulin resistance ameliorating agent, a weight gain control agent, a weight loss agent, a liver weight loss agent, comprising a retinoid and administered to a non-genetically modified animal liver disease patient, Built-in fat mass inhibitor, food intake inhibitor, caloric intake inhibitor, blood AST reducer, blood ALT reducer, fatty deposition inhibitor in liver tissue, free fatty acid reducer in liver tissue, liver tissue Neutral fat reducing agent, total cholesterol level reducing agent in liver tissue, blood sugar level lowering agent, blood insulin level lowering agent, impaired glucose tolerance improving agent, insulin sensitivity improving agent, leptin resistance improving agent, blood leptin level One or more drugs selected from the group consisting of a reducing agent, a blood free fatty acid reducing agent, and a blood bad adipocytokine reducing agent are provided.

  This drug is administered to non-genetically modified animal liver disease patients in the examples described below, and improves insulin resistance, weight gain control, weight loss, liver weight loss, suppression of increased internal fat mass, suppression of food intake, suppression of caloric intake Blood AST reduction, blood ALT reduction, liver tissue fat deposition suppression, liver tissue free fatty acid reduction, liver tissue neutral fat reduction, liver tissue total cholesterol content reduction, blood sugar level reduction, blood One or more effects selected from the group consisting of: reducing insulin concentration, improving glucose tolerance, improving insulin sensitivity, improving leptin resistance, reducing blood leptin concentration, reducing blood free fatty acids, and reducing blood bad adipocytokines Contains retinoids that have been demonstrated to produce Therefore, if this drug is used, effects according to various purposes such as treatment of diseases associated with the above effects can be exerted on non-genetically modified animal liver disease patients.

  According to the present invention, a liver weight-reducing agent, a built-in fat mass increase inhibitor, a blood AST, comprising a retinoid and administered to a non-alcoholic fatty liver disease patient or an insulin resistant patient Reducing agent, Blood ALT reducing agent, Liver tissue fat deposition inhibitor, Liver tissue free fatty acid reducing agent, Liver tissue neutral fat reducing agent, Liver tissue total cholesterol level reducing agent, Leptin resistance One or more drugs selected from the group consisting of an improving agent, a blood leptin concentration reducing agent, a blood free fatty acid reducing agent, and a blood bad adipocytokine reducing agent are provided.

  In the examples described below, this drug is administered to patients with nonalcoholic fatty liver disease or insulin resistance, and hepatic weight reduction, suppression of increased internal fat mass, blood AST reduction, blood ALT reduction, liver tissue Suppression of fat deposition, reduction of free fatty acid in liver tissue, reduction of neutral fat in liver tissue, reduction of total cholesterol in liver tissue, improvement of leptin resistance, reduction of blood leptin concentration, reduction of blood free fatty acid, and blood It contains a retinoid that has been demonstrated to exhibit one or more effects selected from the group consisting of a reduction in bad adipocytokines. Therefore, if this drug is used, effects according to various purposes such as treatment of diseases associated with the above effects can be exerted on non-alcoholic fatty liver disease patients or insulin resistant patients.

  Further, according to the present invention, a retinoid-containing leptin resistance improving agent, a blood leptin concentration reducing agent, and an insulin resistance improving agent that improves insulin resistance depending on leptin resistance are selected. One or more drugs are provided. In the examples described later, this drug demonstrates that it has one or more effects selected from the group consisting of improving leptin resistance, lowering blood leptin concentration, and improving insulin resistance depending on leptin resistance. Contains retinoids. Therefore, if this medicine is used, effects according to various purposes such as treatment of diseases associated with the above effects can be obtained.

  Further, according to the present invention, one or more selected from the group consisting of non-alcoholic fatty liver disease, hepatitis, liver cancer, dyslipidemia, diabetes, hypertension, and arteriosclerosis, comprising any of the above drugs. A therapeutic for a disease is provided. If this therapeutic agent is used, it is possible to treat the above diseases.

  Moreover, according to this invention, the diagnostic agent of non-alcoholic fatty liver disease or insulin resistance containing any one of the said medicines is provided. By using this diagnostic agent, it is possible to diagnose nonalcoholic fatty liver disease or insulin resistance.

  According to the present invention, a novel drug containing a retinoid based on the function of a retinoid that has not been demonstrated so far can be obtained.

FIG. 1 is a diagram showing typical retinoid types and molecular structures. FIG. 2 is a diagram showing a procedure for creating a NAFLD model mouse. FIG. 3 shows the results of investigating changes in body weight (A, body weight; B, liver weight; C, liver weight ratio; D, visceral fat mass) of mice. Figure 4 shows the results of an investigation of mouse food intake (A, daily food intake; B, daily retinoid intake (retinol equivalent); C, daily caloric intake). is there. FIG. 5 shows the results of investigating serum AST (A) and ALT (B) activities in mice. FIG. 6 shows HE staining of liver tissue (lipid droplets with white spots deposited. A, Normal group; B, HFHFr> Normal group; C, HFHFr> Normal + ATRA group; D, HFHFr> HFHFr group; E, HFHFr> HFHFr + ATRA group) results. FIG. 7 shows oilredO staining of liver tissue (lipid droplets with red dots deposited; A, Normal group; B, HFHFr> Normal group; C, HFHFr> Normal + ATRA group; D, HFHFr> HFHFr group; E, HFHFr> HFHFr + ATRA group) results. FIG. 8 shows the results of investigation of liver fat content (A, free fatty acid (NEFA); B, neutral fat (TG); C, total cholesterol). FIG. 9 shows the results of examining the amount of neutral fat (TG) (A) in serum. FIG. 10 shows the results of investigation on insulin resistance (A, fasting blood glucose level; B, fasting serum insulin concentration; C, insulin resistance index (HOMA-IR)). FIG. 11 shows the results of investigation on insulin sensitivity (A, glucose tolerance test (time change); B, glucose tolerance test (area under the curve (AUC)); C, insulin tolerance test). FIG. 12 shows the results of investigating serum cytokine concentrations (A, insulin; B, leptin; C, free fatty acid) under free feeding. FIG. 13 shows changes in body weight of genetic insulin resistance model mice (A, C, E, KK-Ay mice; B, D, F, ob / ob mice; A, B, weight changes; C, D, liver weight) (Ratio; E, F, visceral fat content). FIG. 14 shows insulin resistance in genetic insulin resistance model mice (A, C, E, G, KK-Ay mice; B, D, F, H, ob / ob mice; A, B, glucose tolerance test ( (Time change); C, D, area under curve (AUC); E, F, fasting serum insulin concentration; G, H, insulin resistance index (HOMA-IR)). FIG. 15 shows the results of measurement of serum leptin concentration (A, KK-Ay mouse; B, ob / ob mouse) in a genetic insulin resistance model mouse.

<Explanation of terms>
The meaning of various terms in this specification will be described as follows.

(1) Retinoid Retinoid is a general term for compounds including retinol, retinal, retinoic acid (RA), and derivatives thereof. All-trans-RA (ATRA) and 9-cis-RA are known as biologically active RAs, and they function through nuclear receptors, which are ligand-induced transcription factors. Has been. Retinoids include the molecules of FIG.

(2) Non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD) includes diseases caused by accumulation of fat in the liver. It is known that insulin resistance is frequently accompanied. NAFLD is a disease concept that includes simple fatty liver and its severe form of non-alcoholic steatohepatitis (NASH). In recent years, the number of patients who develop liver cancer from NASH has increased. Urgent development is required.

(3) Insulin resistance Insulin resistance is a concept that includes a state in which the action efficiency of insulin is reduced, or a state in which insulin is sufficiently present but the blood glucose level does not decrease. From the perspective of biology, it is considered that Glut4 in cells does not migrate efficiently onto the cell membrane even when insulin is stimulated. Based on obesity, insulin resistance is induced and may cause diabetes, dyslipidemia, hypertension, arteriosclerosis and the like.

(4) Leptin resistance Leptin resistance is a concept including a state in which leptin is sufficiently present but the action efficiency of leptin is reduced. Leptin is known to act to suppress food loss through the hypothalamic receptor.

Hereinafter, embodiments of the present invention will be described in detail. For similar contents,
In order to avoid repeated complications, description will be omitted as appropriate.

<Embodiment 1: Drug containing retinoid>
This embodiment contains a retinoid, and is administered to a non-genetically modified animal liver disease patient, characterized in that it is an insulin resistance ameliorating agent, a weight gain control agent, a weight loss agent, a liver weight loss agent, a built-in fat Volume increase inhibitor, food intake inhibitor, caloric intake inhibitor, blood AST reducer, blood ALT reducer, fatty deposition inhibitor in liver tissue, free fatty acid reducer in liver tissue, medium in liver tissue Fatty fat reducing agent, total cholesterol level reducing agent in liver tissue, blood sugar level lowering agent, blood insulin level lowering agent, impaired glucose tolerance improving agent, insulin sensitivity improving agent, leptin resistance improving agent, blood leptin level lowering agent , One or more agents selected from the group consisting of a blood free fatty acid reducing agent and a blood bad adipocytokine reducing agent. As demonstrated in the examples described below, retinoids are administered to non-genetically modified animal liver disease patients to improve insulin resistance, control body weight gain, decrease body weight, decrease liver weight, suppress increase in internal fat mass, Dietary suppression, caloric intake suppression, blood AST decrease, blood ALT decrease, liver tissue fat deposition suppression, liver tissue free fatty acid decrease, liver tissue neutral fat decrease, liver tissue total cholesterol content decrease , Decreased blood glucose level, decreased blood insulin concentration, improved glucose tolerance, improved insulin sensitivity, improved leptin resistance, decreased blood leptin concentration, decreased blood free fatty acid, and decreased blood bad adipocytokines There are one or more effects. Therefore, the above-mentioned drug containing a retinoid can be suitably used for non-genetically modified animal liver disease patients according to various purposes such as treatment of diseases related to the above effects.

  The above-mentioned liver disease patient may be a non-alcoholic fatty liver disease patient. This is because the retinoid contained in the drug exerts the above-described effects such as weight gain control on patients with nonalcoholic fatty liver disease, as demonstrated in Examples described later. In this case, the above-mentioned drug containing a retinoid can be suitably used for non-alcoholic fatty liver disease patients according to various purposes such as treatment of diseases related to the above effects.

  The liver disease patient may be an insulin resistant patient. This is because the retinoid contained in the drug exerts the above-mentioned effects such as weight gain control on an insulin resistant patient, as demonstrated in Examples described later. In this case, the above-mentioned drug containing a retinoid can be suitably used for an insulin resistant patient according to various purposes such as treatment of a disease related to the above effect.

  Another embodiment of the present invention contains a retinoid and is administered to a non-alcoholic fatty liver disease patient, a liver weight reducing agent, a built-in fat mass inhibitor, a blood AST reducing agent, Blood ALT reducer, liver tissue fat deposition inhibitor, liver tissue free fatty acid reducer, liver tissue neutral fat reducer, liver cholesterol total cholesterol reducer, leptin resistance improver, One or more drugs selected from the group consisting of a blood leptin concentration-lowering agent, a blood free fatty acid reducing agent, and a blood bad adipocytokine reducing agent. Retinoids are administered to patients with nonalcoholic fatty liver disease, as demonstrated in the examples described below, and decrease in liver weight, suppression of increased internal fat mass, decrease in blood AST, decrease in blood ALT, Suppression of fat deposition, reduction of free fatty acid in liver tissue, reduction of neutral fat in liver tissue, reduction of total cholesterol in liver tissue, improvement of leptin resistance, reduction of blood leptin concentration, reduction of blood free fatty acid, and blood It exhibits one or more effects selected from the group consisting of the reduction of bad adipocytokines. Therefore, the above-mentioned drug containing a retinoid can be suitably used for non-alcoholic fatty liver disease patients according to various purposes such as treatment of diseases related to the above effects.

  Another embodiment of the present invention comprises a retinoid-containing and administered to an insulin resistant patient, a liver weight reducing agent, a built-in fat mass inhibitor, a blood AST reducing agent, a blood ALT Reducer, Fat deposition inhibitor in liver tissue, Free fatty acid reducer in liver tissue, Neutral fat reducer in liver tissue, Total cholesterol reducer in liver tissue, Leptin resistance improver, Blood leptin One or more drugs selected from the group consisting of a concentration reducing agent, a blood free fatty acid reducing agent, and a blood bad adipocytokine reducing agent. Retinoids are administered to patients with insulin resistance, as demonstrated in the examples described below, and decrease in liver weight, suppression of increased internal fat mass, decrease in blood AST, decrease in blood ALT, suppression of fat deposition in liver tissue. , Decreased free fatty acid in liver tissue, decreased neutral fat in liver tissue, decreased total cholesterol in liver tissue, improved leptin resistance, decreased blood leptin concentration, decreased blood free fatty acid, and blood bad adipocytokine There is one or more effects selected from the group consisting of reduction. Therefore, the said medicine containing a retinoid can be used suitably according to various objectives, such as a treatment of the disease relevant to the said effect with respect to an insulin resistant patient.

  Another embodiment of the present invention is selected from the group consisting of a retinoid, a leptin resistance improving agent, a blood leptin concentration reducing agent, and an insulin resistance improving agent that improves insulin resistance depending on leptin resistance. One or more drugs. The retinoid is selected from the group consisting of improved leptin resistance, decreased blood leptin concentration, and improved insulin resistance that improves insulin resistance depending on leptin resistance, as demonstrated in the examples below. There are one or more effects. Therefore, the said medicine containing a retinoid can be used conveniently according to various objectives, such as treatment of the disease relevant to the said effect.

  The retinoid contained in any drug containing the above-mentioned retinoid includes one or more compounds selected from the group consisting of retinol, retinal, and retinoic acid, or derivatives of the compounds. The retinoic acid includes ATRA (all-trans retinoic acid) or 9-cis-RA. The retinoid contained in any of the aforementioned retinoid-containing drugs is preferably ATRA or a derivative thereof, and more preferably ATRA. This is because it has been demonstrated in the examples described later that ATRA has the various effects described above.

  Moreover, when evaluating the effect of a retinoid, it is preferable to carry out on conditions more nearly natural. Since stable mouse evaluation results have been obtained in the examples described later, it is preferable to construct a mouse evaluation system based on the diet composition and administration method. This method is advantageous in that it is closer to natural conditions and does not cause an unexpected expression system due to genetic modification.

  In the present specification, the “non-genetically modified animal” refers to an animal excluding, for example, a transgenic animal into which a specific gene is introduced from the outside or a knockout animal in which a specific gene is destroyed and deleted. Most naturally occurring animals are non-genetically modified animals.

  As used herein, “insulin resistance improving agent” includes an agent having an effect of improving insulin resistance. In the present specification, the “weight gain control agent” includes a drug having an effect of suppressing the weight gained when eating a diet, compared to the control group. As used herein, the term “weight-reducing agent” includes an agent having an effect of significantly reducing body weight compared to a control group. It has been described in [Goodpaster et al., Diabetes 1999; 48: 839-47.] That insulin resistance is improved by weight loss. Therefore, the weight gain control agent or weight loss agent can be expected to have an effect of improving insulin resistance by a weight loss effect or a weight gain suppression effect.

  In the present specification, the “liver weight reducing agent” includes an agent having an effect of significantly reducing the liver weight as compared with the control group. In the present specification, the “internal fat mass increase inhibitor” includes an agent having an effect of significantly reducing the weight of visceral fat compared to the control group. In the present specification, the “feeding suppressant” includes a drug having an effect of preferentially suppressing the intake of food compared to the control group. In the present specification, the “calorie intake inhibitor” includes a drug having an effect of suppressing the calorie intake more than the control group. In the present specification, the “blood AST reducing agent” includes an agent having an effect of significantly reducing the blood AST amount as compared with the control group. In the present specification, the “blood ALT reducing agent” includes an agent having an effect of significantly reducing the blood ALT amount as compared with the control group. In the present specification, the “fatty deposition inhibitor in liver tissue” includes a drug having an effect of preferentially suppressing the amount of fat deposition in liver tissue as compared with the control group. In the present specification, the “free fatty acid reducing agent in liver tissue” includes a drug having an effect of significantly reducing the amount of free fatty acid in liver tissue as compared with the control group. In the present specification, the “neutral fat reducing agent in liver tissue” includes an agent having an effect of significantly reducing the amount of neutral fat in liver tissue as compared with the control group. In the present specification, the “total cholesterol amount-reducing agent in liver tissue” includes an agent having an effect of significantly reducing the total cholesterol amount as compared with the control group.

  In the present specification, the “blood sugar level lowering agent” includes a drug having an effect of lowering blood sugar level. As used herein, “blood insulin level-lowering agent” includes a drug having an effect of lowering blood insulin level. In the present specification, the “glucose tolerance improving agent” includes a drug having an effect of improving a state in which the metabolic ability of a living body with respect to sugar is abnormal. As used herein, the term “insulin sensitivity improving agent” includes a drug having an effect of improving a state in which insulin sensitivity is abnormal. In the present specification, the “leptin resistance improving agent” includes an agent having an effect of improving leptin resistance. In the present specification, the “blood leptin level-lowering agent” includes a drug having an effect of laxatively reducing the blood level of peptin. In the present specification, the “blood free fatty acid reducing agent” includes a drug having an effect of reducing the amount of isolated fatty acid in blood. As used herein, “blood bad adipocytokine-reducing agent” includes an agent having an effect of reducing blood bad adipocytokines. As used herein, “an insulin resistance ameliorating agent that improves insulin resistance depending on leptin resistance” includes an agent having an effect of improving symptoms of insulin resistance caused by leptin resistance.

  As used herein, “significantly” includes, for example, a case where a statistically significant difference between a control group and a test group is evaluated using a Student's t test, and p <0.05. . In the present specification, the “control group” refers to a sample placed under conditions different from those of the group to be inspected, and can be represented by a concept within a range normally used in the technical field.

In this specification, “derivative” means that when an organic compound is considered as a matrix, the structure and properties of the matrix are greatly increased by introduction of a functional group, oxidation, reduction, substitution of atoms or addition of atoms. It means a compound that has been modified to the extent that it does not change. The modification may be performed as an actual chemical reaction, but it may be performed on a desk. The derivative is preferably a pharmacologically acceptable derivative. In the present specification, the “pharmacologically acceptable derivative” is not limited as long as it has a desired effect, and is a pharmacologically acceptable salt, solvate, isomer, or compound of the present invention. Includes forms of prodrugs and the like (eg esters). This pharmacologically acceptable derivative also includes any other compound that, when administered to a patient, is provided (directly or indirectly) a compound according to the invention or an active metabolite thereof or residue thereof. Such pharmacologically acceptable derivatives can be obtained by those skilled in the art without undue experimentation. For example, [Burger's Medicinal Chemistry And Drug Discovery, 5 th Edition, Vol 1: Principles and Practice] can refer to. A pharmacologically acceptable salt or solvate of the compound according to the present invention is preferred. The desired effect includes an effect substantially equivalent to that of the compound according to the present invention.

  In the present specification, the “pharmacologically acceptable salt” is not particularly limited. For example, it is formed with an anion salt formed with any acidic (eg, carboxyl) group, or formed with any basic (eg, amino) group. Cationic salt. Salts include inorganic and organic salts, including those described in [Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19]. As used herein, a “solvate” is a compound formed by a solute and a solvent. As for the solvate, for example, [J. Honig et al., The Van Nostrand Chemist's Dictionary P650 (1953)] can be referred to. If the solvent is water, the solvate formed is a hydrate. This solvent is preferably one that does not interfere with the biological activity of the solute. Examples of such preferred solvents include, without limitation, water, ethanol, and acetic acid. The most preferred solvent is water. The compound according to the present invention or a salt thereof absorbs moisture when exposed to air or recrystallizes, and in some cases has moisture absorption water or can be a hydrate. As used herein, “isomer” includes molecules having the same molecular formula but different structures. Includes enantiomers (enantiomers), geometric (cis / trans) isomers, or isomers having one or more asymmetric centers that are not mirror images of one another (diastereomers). As used herein, a “prodrug” is a compound that is a precursor, and undergoes a chemical change by metabolic processes or various chemical reactions when the compound is administered to a subject, and the compound according to the present invention or a compound thereof Including compounds that yield salts or solvates thereof. Regarding prodrugs, for example, [T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14] can be referred to.

  In the present specification, the “derivative” includes, for example, a compound having a 90% or higher similarity (tanimoto coefficient) of Compound Structure Search of PubChem as long as it is a compound having a desired effect. The lower limit value of the tanimoto coefficient to be included in the derivative is not particularly limited, but is preferably 95% or more, more preferably 96% or more, more preferably 97% or more, more preferably 98% or more. Yes, more preferably 99% or more. The greater the degree of similarity (tanimoto coefficient), the higher the possibility that it is a derivative whose structure, physiological activity, etc. approximate to the parent body. The formula for calculating the tanimoto coefficient is as follows, and is the similarity coefficient between the authoritative compounds most frequently used in the field of chemoinformatics. The tanimoto coefficient calculation formula can also be referred from the PubChem website.

Tanimoto = AB / (A + B-AB)
Where:
Tanimoto is the Tanimoto score, a fraction between 0 and 1.
AB is the count of bits set after bit-wise & of fingerprints A and B
A is the count of bits set in fingerprint A
B is the count of bits set in fingerprint B

  Examples of the compound having a similarity (tanimoto coefficient) of 95% or more with respect to ATRA include, for example, PubChem CID (Compound ID) of 5538, 444795, 449171, 4136524, 5282379, 5268825, 5496917, 6419708, 6439661, 6439749, 6660993 , 6913131,6913136,6913160,9796370,9839397,9861147,9972326,9972327,9995220,10017822,10017935,10040620,10041353,10063649,10086397,10086398,10149682,10267048,10286439,10335106,10357701,10380944,10525032,10470200 , 10518761,10566385,10638113,10881132,11738545,12358676,12358678,18458354,18637768,19609228,21590819,23275881,25145416,44725022,9860303,9929074,10015486,10125803,10266931,10286753,10314319,10474100,10712359,11141 , 18696002,18696006,21651187,22239079,25141345,44393163,44579060,167095,5355027,10087786,10193246,10215224,10358907,10426543,11266097,15125882,18977383,19063167,19360964,19609253,2 0830941, 2226220, 23002673, 23181726, 23208908, 25011742, 4314230, 44579056, 44579100, 9830767, 10636975, or 11000660, or one or more compounds selected from the group consisting of 11000660.

<Embodiment 2: A therapeutic agent containing a retinoid>
Another embodiment of the present invention is a group consisting of non-alcoholic fatty liver disease, hepatitis, liver cancer, dyslipidemia, diabetes, hypertension, and arteriosclerosis, comprising any drug containing the above-mentioned retinoid It is a therapeutic agent for one or more diseases selected from. Since this therapeutic agent includes a retinoid-containing drug having the above-mentioned various effects, non-alcoholic fatty liver disease, hepatitis, liver cancer, dyslipidemia, diabetes, hypertension due to the effect of the drug And arteriosclerosis, can be suitably used for the treatment of one or more diseases selected from the group consisting of. For example, insulin resistance is well known to cause the above diseases.

  In addition, the term “treatment” as used herein refers to the ability to exert a preventive or symptomatic improvement effect on one or more symptoms associated with a patient's disease or disease.

  In the present specification, “patient” refers to a human or other mammals (eg, mouse, rat, rabbit, cow, monkey, chimpanzee, pig, horse, sheep, goat, dog, cat, guinea pig, hamster, etc.). Including. Preferred are mouse, rat, monkey, chimpanzee, or human, and particularly preferred is human. This is because, in the case of humans, any of the above-mentioned drugs containing retinoids can be used for the treatment of human diseases, the development of human therapeutics or diagnostics, and the like. In addition, mice, rats, monkeys, and chimpanzees have been widely used as model animals for research all over the world, and many characteristics have been clarified. By investigating the pharmacology of a drug, particularly useful information can be obtained for the development of therapeutic drugs and the like.

  In addition, when any of the aforementioned retinoid-containing drugs is used as a therapeutic or prophylactic drug, it can be administered alone, but usually one or more pharmacologically acceptable carriers. And is preferably provided as a pharmaceutical formulation prepared by any method well known in the pharmaceutical arts. It is also possible to administer the precursor of any drug containing the above-mentioned retinoid without directly using any drug containing the above-mentioned retinoid.

  In addition, the administration route for administering any of the above-mentioned drugs containing retinoids to the living body is preferably the most effective route for treatment. Oral administration or oral, intratracheal, rectal, subcutaneous Parenteral administration, such as intramuscular, intraperitoneal, intraocular or intravenous, can be given and can be administered systemically or locally. The administration route is preferably oral administration. When any drug containing the above-mentioned retinoid can exert a desired function in the affected area after subcutaneous or intravenous administration, it may be subcutaneous or intravenous administration.

  Examples of the dosage form include capsules, tablets, granules, syrups, emulsions, injections, suppositories, sprays, ointments, tapes and the like. Suitable formulations for oral administration include emulsions, syrups, capsules, tablets, powders, granules and the like. Liquid preparations such as emulsions and syrups include water, sucrose, sorbitol, sugars such as fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil, p-hydroxybenzoic acid Preservatives such as esters, and flavors such as strawberry flavor and peppermint can be used as additives. Furthermore, capsules, tablets, powders, granules, etc. are excipients such as lactose, glucose, sucrose and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol , Hydroxypropylcellulose, gelatin and other binders, surfactants such as fatty acid esters, plasticizers such as glycerin and the like can be used as additives.

  Formulations suitable for parenteral administration include injections, suppositories, sprays and the like. Aqueous solutions for injection include, for example, isotonic solutions containing physiological saline, glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol and sodium chloride, and suitable solubilizers such as Alcohols, specifically ethanol, polyalcohols such as propylene glycol, polyethylene glycol, nonionic surfactants such as polysorbate 80 (TM), HCO-50 may be used in combination. Suppositories can be prepared using a carrier such as cacao butter, hydrogenated fat or carboxylic acid. Sprays do not irritate any of the above-mentioned retinoid-containing drugs or the recipient's oral cavity or airway mucosa, and any of the above-mentioned retinoid-containing drugs are dispersed as fine particles for easy absorption. It can be prepared using a carrier to be prepared. Specific examples of the carrier include lactose and glycerin. Depending on the properties of the above-mentioned retinoid-containing drug and the carrier used, it is possible to formulate aerosols, dry powders, and the like. In these parenteral preparations, the components exemplified as additives for oral preparations can also be added.

  The prophylactic or therapeutic agent includes a buffer (eg, phosphate buffer, sodium acetate buffer), a soothing agent (eg, benzalkonium chloride, procaine, etc.), a stabilizer (eg, human serum). Albumin, polyethylene glycol, etc.), preservatives (eg, benzyl alcohol, phenol, etc.), antioxidants and the like. The prepared injection solution is usually filled in a suitable ampoule. Since the preparation thus obtained is safe and has low toxicity, it can be administered to, for example, humans and mammals (eg, rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.). Can do.

  The administration method can be appropriately selected depending on the age, symptoms, target organs, etc. of the patient. The dosage of the pharmaceutical composition containing any of the above-mentioned drugs containing retinoids can be selected, for example, in the range of 0.0001 mg to 1000 mg per kg body weight. Alternatively, for example, the dose can be selected in the range of 0.001 to 100000 mg / body per patient, but is not necessarily limited to these values. It varies depending on the intended therapeutic effect, administration method, treatment period, age, weight, and the like. The dose and administration method vary depending on the weight, age, symptoms, etc. of the patient, but can be appropriately selected by those skilled in the art. It may also be administered in combination with an appropriate chemotherapeutic agent.

  Retinoids are conventionally known to have a risk of side effects and side effects, and it is dangerous to take them easily with little evidence. Therefore, it is preferable to take a dose at a dose / administration interval at which side effects are suppressed while obtaining a desired pharmacological effect.

  As used herein, “hepatitis” is a general term for diseases that cause inflammation in the liver and cause some symptoms such as fever, jaundice, or general malaise. The causes of hepatitis vary and include viruses, alcohol, drugs, autoimmunity, or overnutrition. Including viral hepatitis, hepatitis due to viruses other than hepatitis virus, alcoholic hepatitis, non-alcoholic steatohepatitis, drug-induced hepatitis, autoimmune hepatitis, or primary biliary cirrhosis. Also included are acute hepatitis, fulminant hepatitis, LOHF (Late Onset Hepatic Failure), and chronic hepatitis.

  As used herein, “liver cancer” includes diseases caused by continued proliferation of liver cells. Hepatocytes capable of causing liver cancer include cells of blood vessels such as bile ducts, portal veins, dendritic cells or hepatocytes. Also included are primary liver cancer and metastatic liver cancer. Many primary liver cancers are known to be hepatocellular carcinoma (HCC).

  As used herein, “cancer” includes a disease caused by normal cells undergoing mutation and continuing to grow. Malignant cancer cells arise from all organs and tissues throughout the body, and when cancer cells grow, they become a mass of cancer tissues and invade and destroy surrounding normal tissues. Cancer is lung cancer, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, kidney cancer, adrenal cancer, biliary tract cancer, breast cancer, colon cancer, small intestine cancer, cervical cancer, endometrial cancer, ovarian cancer, bladder cancer, prostate cancer, Ureteral cancer, renal pelvic cancer, ureteral cancer, penile cancer, testicular cancer, brain tumor, cancer of central nervous system, cancer of peripheral nervous system, head and neck cancer (oral cancer, pharyngeal cancer, laryngeal cancer, nasal cavity / sinus cancer, Salivary gland cancer, thyroid cancer, etc.), skin cancer, melanoma, thyroid cancer, salivary gland cancer, blood cancer, malignant lymphoma, carcinoma or sarcoma.

  As used herein, “dyslipidemia” is a symptom in which lipids in blood are excessive or insufficient. Includes hypercholesterolemia, high LDL cholesterolemia, low HDL cholesterolemia, or hypertriglyceridemia. It is thought to cause arteriosclerosis, myocardial infarction, and stroke.

  In the present specification, “diabetes” is a general term for diseases that cause some symptoms due to high blood glucose level. Includes type 1 diabetes, type 2 diabetes, due to genetic abnormalities, secondary diabetes, or gestational diabetes.

  As used herein, “hypertension” is a symptom in which blood pressure is maintained high beyond the normal range. Includes essential hypertension or secondary hypertension.

  As used herein, “arteriosclerosis” refers to various pathologies caused by hardening of an artery. Arterial sclerosis includes atherosclerosis, arteriosclerosis, or Menkelberg-type sclerosis. It is known to cause ischemic heart disease and cerebrovascular disorder.

  In addition, another embodiment of the present invention is a diagnostic agent for nonalcoholic fatty liver disease or insulin resistance, including any drug containing the above-mentioned retinoid. This diagnostic agent contains a retinoid that has been demonstrated to significantly reduce serum AST or ALT levels in non-alcoholic fatty liver disease or insulin resistant model mice in the examples described below. . In FIGS. 5A and 5B of Examples described later, a significant decrease in serum AST concentration or serum ALT concentration due to retinoid is observed in the HFHFr> HFHFr group and the HFHFr> HFHFr + ATRA group. That is, when non-alcoholic fatty liver disease or insulin resistance develops, it is considered that serum AST concentration or serum ALT concentration decreases when retinoid is administered for a certain period. Therefore, it is considered that whether or not non-alcoholic fatty liver disease or insulin resistance is developed can be diagnosed by measuring the serum AST concentration or serum ALT concentration after administering the above diagnostic agent to a patient for a certain period of time. In this case, if the serum AST concentration or serum ALT concentration decreases, it is likely that non-alcoholic fatty liver disease or insulin resistance has developed. Thus, the diagnostic agent can be suitably used for diagnosis of non-alcoholic fatty liver disease or insulin resistance by the method of investigating biomolecules that vary based on the function of the retinoid.

  As used herein, the term “diagnostic agent” refers to a substance that can be used for diagnosing a subject's disease or disease potential, or for examining a disease-related substance in a test sample derived from a subject.

  Moreover, other embodiment of this invention is a reagent containing the chemical | medical agent containing the above-mentioned retinoid. This reagent can be used as a research reagent through the effects of any of the drugs containing retinoids described above. Moreover, you may use it with the instruction | indication which described the usage method or usage example at the time of using as a reagent, the text which described the location of the instruction | indication, or various buffers.

  Any drug containing the above-mentioned retinoid can be used as an additive for assisting animal growth in livestock through the effects of any drug containing the above-mentioned retinoid.

  As mentioned above, although embodiment of this invention was described, these are illustrations of this invention and various structures other than the above are also employable.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further, this invention is not limited to these.

<Example 1: Establishment of NAFLD model mouse>
Wild-type C57BL / 6 mice (male, 6-week-old; Charles River, Japan) were fed a normal diet (MF diet made of oriental yeast) or a high-fat high-fructose (HFHFr) diet for 16 weeks (FIG. 2). Mice fed the normal diet were bred on a normal diet for an additional 4 weeks and used as controls. Mice fed the HFHFr diet were divided into 4 groups, each fed a normal diet, ATRA (SIGMA) supplemented regular diet, HFHFr diet, ATRA supplemented HFHFr diet, and raised for 4 weeks. The ingredients for each diet are shown in Table 1. Mice were sacrificed 20 weeks after the start of breeding, and liver, blood and visceral fat were collected. The model mouse established here was used in the following examples.

  Various experimental methods used in Examples 2 to 10 described later are shown below.

(1) Measurement of liver lipid content The lipid content of the liver was determined by NEFA (free fatty acid) C-test Wako and triglyceride (neutral fat) E-test according to the method of He et al. (Hepatology. 2007; 46: 1392-1403). Wako and cholesterol E test were measured by Wako (all Wako Pure Chemical Industries). In addition, frozen sections were prepared and oil red O staining was performed.

(2) Measurement of insulin resistance index (HOMA-IR)
Blood was collected from the tail vein of mice after fasting for 12 hours, and fasting blood glucose was measured using Carefast (Nipro). Serum was separated from the collected blood, and the fasting serum insulin concentration was measured with a mouse insulin ELISA kit (Morinaga Biochemical Laboratories). HOMA-IR was calculated by the following formula. Fasting blood glucose (mM) × Fasting serum insulin concentration (mU / L) /22.4

(3) Glucose tolerance test and insulin tolerance test
Glucose was intraperitoneally administered to mice fasted for 12 hours to a body weight of 1 g / kg, and blood glucose levels were measured every 0 (before administration), 15, 30, 60, and 120 minutes. The area under the curve (AUC0-120) for each mouse was calculated based on the blood glucose level at each measurement point.

  Insulin tolerance test, as above, insulin (Humalin R; Eli Lilly Japan) was administered to the abdominal cavity of fasted mice at 1 U / kg body weight, and 0 (pre-dose), every 20, 40, 60 minutes The blood glucose level was measured. Data was expressed as a percentage (%) of blood glucose level at each hour relative to before insulin administration (0 minutes).

(4) Quantification of cytokines and lipids in serum Blood from freely fed mice was collected and serum was separated. Insulin was measured with the kit described above, and leptin was measured with the mouse leptin ELISA kit. The concentration of free fatty acid and neutral fat in serum was measured by the above kit.

(5) Examination by genetic insulin resistance model
Divide KK-Ay mice (male, 6-week-old; Claire Japan) and ob / ob mice (male, 6-week-old; Nippon Charles River) into 2 groups of 1 group and 2 groups. Bred for 4 weeks. KK-Ay mice were reared individually.

<Example 2: Weight change>
The change in the body weight of the mouse (FIG. 3A) decreased to almost the same value by 19 weeks in the HFHFr> Normal + ATRA group compared to the Normal group, and significantly decreased at 20 weeks. HFHFr> HFHFr + ATRA also decreased to almost the same value as the Normal group by 20 weeks. The HFHFr> Normal group showed a gradual decrease compared to the HFHFr> Normal + ATRA group, but the body weight was measured until week 25, but the body weight remained significantly higher than the Normal group (data not shown) Absent). The HFHFr> HFHFr group showed moderate weight gain up to 16-20 weeks. Based on the above, it was shown that weight loss was obtained by feeding ATRA supplemented food to NAFLD model mice.

  Liver weight (Fig. 3B) was almost the same in the HFHFr> Normal and HFHFr> Normal + ATRA groups as in the Normal group. Compared with the HFHFr> Normal group, a significant decrease was observed in the HFHFr> Normal + ATRA group. The HFHFr> HFHFr group showed a significant increase compared to the Normal group and the HFHFr> HFHFr + ATRA group. The liver weight ratio (FIG. 3C) indicating liver damage was significantly increased in the HFHFr> HFHFr group, and slightly increased and decreased in the HFHFr> Normal + ATRA group and the HFHFr> HFHFr + ATRA group. These results suggest that liver damage can be reduced by feeding ATRA supplemented food to NAFLD model mice.

  Visceral fat mass (Fig. 3D) showed a significant increase in HFHFr> Normal, HFHFr> HFHFr, HFHFr> HFHFr + ATRA group compared to Normal group, but almost the same value in HFHFr> Normal + ATRA group It was decreasing until. At this time, the visceral fat mass was significantly decreased in the HFHFr> Normal + ATRA group compared to the HFHFr> Normal group and in the HFHFr> HFHFr + ATRA group compared to the HFHFr> HFHFr group. These results suggest that the reduction of visceral fat is partly involved in the weight loss caused by ATRA in NAFLD model mice.

<Example 3: Feeding amount>
The daily food intake (Fig. 4A) for each week of mice decreased as a whole in 16-18 weeks in the HFHFr> Normal, HFHFr> Normal + ATRA, and HFHF> HFHFr groups compared to the control Normal group. Although there was a trend, no change was observed at 18-20 weeks. However, in the HFHFr> HFHFR + ATRA group, a significant decrease in food consumption was observed up to 20 weeks. Although there was no significant difference between the HFHFr> Normal group and the HFHFr> Normal + ATRA group, the HFHFr> HFHFr + ATRA group showed a decreasing trend throughout the week compared to the HFHFr> HFHFr group.

  Retinoid intake (FIG. 4B) was 12-20 μg retinol equivalent (μgRE) / day / individual in the Normal group and HFHFr> Normal group, and no significant difference was observed. In the HFHFr> HFHFr group, there was a significant decrease compared to about 3 μgRE / day / individual and the Normal group. On the other hand, in the HFHFr> Normal + ATRA and HFHFr> HFHFr + ATRA groups, the dose was 90-153 μgRE / day / individual. When converted to 1 kg body weight as a whole, it was 0.06 to 3.25 mg RE / day / kg body weight.

  In caloric intake (Fig. 4C), compared with the Normal group, the HFHFr> Normal, HFHFr> Normal + ATRA, and HFHFr> HFHFr + ATRA groups showed a decreasing trend from 16-18 weeks, but at 18-20 weeks. No change was observed. The HFHFr> HFHFr group had increased caloric intake throughout each week compared to Normal and HFHFr> HFHFr + ATRA.

<Example 4: Evaluation of liver function>
The liver weight ratio suggests that ATRA supplemented diet improves liver function. Therefore, in order to examine liver function in more detail, serum AST and ALT activities were then measured (FIG. 5AB). As a result, there was no significant difference between the HFHFr> Normal group and the HFHFr> Normal + ATRA group, but both increased AST and ALT activities compared to the Normal group. However, the HFHFr> HFHFr group and the HFHFr> HFHFr + ATRA group showed a significant increase compared to the Normal group, but the HFHFr> HFHFr + ATRA group was significantly less active. Based on the above, it was found that ATRA-added diet improves liver function in NAFLD model mice.

<Example 5: Liver fat content>
As a result of HE staining of the liver tissue (Fig. 6), large droplet fat deposition around the portal vein was observed, and in the HFHFr group, droplet fat deposition around the central vein was also observed. The degree of fat deposition decreased in the order of HFHFr> HFHFr group>HFHFr> HFHFr + ATRA group>HFHFr> Normal group>HFHFr> Normal + ATRA group> Normal group. This tendency was the same in oil red O staining (FIG. 7) that specifically stains fat droplets.

  In order to evaluate the amount of liver lipid more quantitatively, free fatty acid (NEFA), neutral fat (TG), and total cholesterol in liver tissue were measured (FIG. 8). As a result, hepatic lipid content increased in the HFHFr> Normal group, the HFHFr> HFHFr group, and the HFHFr> HFHFr + ATRA group. Furthermore, a significant decrease in liver lipid content was observed in the HFHFr> Normal + ATRA group compared to the HFHFr> Normal group. However, there was no significant difference between the HFHFr> HFHFr group and the HFHFr> HFHFr + ATRA group. Based on the above, it was suggested that feeding ATRA supplemented diets to NAFLD model mice decreased liver fat content and, as a result, improved fatty liver.

  Furthermore, the amount of TG in serum was measured (FIG. 9). As a result, there was no significant difference in the amount of TG with or without the addition of ATRA. It is known that an increase in TG is a side effect of ATRA, and the result of this Example was a good result indicating that no side effect of ATRA occurred.

<Example 6: Insulin resistance>
When fasting blood glucose level (Fig. 10A) and fasting serum insulin concentration (Fig. 10B) were measured, HFHFr> Normal + ATRA group and HFHFr> HFHFr + ATRA group were compared to HFHFr> Normal group and HFHFr> HFHFr group, respectively. A significant decrease was observed. Fasting blood glucose levels in the HFHFr> Normal + ATRA group and HFHFr> HFHFr + ATRA group were also significantly lower than those in the Normal group. On the other hand, serum insulin concentrations in the HFHFr> Normal group and the HFHFr> HFHFr group were significantly higher than those in the Normal group. Insulin resistance index (HOMA-IR) calculated from fasting blood glucose level and fasting serum insulin concentration (HOMA-IR) (Fig. 10C) showed a significant increase in HFHFr> Normal group and HFHFr> HFHFr group, and HFHFr> Normal + ATRA The group and HFHFr> HFHFr + ATRA group had almost the same value as the Normal group. From the above results, it was clarified that insulin resistance was improved by feeding ATRA supplemented food to NAFLD model mice.

<Example 7: Insulin sensitivity>
Insulin sensitivity was assessed by a glucose tolerance test (FIG. 11AB) and an insulin tolerance test (FIG. 11C). As a result, abnormal glucose tolerance was improved in the HFHFr> Normal + ATRA group and HFHFr> HFHFr + ATRA group, and the decrease in blood glucose level due to insulin load was significantly increased in the HFHFr> Normal + ATRA group and HFHFr> HFHFr + ATRA group. Was. From the above results, it became clear that the insulin sensitivity of NAFLD model mice was restored by ATRA supplemented diet.

<Example 8: Serum adipokine concentration>
When the concentrations of insulin (Fig. 12A) and leptin (Fig. 12B) contained in the serum of freely fed mice were measured, the HFHFr> Normal + ATRA group and HFHFr> HFHFr + ATRA group were HFHFr> Normal group and HFHFr> A significant decrease was observed in the HFHFr group. In the HFHFr> HFHFr group, both insulin and leptin increased markedly compared to Normal, and the same trend was observed in the HFHFr> Normal group, although not as high as the HFHFr> HFHFr group. These results suggest that insulin and leptin resistance, which are frequently observed in NAFLD patients, are improved by the ATRA diet.

  Free fatty acids in the blood are considered as bad adipocytokines that reduce insulin sensitivity among cytokines derived from adipocytes (adipocytokines). Thus, when the serum free fatty acid concentration (FIG. 12C) of mice under free feeding was measured, the HFHFr> Normal + ATRA group showed a significant decrease compared to the Normal group and the HFHFr> Normal group. From the above results, it was clarified that the free fatty acid, which is one of the bad adipokines, is reduced by the ATRA-added diet.

<Example 9: Change in body weight in a genetic insulin resistance model>
We investigated the effect of ATRA-added normal diet on KK-Ay and ob / ob mice in commonly used genetic insulin resistance model mice. KK-Ay is a mouse into which a gene that induces insulin resistance has been introduced. ob / ob is a mouse that lacks the leptin gene and has acquired insulin resistance. As a result, suppression of weight gain was observed in the group fed with the ATRA-added diet of both mice (FIG. 13AB). However, the liver-to-body ratio did not change with KK-Ay, and a significant decrease was observed in ob / ob with the ATRA-added diet (FIG. 13CD). Conversely, visceral fat showed a decreasing trend in KK-Ay and no change in ob / ob (FIG. 13EF). These results suggested that the ATRA-added diet also caused weight loss in the genetic insulin resistance model mice, but the effect on each tissue may differ depending on the genetic background.

<Example 10: Insulin resistance in a genetic insulin resistance model mouse>
As a result of the glucose tolerance test (FIG. 14ABCD), the ATRA-added diet improved glucose tolerance abnormality only for KK-Ay. Fasting serum insulin concentration (FIG. 14EF) and HOMA-IR (FIG. 14GH) also showed improvement in insulin resistance with KK-Ay alone. Moreover, the result of having measured the serum leptin concentration of both mice is shown in FIG. From the above results, it can be considered that the insulin resistance improving action by the ATRA-added diet depends on the genetic background and that the insulin resistance accompanying leptin resistance is improving. Furthermore, this action by ATRA was suggested to involve the leptin mechanism. This means that when a mouse that has been artificially deficient in leptin or a leptin receptor gene is used as a model animal in the evaluation of ATRA to improve insulin resistance, it is normal mouse (artificially This suggests that it is difficult to apply the evaluation results to mice that are not gene-deficient.

<Consideration of results>
As a result of the above examples, ATRA improved insulin resistance, weight gain control, weight loss, liver weight loss, suppression of internal fat mass increase, suppression of food intake, caloric intake suppression, blood AST decrease, blood ALT decrease, Inhibition of fat deposition in liver tissue, decrease in free fatty acid in liver tissue, decrease in neutral fat in liver tissue, decrease in total cholesterol in liver tissue, decrease in blood glucose level, decrease in blood insulin concentration, improvement in impaired glucose tolerance, insulin It has been shown to have numerous effects, including improved sensitivity, improved leptin resistance, decreased blood leptin levels, decreased blood free fatty acids, decreased blood adipocytokines in blood, or improved insulin resistance dependent on leptin resistance It was. It is considered that ATRA can be used for the treatment of various diseases such as NAFLD by utilizing these various effects related to improvement of insulin resistance. In addition to the above effects, it is also suggested that side effects are suppressed in the range where ATRA is used in the examples.

  Moreover, when evaluating the effect of ATRA administration to mice in Example 10, it is suggested that artificial modification of the leptin gene of model mice affects the evaluation results. On the other hand, in Example 1, administration of an HFHFr diet to mice for a certain period of time has succeeded in establishing an insulin resistant model mouse without artificial genetic modification. In Examples 2 to 8, various evaluations are performed using the model mouse. Therefore, it is considered that the evaluation results of Examples 2 to 8 were able to evaluate the effects of ATRA on non-genetically modified animals with high accuracy. In addition, when considering later based on the obtained results, the fact that many new effects were found in this example is due to the use of a more natural evaluation system as described above. Maybe.

In the above, this invention was demonstrated based on the Example. It is to be understood by those skilled in the art that this embodiment is merely an example, and that various modifications are possible and that such modifications are within the scope of the present invention.

Claims (6)

Containing a retinoid and being administered to a non-genetically modified animal liver disease patient,
The retinoid is retinol, retinal, retinoic acid or a derivative thereof, retinyl ester, all-trans retinol, 14-hydroxy-retro retinol, β-carotene, all-trans retinal, all-trans retinoic acid, and 9-cis retinoic acid. is one or more compounds selected from the group consisting of,
The derivative is
3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
3- [2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] hept-2-enoic acid,
(2Z, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4Z, 6E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6-trienoic acid,
(2E, 4Z, 6E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6-trienoic acid,
(2Z, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -9- (2-ethyl-6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid,
(2E, 4Z, 6E, 8Z) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -5,6-ditrithionona-2,4,6,8-tetraenoic Acid,
(2Z, 4E, 6Z, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2Z, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -5-trithionona-2,4,6,8-tetraenoic acid,
(2E, 4Z, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -5-trithionona-2,4,6,8-tetraenoic acid,
(2E, 4Z, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4Z, 6E, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2Z, 4Z, 6E, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2E, 4Z, 6Z, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2E, 4E, 6Z, 8E) -9- (3,4-dideuterio-2,6,6-trimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic Acid,
(2Z, 4E, 6E, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2E, 4E, 6Z, 8E) -9- (4,5-dideuterio-2,6,6-trimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic Acid,
(2E, 4E, 6E, 8E) -3-ethyl-7-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6Z, 8E) -9- [2,6-Dimethyl-6- (trideuteriomethyl) cyclohexen-1-yl] -3,7-dimethylnona-2,4,6,8-tetraeno Ic Acid,
(2E, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethyl-3,4-ditrithiocyclohexen-1-yl) nona-2,4,6,8-tetra Enoic Acid,
(2Z, 4Z, 6Z, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2E, 4E, 6Z, 8E) -3,6,7-trimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6Z, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2E, 4E, 6Z, 8E) -7-ethyl-3-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6-trienoic acid,
(2E, 4E, 6Z, 8E) -3,7-Dimethyl-9- (2,6,6-trimethyl-4,5-ditrithiocyclohexen-1-yl) nona-2,4,6,8-tetra Enoic Acid,
(2E, 4E, 6Z, 8E) -3-ethyl-7-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6Z, 8E) -4,5-Dideuterio-3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraeno Ic Acid,
(2E, 4Z, 6Z, 8E) -4,5-Dideuterio-3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraeno Ic Acid,
(2E, 4E, 8E) -3-Methyl-7-methylidene-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,8-trienoic acid,
(2E, 4E, 6Z, 8E) -7-Methyl-9- (2,6,6-trimethylcyclohexen-1-yl) -3- (tritrithiomethyl) nona-2,4,6,8-tetraeno Ic Acid,
(2E, 4E, 6Z, 8E) -7-Methyl-3- (trideuteriomethyl) -9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetra Enoic Acid,
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4Z, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) deca-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -9- [3,3-dideuterio-6,6-dimethyl-2- (trideuteriomethyl) cyclohexen-1-yl] -3,7-dimethylnona-2,4, 6,8-tetraenoic acid,
(2E, 4E, 6E, 8Z) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4E, 8E) -3-Methyl-7-methylidene-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,8-trienoic acid,
(2Z, 4Z, 6E, 8Z) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4E, 6Z, 8Z) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid; zinc,
(2E, 4E, 6E) -5-methyl-7- (2,6,6-trimethylcyclohexen-1-yl) hepta-2,4,6-trienoic acid,
(2E, 4E, 6Z) -3-methyl-7-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] deca-2,4,6-trienoic acid,
(2E, 4E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,8-trienoic acid,
(2E, 4E, 6Z, 8E) -7-tert-Butyl-3-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid ,
(2E, 4E, 6E, 8E, 10E) -5,9-Dimethyl-11- (2,6,6-trimethylcyclohexen-1-yl) undeca-2,4,6,8,10-pentaenoic acid ,
(Z) -3-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] hept-2-enoic acid,
(2E, 4E, 6E, 8E, 10E, 12E) -3,7,11-trimethyl-13- (2,6,6-trimethylcyclohexen-1-yl) trideca-2,4,6,8,10, 12-hexaenoic acid,
(2E, 4E, 6Z) -3-methyl-7-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] undeca-2,4,6-trienoic acid,
(2E, 4E, 6E, 8E) -4,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -7-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -9- (2-butyl-6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid,
(2Z, 4E, 8E) -7-methylidene-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,8-trienoic acid,
(2E, 4E, 6Z, 8E) -9- (2-butyl-6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid,
3-methyl-5- (2,6,6-trimethylcyclohexen-1-yl) penta-2,4-dienoic acid,
(2E, 4E) -3-methyl-5- (2,6,6-trimethylcyclohexen-1-yl) penta-2,4-dienoic acid,
(Z, 4E) -3-Methyl-4- [3-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] cyclohex-2-en-1-ylidene] but- 2-Enoic acid,
(2E, 4E) -3-Methyl-6- [1-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] cyclopropyl] hexa-2,4-dienoic Acid,
(2E, 4E, 6Z, 8E) -3-Methyl-7-propan-2-yl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraeno Ic Acid,
(Z, 4E) -3-Methyl-4-[(4E) -3-methyl-4-[(2,6,6-trimethylcyclohexen-1-yl) methylidene] cyclohexa-2,5-diene-1- Iriden] But-2-Enoic Acid,
(E, 4E) -3-Methyl-4- [3-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] cyclohex-2-en-1-ylidene] but- 2-Enoic acid,
(2Z, 4E, 8E) -3-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,8-triene-6-inoic acid,
(2E, 4E, 6E, 8E) -2,3,7-trimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,5,6,6-tetramethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E) -3-Methyl-5- [2-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] cyclopenten-1-yl] penta-2,4- Jenoic acid,
(2E, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,5,6,6-tetramethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -2,3-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,8-dienoic acid,
(2Z, 5E) -7-methyl-3-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] nona-2,5-dienoic acid,
(2E, 4E, 6E, 8E) -9- [6,6-Dimethyl-2- (2-methylpropyl) cyclohexen-1-yl] -3,7-dimethylnona-2,4,6,8-tetraeno Ic Acid,
(2E, 4E, 6Z, 8E) -9- [6,6-Dimethyl-2- (2-methylpropyl) cyclohexen-1-yl] -3,7-dimethylnona-2,4,6,8-tetraeno Ic Acid,
(2Z, 4E, 6Z, 8E) -9- (6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -9- (6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid, and
(2E, 4E, 6Z, 8E) -9- (6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid,
One or more compounds selected from the group consisting of:
From the group consisting of feeding inhibitors, caloric intake inhibitors, blood ALT reducing agents, fat deposition inhibitors in liver tissues, neutral fat reducing agents in liver tissues, and total cholesterol level reducing agents in liver tissues One or more selected drugs (provided that insulin resistance, leptin resistance, fatty liver, steatohepatitis due to retinoic acid dysfunction, nonalcoholic steatohepatitis, or diabetes preventive or therapeutic agent, blood glucose level lowering agent And excluding insulin sensitizers).   2. The drug according to claim 1, wherein the one or more drugs are one or more drugs selected from the group consisting of an eating inhibitor and a caloric intake inhibitor. The retinoid is selected from the group consisting of retinol, retinal, retinoic acid, retinyl ester, all-trans retinol, 14-hydroxy-retro retinol, β-carotene, all-trans retinal, all-trans retinoic acid, and 9-cis retinoic acid. 3. The drug according to claim 1 or 2 , which is one or more compounds. From the group consisting of retinol, retinal, retinoic acid or derivatives thereof, retinyl ester, all-trans retinol, 14-hydroxy-retro retinol, β-carotene, all-trans retinal, all-trans retinoic acid, and 9-cis retinoic acid contain one or more compounds selected,
The derivative is
3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
3- [2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] hept-2-enoic acid,
(2Z, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4Z, 6E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6-trienoic acid,
(2E, 4Z, 6E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6-trienoic acid,
(2Z, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -9- (2-ethyl-6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid,
(2E, 4Z, 6E, 8Z) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -5,6-ditrithionona-2,4,6,8-tetraenoic Acid,
(2Z, 4E, 6Z, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2Z, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -5-trithionona-2,4,6,8-tetraenoic acid,
(2E, 4Z, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -5-trithionona-2,4,6,8-tetraenoic acid,
(2E, 4Z, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4Z, 6E, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2Z, 4Z, 6E, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2E, 4Z, 6Z, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2E, 4E, 6Z, 8E) -9- (3,4-dideuterio-2,6,6-trimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic Acid,
(2Z, 4E, 6E, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2E, 4E, 6Z, 8E) -9- (4,5-dideuterio-2,6,6-trimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic Acid,
(2E, 4E, 6E, 8E) -3-ethyl-7-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6Z, 8E) -9- [2,6-Dimethyl-6- (trideuteriomethyl) cyclohexen-1-yl] -3,7-dimethylnona-2,4,6,8-tetraeno Ic Acid,
(2E, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,6,6-trimethyl-3,4-ditrithiocyclohexen-1-yl) nona-2,4,6,8-tetra Enoic Acid,
(2Z, 4Z, 6Z, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2E, 4E, 6Z, 8E) -3,6,7-trimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6Z, 8E) -3,7-Dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) -4,5-ditrithionona-2,4,6,8-tetraenoic Acid,
(2E, 4E, 6Z, 8E) -7-ethyl-3-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6-trienoic acid,
(2E, 4E, 6Z, 8E) -3,7-Dimethyl-9- (2,6,6-trimethyl-4,5-ditrithiocyclohexen-1-yl) nona-2,4,6,8-tetra Enoic Acid,
(2E, 4E, 6Z, 8E) -3-ethyl-7-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6Z, 8E) -4,5-Dideuterio-3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraeno Ic Acid,
(2E, 4Z, 6Z, 8E) -4,5-Dideuterio-3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraeno Ic Acid,
(2E, 4E, 8E) -3-Methyl-7-methylidene-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,8-trienoic acid,
(2E, 4E, 6Z, 8E) -7-Methyl-9- (2,6,6-trimethylcyclohexen-1-yl) -3- (tritrithiomethyl) nona-2,4,6,8-tetraeno Ic Acid,
(2E, 4E, 6Z, 8E) -7-Methyl-3- (trideuteriomethyl) -9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetra Enoic Acid,
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4Z, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) deca-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -9- [3,3-dideuterio-6,6-dimethyl-2- (trideuteriomethyl) cyclohexen-1-yl] -3,7-dimethylnona-2,4, 6,8-tetraenoic acid,
(2E, 4E, 6E, 8Z) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4E, 8E) -3-Methyl-7-methylidene-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,8-trienoic acid,
(2Z, 4Z, 6E, 8Z) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2Z, 4E, 6Z, 8Z) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid; zinc,
(2E, 4E, 6E) -5-methyl-7- (2,6,6-trimethylcyclohexen-1-yl) hepta-2,4,6-trienoic acid,
(2E, 4E, 6Z) -3-methyl-7-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] deca-2,4,6-trienoic acid,
(2E, 4E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,8-trienoic acid,
(2E, 4E, 6Z, 8E) -7-tert-Butyl-3-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid ,
(2E, 4E, 6E, 8E, 10E) -5,9-Dimethyl-11- (2,6,6-trimethylcyclohexen-1-yl) undeca-2,4,6,8,10-pentaenoic acid ,
(Z) -3-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] hept-2-enoic acid,
(2E, 4E, 6E, 8E, 10E, 12E) -3,7,11-trimethyl-13- (2,6,6-trimethylcyclohexen-1-yl) trideca-2,4,6,8,10, 12-hexaenoic acid,
(2E, 4E, 6Z) -3-methyl-7-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] undeca-2,4,6-trienoic acid,
(2E, 4E, 6E, 8E) -4,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -7-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -9- (2-butyl-6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid,
(2Z, 4E, 8E) -7-methylidene-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,8-trienoic acid,
(2E, 4E, 6Z, 8E) -9- (2-butyl-6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid,
3-methyl-5- (2,6,6-trimethylcyclohexen-1-yl) penta-2,4-dienoic acid,
(2E, 4E) -3-methyl-5- (2,6,6-trimethylcyclohexen-1-yl) penta-2,4-dienoic acid,
(Z, 4E) -3-Methyl-4- [3-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] cyclohex-2-en-1-ylidene] but- 2-Enoic acid,
(2E, 4E) -3-Methyl-6- [1-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] cyclopropyl] hexa-2,4-dienoic Acid,
(2E, 4E, 6Z, 8E) -3-Methyl-7-propan-2-yl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraeno Ic Acid,
(Z, 4E) -3-Methyl-4-[(4E) -3-methyl-4-[(2,6,6-trimethylcyclohexen-1-yl) methylidene] cyclohexa-2,5-diene-1- Iriden] But-2-Enoic Acid,
(E, 4E) -3-Methyl-4- [3-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] cyclohex-2-en-1-ylidene] but- 2-Enoic acid,
(2Z, 4E, 8E) -3-methyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,8-triene-6-inoic acid,
(2E, 4E, 6E, 8E) -2,3,7-trimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,5,6,6-tetramethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E) -3-Methyl-5- [2-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] cyclopenten-1-yl] penta-2,4- Jenoic acid,
(2E, 4E, 6Z, 8E) -3,7-dimethyl-9- (2,5,6,6-tetramethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -2,3-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,4,6,8-tetraenoic acid,
(2E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohexen-1-yl) nona-2,8-dienoic acid,
(2Z, 5E) -7-methyl-3-[(E) -2- (2,6,6-trimethylcyclohexen-1-yl) ethenyl] nona-2,5-dienoic acid,
(2E, 4E, 6E, 8E) -9- [6,6-Dimethyl-2- (2-methylpropyl) cyclohexen-1-yl] -3,7-dimethylnona-2,4,6,8-tetraeno Ic Acid,
(2E, 4E, 6Z, 8E) -9- [6,6-Dimethyl-2- (2-methylpropyl) cyclohexen-1-yl] -3,7-dimethylnona-2,4,6,8-tetraeno Ic Acid,
(2Z, 4E, 6Z, 8E) -9- (6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid,
(2E, 4E, 6E, 8E) -9- (6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid, and
(2E, 4E, 6Z, 8E) -9- (6,6-dimethylcyclohexen-1-yl) -3,7-dimethylnona-2,4,6,8-tetraenoic acid,
One or more compounds selected from the group consisting of:
From the group consisting of feeding inhibitors, caloric intake inhibitors, blood ALT reducing agents, fat deposition inhibitors in liver tissues, neutral fat reducing agents in liver tissues, and total cholesterol level reducing agents in liver tissues One or more selected drugs (provided that insulin resistance, leptin resistance, fatty liver, steatohepatitis due to retinoic acid dysfunction, nonalcoholic steatohepatitis, or diabetes preventive or therapeutic agent, blood glucose level lowering agent And excluding insulin sensitizers). 5. The drug according to claim 4 , wherein the one or more drugs are one or more drugs selected from the group consisting of an eating inhibitor and a calorie intake inhibitor. Characterized in that it is orally administered agent according to any one of claims 1 to 5.