JP2020075896A - Anti-influenza action of neuropeptide y and receptor thereof - Google Patents

Abstract

To provide a new treatment approach to influenza virus infection.SOLUTION: This invention relates to a pharmaceutical composition or the like for preventing and/or treating influenza virus infection, characterized by blocking the functions of neuropeptide Y and a receptor thereof.SELECTED DRAWING: None

Description

  The present invention generally relates to research on the mechanism of the onset and / or severity of influenza virus infections. In particular, the present invention relates to pharmaceutical compositions, vaccines, related biomarkers and related screening methods for preventing and / or treating influenza virus infections.

  Influenza A virus causes pandemics worldwide and is a major cause of morbidity and mortality, especially in patients with risk factors such as obesity, diabetes and asthma (Non-Patent Document 1). Furthermore, highly pathogenic influenza viruses, such as the avian influenza H5N1 virus, cause severe infections in humans with mortality rates as high as 60% (Non-Patent Document 2). Severe influenza virus infections are characterized by excessive lung tissue inflammation and virus replication, and present with severe respiratory failure requiring critical care in the intensive care unit (ICU) (Non-Patent Document 2). However, to date, no effective therapy has been developed that can treat severe influenza virus infections.

  Crosstalk between the autonomic nervous system and the immune system, which are classified into sympathetic nerves and parasympathetic nerves, is considered to be an important biological process in health and disease (Non-patent Documents 3 and 4). Activation of the sympathetic nervous system (SNS) by various stimuli releases catecholamine (CA) and activates the immune system (Non-Patent Document 5). In addition to SNS-derived neural CA, CA de novo synthesis of phagocytes has been shown to enhance the acute inflammatory response (Non-Patent Document 6). Similar to CA, with respect to neuropeptide Y (NPY), SNS-derived NPY is usually present at sympathetic nerve endings, is released by SNS stimulation, and is a specific Y receptor expressed by immune cells (eg, Y1, Y2, Y5). ) Has been shown to regulate immune function (Non-patent Documents 7, 8 and 9). However, it is unclear whether NPY that is not derived from the nervous system contributes to the disease. In particular, there have been no reports to date showing that NPY is involved in influenza virus infection.

  NPY is a 36 amino acid peptide belonging to the pancreatic polypeptide system and was first isolated from porcine brain in 1982 (Non-Patent Document 9). NPY is present in all sympathetic nerves innervating the cardiovascular system and is the most abundant peptide in the brain and heart. Furthermore, in rats but not in humans, NPY is also found extraneuronally in platelets and endothelium (Zukovska-Grojec et al., 1993). Originally, NPY was known as an effective vasoconstrictor and neuromodulator. NPY released by stress, exercise and myocardial ischemia is associated with coronary heart disease, congestive heart failure, and hypertension (Zukovska-Grojec et al., 1998). Recently, NPY has been recognized for its ability to enhance appetite and is suspected to play an important role in obesity and diabetes (Kalra et al., 1999). Furthermore, NPY has been shown to regulate immune function through trafficking of immune cells, T cell differentiation, cytokine secretion, and the like (Non-Patent Document 10). However, there are no reports so far regarding the role of NPY in the pathological condition of influenza virus infection.

  Six NPY receptors, Y1R, Y2R, Y3R, Y4R, Y5R and Y6R subtypes, have been cloned and belong to the rhodopsin-like G protein-coupled 7-transmembrane receptor (GPCR). Two of the six NPY receptor subclasses, Y1R and Y5R, considered to be the most important receptor subtypes that regulate food intake and energy expenditure, have been cloned to date (Non-Patent Document 11). .. Various animal studies have shown that activation of neuropeptide Y receptors is associated with stimulation of consumption behavior (Flood and Morley Peptides, 10,963-966 (1989), Leibowitz and Alexander, Peptides, 12,1251-1260 (1991). , and Stanley et al., Peptides, 13,581-587 (1992)) and are also associated with vasoconstriction (Non-patent Documents 12, 13 and 14). Furthermore, it has been described that NPY is a potent stimulant of food intake and an inducer of vasoconstriction that causes hypertension in animals (Non-Patent Document 15). They also point out that low levels of NPY are associated with loss of appetite, clearly demonstrating that in animals, compounds that inhibit the activity of NPY reduce hypertension and appetite.

Thus, the NPY-YR axis composed of NPY and NPY receptor (YR) subtypes, that is, an agent capable of cleaving NPY bond in NPY and multiple NPY receptor subtypes, is obesity, anorexia nervosa. , A number of eating disorders including bulimia; disorders related to obesity, including insulin resistance, diabetes, hyperlipidemia and hypertension, and other therapeutic regimens in which blockade of NPY activity would be beneficial. It has been reported. It has been reported that a compound that inhibits the NPY-YR axis exhibits an antifeeding effect and an antiobesity effect (Non-Patent Document 16).
However, it has not been shown so far that the inhibition of the NPY-YR axis affects the pathophysiology of influenza virus infection and can be a therapeutic drug.

Special table 2017-6 bulletin

Clark, N. M. & Lynch, J. P., 3rd. Semin Respir Crit Care Med 32, 373-392, doi: 10.1055 / s-0031-1283278 (2011)) Beigel, J. H. et al. The New England journal of medicine 353, 1374-1385 (2005) Tracey, K. J. Nature 420, 853-859, doi: 10.1038 / nature 01321 (2002) Sternberg, E. M. Nature reviews. Immunology 6, 318-328, doi: 10.1038 / nri1810 (2006) Madden, K.S. Developmental and comparative immunology, doi: 10.1016 / j.dci.2016.04.015 (2016) Flierl, M. A. et al. Nature 449, 721-725, doi: 10.1038 / nature06185 (2007) Bedoui, S. et al. Journal of neuroimmunology 134, 1-11 (2003) Wheway, J., Herzog, H. & Mackay, F. Current topics in medicinal chemistry 7, 1743-1752 (2007) Dimitrijevic, M. & Stanojevic, S. Amino acids 45, 41-53, doi: 10.1007 / s00726-011-1185-7 (2013). Tatemoto, K., Carlquist, M. and Mutt, V., Nature, 296 (1982) 659-660. Dimitrijevic M, Stanojevic S. Amino Acids. 2013 Jul; 45 (1): 41-53 Balasubramaniam, A., Am. J. of Surgery, 183,430-434 (2002) Wahlestedt, et.al., Regul. Peptides, 13,307-318 (1986) McCauley and Wesffall J. Pharmacol. Exp. Ther. 261,863-868 (1992) Grundemar, et. Al., Br. J. Pharmacol. 105,45-50 (1992) Grundemarand Hakanson TiPS, May 1'994 [Vol.15], 153-159 Brothers SP, Wahlestedt C. EMBO Mol Med. 2010 Nov; 2 (11): 429-39

  The present invention aims to elucidate the underlying mechanism that regulates antiviral and proinflammatory responses in influenza virus infections, and based on that, provide new therapeutic approaches to influenza virus infections.

  Although the role of SNS-derived NPY in the regulation of immune cell function has already been established, few studies have focused on the role of NPY in the regulation of immune cell function (Non-Patent Document 7). Therefore, we investigated the function of NPY in the pathogenesis of severe influenza virus infection. As a result, we found for the first time the underlying mechanism by which NPY and Y1 receptors (Y1R) may regulate antiviral and proinflammatory responses to severe influenza virus infection in phagocytes. .. Based on that, a new therapeutic approach for influenza virus infectious diseases focusing on the NPY-YR axis was completed.

Therefore, the present invention includes the following aspects.
<Pharmaceutical composition>
[1]
A pharmaceutical composition for preventing and / or treating influenza virus infection, which comprises an inhibitor of the NPY-YR axis.
[2]
The NPY-YR axis inhibitor is selected from among NPY analogs, antibodies against NPY or functional fragments or derivatives thereof, YR analogs, and antibodies against YR or functional fragments or derivatives thereof [1] The described pharmaceutical composition.
[3]
The pharmaceutical composition according to [2], wherein the inhibitor of NPY-YR axis is a substance related to NPY.
[4]
The pharmaceutical composition according to [3], wherein the analogue of NPY is a compound that inhibits the binding between NPY and Y1R, Y2R, Y4R and Y5R subtypes.
[5]
The pharmaceutical composition according to [4], wherein the compound is the following compound.
Antagonist of neuropeptide Y, Goro Katsuura et al., “Obesity Study” vol8 No.1 84-85, 2002; Anti-obesity action of novel neuropeptide Y Y5 receptor antagonist S-2367, Hideo Yukioka, Journal of Japanese Pharmacology 136.270-274 , 2010.
[6]
The pharmaceutical composition according to [1], wherein the NPY-YR axis inhibitor is selected from an antibody against NPY or a functional fragment or derivative thereof, and an antibody against YR or a functional fragment or derivative thereof.
[7]
The pharmaceutical composition according to any one of [1] to [6], wherein the influenza virus infection is a severe influenza virus infection.

<Screening method>
[8]
A method for screening a substance for preventing and / or treating an influenza virus infection, wherein the inhibitory function for the NPY-YR axis is used as an index.
[9]
The screening method according to [8], wherein the influenza virus infection is a severe influenza virus infection.
[10]
A method of screening substances for the prevention and / or treatment of influenza virus infections, which comprises the following steps:
(A) preparing a system of NPY-YR axes containing biological cells expressing NPY and YR,
(B) contacting the system with a candidate compound of a substance for preventing and / or treating influenza virus infection,
(C) Whether the candidate compound exerts an inhibitory function in the NPY-YR axis system,
(D) A method of identifying the candidate compound as a substance for preventing and / or treating an influenza virus infection if the candidate compound exhibits an inhibitory function.
[11]
The screening method according to [10], wherein the influenza virus infection is a severe influenza virus infection.
[12]
The screening method according to [10] or [11], wherein the biological cells expressing NPY and YR are phagocytic cells.

<Biomarker related>
[13]
A method of determining future severity of an influenza virus infection, comprising:
(A1) a step of measuring the amount of NPY in the blood of the subject (test biomarker amount),
(B1) a step of comparing the amount of the test biomarker with the amount of NPY (the control biomarker amount) in the blood of a non-virus-infected sample, and (c1) the amount of the test biomarker is more than the control biomarker amount A method for determining that a subject has a severe influenza virus infection when the number is high.
[14]
The method according to [13], wherein the amount of the control biomarker is below the detection limit.
[15]
A biomarker that is NPY in blood that can determine future severity of influenza virus infection.
[16]
Use of blood NPY as a bimarker with which future severity of influenza virus infection can be determined.

<Vaccine 1>
[17]
A vaccine for preventing and / or treating influenza virus infections, which vaccine comprises NPY bound to a pharmaceutically acceptable carrier.
[18]
Vaccine according to [1] 7, characterized in that the carrier is a protein carrier.
[19]
The vaccine according to [18], wherein the protein carrier is selected from the group consisting of keyhole limpet hemocyanin (KLH), tetanus toxoid (TT) or diphtheria toxoid (DT).
[20]
The vaccine according to any one of [17] to [19], wherein NPY is formulated with an adjuvant.
[21]
The vaccine according to [20], wherein the adjuvant is alum.
[22]
The vaccine according to any one of [17] to [21], wherein the influenza virus infection is a severe influenza virus infection.
[23]
Use of NPY for the manufacture of a vaccine for the prevention and / or treatment of influenza virus infection.

<Vaccine 2>
[24]
A vaccine for preventing and / or treating influenza virus infection, which comprises a nucleic acid-based vaccine comprising a polynucleotide encoding NPY.
[25]
The nucleic acid-based vaccine according to [24], wherein the polynucleotide is DNA and is a DNA vaccine.
[26]
The nucleic acid-based vaccine according to [24], wherein the polynucleotide is RNA and is an RNA vaccine.
[27]
The nucleic acid-based vaccine according to any one of [24] to [27], wherein the polynucleotide is present in a plasmid vector.

FIG. 1 is a graph showing the results of measuring the expression level of NPY mRNA in the lung of a mouse model intratracheally infected with the influenza virus H1N1 / PR8 strain over time. FIG. 2 is a graph showing the results of time-dependent measurement of the expression level of NPY protein in the lungs of a mouse model intratracheally infected with influenza virus H1N1 / PR8 strain. FIG. 3 shows that the numbers of NPY-GFP positive alveolar macrophages (CD11c + Siglec-F +), interstitial macrophages (CD11b + F4 / 80 +) and monocytes (Ly6-C + CD11b +) increased remarkably after virus infection, Neutrophils (CD11b + Ly6-G +), myeloid dendritic cells (mDCs) (CD11c + CD103 +) and T cells (CD3 +) do not show NPY-GFP signal under uninfected or infected conditions It is an analysis result of the flow cytometry showing that. FIG. 4 is a graph showing that sympathectomy does not affect NPY production in virus-infected lungs in mice that have undergone chemical sympathectomy. FIG. 5 is a graph showing the survival rate after infection of WT (wild type) mice and NPY KO mice with influenza virus H1N1 / PR8 strain having a 56.2TCID50 titer. FIG. 6 is a graph showing the survival rate after infecting WT (wild type) mice and NPY KO mice with 250 TCID50 titer of influenza virus H1N1 / PR8 strain. FIG. 7 is a photograph showing a comparison of lung tissue damage by histological analysis after infecting WT (wild type) mice and NPY KO mice with 250 TCID50 titer of influenza virus H1N1 / PR8 strain. FIG. 8 is a graph showing a comparison of pulmonary edema formation after infection of WT (wild type) mice and NPY KO mice with 250 TCID50 titer of influenza virus H1N1 / PR8 strain. FIG. 9 is a graph showing a comparison of viral replication assessed by viral NP mRNA expression after infection of WT (wild type) and NPY KO mice with 250TCID50 titer of influenza virus H1N1 / PR8 strain. FIG. 10 shows the proinflammatory cytokines Cxcl1, Cxcl2 and Il-6, and the anti-inflammatory cytokine IL after infection of WT (wild type) mice and NPY KO mice with 250TCID50 titer of influenza virus H1N1 / PR8 strain. 10 is a graph showing a comparison of mRNA expression of -10 and IL12b. FIG. 11 is a comparison of alveolar, interstitial macrophage, monocyte and neutrophil cell numbers after infection of WT (wild type) mice and NPY KO mice with 250TCID50 titer of influenza virus H1N1 / PR8 strain. It is a graph which shows. FIG. 12 is a graph showing the survival rates of WT and NPY KO mice after transpantracheally infected with a pandemic H1N1 / 2009 strain (A / California / 04/2009 H1N1). Figure 13: Frozen lung sections obtained from uninfected and virus-infected WT mice were double immunostained with Y1R Ab and CD11c, CD11b, Ly6-G, Ly6-C, CD103, CD3 or NK1.1 Ab. It is a graph which quantified the obtained image data. FIG. 14 is a graph showing a comparison of survival rates after infection of influenza virus H1N1 / PR8 strains in WT mice and Y1R ^PC-KO mice in which phagocytic cell-specific deletion of Y1 receptor (Y1R) was performed. FIG. 15 is a photograph showing a comparison of lung tissue images after infection of influenza virus H1N1 / PR8 strains in WT mice and Y1R ^PC-KO mice in which phagocytic cell-specific deletion of Y1 receptor (Y1R) was carried out. . FIG. 16 is a graph showing a comparison of virus replication in lung tissues after infection of influenza virus H1N1 / PR8 strains in WT mice and Y1R ^PC-KO mice in which phagocytic cell-specific deletion of Y1 receptor (Y1R) was carried out. Is. FIG. 17 shows the expression of proinflammatory cytokines in lung tissue after infection of influenza virus H1N1 / PR8 strains in WT mice and Y1R ^PC-KO mice in which phagocytic cell-specific deletion of Y1 receptor (Y1R) was carried out. It is a graph which shows comparison. FIG. 18 is a virus titer as an index of virus replication after infection of influenza virus H1N1 / PR8 strains in WT mice and Y1R ^PC-KO mice in which phagocytic cell-specific deletion of Y1 receptor (Y1R) was carried out. 5 is a graph showing a comparison of FIG. 19 shows a comparison of IL-6 protein levels in the lungs after infection of influenza virus H1N1 / PR8 strains in WT mice and Y1R ^PC-KO mice in which phagocytic cell-specific deletion of Y1 receptor (Y1R) was performed. It is a graph shown. FIG. 20 is a graph showing increase in survival rate of virus-infected mice with Y1 receptor inhibitor BIBO3304. FIG. 21 is a graph showing that blood NPY concentration increases with time after infection of WT mice with the virus H1N1 / PR8 strain.

<Antiviral pharmaceutical composition>
One aspect of the present invention provides a pharmaceutical composition for preventing and / or treating influenza virus infection, which comprises an inhibitor of the NPY-YR axis. The details will be described below.
The “NPY-YR axis” in the “NPY-YR axis inhibitor” is a structure composed of NPY and six NPY receptors (YR), Y1R, Y2R, Y3R, Y4R, Y5R and Y6R subtypes. And / or functional relationship. In the present specification, it is shown that the mouse Y1R deficient receptor and the Y1R inhibitor improve the pathological condition of influenza virus infection (Example 4). In addition to this result, it is shown that the pathological condition of severe influenza virus infection is improved in mice lacking the ligand NPY (Example 2). Since NPY is a ligand for all six NPY receptor subtypes, it is considered that all YR subtypes capable of binding NPY constitute the “NPY-YR axis”.

  The “inhibitor” in the “inhibitor of the NPY-YR axis” means any substance that blocks the structural and / or functional relationship of the NPY-YR axis, and the mode of blocking is physical and functional. It doesn't matter. Although many pharmacological actions of NPY have been found to date, it has been clarified that the NPY-YR axis is involved in food intake regulation, and pharmaceutical companies around the world have so far studied various food intake inhibitors, We are researching and developing anti-obesity substances. The present invention includes all of these known NPY-YR axis inhibitors, and NPY-YR axis inhibitors that will be found in the future, in view of the essence of the present invention. Is obvious.

  This time, in the phagocytic cells of the lung infected with the severe influenza virus, de novo synthesis of NPY and increased expression of its receptor YR were shown (Example 1). In addition, deficiency of NPY gene or YR gene of phagocytic cells significantly improved the pathology of severe influenza virus infection characterized by excessive viral replication and lung inflammation. It was thus found that the NPY-YR axis could be a novel therapeutic target for deadly influenza virus infections. The "NPY-YR axis inhibitor" is not bound by any particular theory, but reduces, inhibits, blocks or prevents influenza virus replication and / or tissue inflammation in the infected host, resulting in an influenza virus life cycle. Those which exert all the effects of suppressing or inhibiting the above, and eliminating or reducing the viral activity, and / or those exhibiting all the effects of eliminating or reducing the tissue inflammation. The inhibitors of the NPY-YR axis in the present invention include all those found so far and those found in the future.

  The NPY-YR axis inhibitor is selected from, for example, NPY analogs, antibodies against NPY or functional fragments or derivatives thereof, YR analogs, and antibodies against YR or functional fragments or derivatives thereof.

  An NPY analog is any substance that inhibits the binding of NPY to Y1R, Y2R, Y3R, Y4R, Y5R and Y6R subtypes, for example, intracellular signal transduction via each receptor subtype of NPY, It refers to a substance that blocks and is also called an NPY receptor antagonist. The NPY receptor agonist of the present invention is not particularly limited in its molecular species as long as it shows affinity for the NPY receptor and functions as an antagonist. Examples of such a molecule include, for example, low molecular weight compounds, proteins and peptides. Can be mentioned. The type of the low molecular weight compound is not particularly limited, and specific examples thereof include natural compounds, organic compounds, and inorganic compounds. Also, the type of the peptide is not particularly limited. NPY, which has been found to have many pharmacological actions to date, is attracting attention because of its strong appetite promoting action. The pharmacological action of NPY is elicited through a 7-transmembrane receptor, and it is currently known that there are six subtypes Y1R to Y6R in mammals. However, Y3R has not been cloned yet, and its existence is questioned. Moreover, since Y6R is not expressed in higher animals such as primates, pharmacological studies are concentrated on four subtypes of Y1R, Y2R, Y4R, and Y5R. (Folia Pharmacol. Jpn.) 127, 88-91 (2006)). In this sense, a preferable NPY analog is a substance that inhibits the binding between NPY and Y1R, Y2R, Y4R and Y5R subtypes.

Specific examples of preferable NPY-related substances are described in the patent documents shown below as examples. It should be understood that all compounds within the scope of the compounds described herein and those specifically exemplified can be used in the present invention, and these are merely exemplary.
1) Inhibitors of the NPY-YR axis whose subtypes have not been identified-Table 2005-508923
Structural formula:

[Wherein R 1 is —O—R 4 or —NR 5 R 6;
R2 is hydrogen, alkyl, cycloalkyl, alkoxy, halogen, heterocyclyl or amino;
R3 is hydrogen, alkyl, amino or halogen;
R4 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl or heterocyclyl;
R5 and R6 are independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl and heterocyclyl, or R5 and R6 together with the N atom to which they are attached. A 5- to 10-membered heterocycle optionally containing a second heteroatom selected from nitrogen, oxygen or sulfur and optionally substituted with one or more substituents independently selected from alkyl and alkoxy. Form a ring;
A1 contains a nitrogen atom bonded to the quinoline ring and optionally a second heteroatom selected from oxygen, sulfur or nitrogen, optionally alkyl, alkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, amino, acetyl. A 5 to 7 membered saturated heterocycle substituted with 1 to 3 substituents independently selected from amino, cyano, tetrahydropyranyloxyalkyl and cycloalkylalkoxy;
A2 is -CH2- or -C (O)-]
And a pharmaceutically acceptable salt or ester thereof.

・ Special table 2005-523901
Structural formula:
[In the formula,
R1 and R2 are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, aryl, aralkyl, arylcarbonyl, aralkylcarbonyl, alkoxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl, heterocyclyl. Carbonyl, heterocyclylalkylcarbonyl, carbocyclyl, carbocyclylalkyl, amino, alkyl-SO2-, aryl-SO2-, heterocyclyl-SO2- or amino-SO2-, or R1 and R2 are Optionally together with the N atom to which it is attached a second heteroatom selected from nitrogen or oxygen, optionally substituted with one or more substituents independently selected from alkyl and alkoxy. Forming a 5- to 10-membered heterocycle;
R3 is hydrogen, alkyl, amino or halogen;
R4 is hydrogen, halogen, heterocyclyl, amino or alkyl;
A is a 5-7 membered saturated heterocycle containing a nitrogen atom bonded to the quinoline ring and optionally containing a second heteroatom selected from oxygen, sulfur or nitrogen, wherein ring A is an alkyl Optionally substituted with 1 to 3 substituents independently selected from alkoxy, hydroxy, amino, acetylamino, cyano, hydroxyalkyl, alkoxyalkyl, cycloalkylalkoxy and cycloalkylalkoxyalkyl]
And the pharmaceutically acceptable salts and esters thereof.

・ Special table 2005-526732
Compounds of the following structural formulas and pharmaceutically acceptable salts and esters thereof:

Wherein R1 is aryl or heteroaryl; R2 is hydrogen, alkyl or cycloalkyl; R3 is hydrogen, alkyl or cycloalkyl; R4 is hydrogen, alkyl or cycloalkyl; R5 is alkyl, cycloalkyl, aryl, heteroaryl; R6 is hydrogen, alkyl or cycloalkyl; A is -C (O)-, -S (O) 2-, -N (R6). -C (O)-or O-C (O)-; n is 2-6; m is zero-2).

・ Special table 2006-502131
Structural formula:
[In the formula,
R1 is aryl or heteroaryl, wherein at least one of the two meta positions of each aryl and heteroaryl group is substituted with R5;
R2 is hydrogen, alkyl or cycloalkyl;
R3 is cycloalkyl, aryl or heteroaryl, wherein at least one of the two ortho positions of each cycloalkyl, aryl and heteroaryl group is substituted with R6;
R4 is hydrogen, alkyl or cycloalkyl;
R5 is hydrogen, cyano, trifluoromethyl, alkyl-SO2-, amino-SO2-, halogen, alkoxy, alkylcarbonyl or aminocarbonyl;
R6 is hydrogen, halogen, cyano, nitro, trifluoromethyl, alkyl, alkoxy, hydroxy or alkoxycarbonyl;
However, one of R5 and R6 is not hydrogen], and pharmaceutically acceptable salts and esters thereof.

・ Special table 2007-501823
Structural formula:
[Wherein R 1 is amino, aryl or heteroaryl;
R2 is hydrogen or alkyl;
R3 is hydrogen, alkyl or halogen;
R4 is alkyl or halogen;
R5 is hydrogen, alkyl or halogen;
a is 0 or 1;
b is 0, 1 or 2.]
And a pharmaceutically acceptable salt or ester thereof.

More specifically, the compound represented by the above structural formula selected from the following compounds and pharmaceutically acceptable salts and esters thereof:
Thiophene-2-sulfonic acid {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -amide;
Thiophene-3-sulfonic acid {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -amide;
5-chloro-thiophene-2-sulfonic acid {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -amide;
2-Fluoro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
3-Fluoro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
4-Fluoro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
2,4-difluoro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
2-Methyl-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
2,5-Dimethyl-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
5-Fluoro-2-methyl-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
3-Methoxy-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
4-Methoxy-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
2-Methoxy-5-methyl-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
2,5-dimethoxy-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
5-chloro-2-methoxy-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -4-trifluoromethoxy-benzenesulfonamide;
N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -3-nitro-benzenesulfonamide;

2-chloro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -5-trifluoromethyl-benzenesulfonamide;
4-chloro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -4-nitro-benzenesulfonamide;
Pyrrolidine-1-sulfonic acid {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -amide;
Dimethylamine-1-sulfonic acid {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -amide;
Thiophene-2-sulfonic acid {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -amide;
5-chloro-thiophene-2-sulfonic acid {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -amide;
3-Fluoro-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
4-Fluoro-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
2-Methyl-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
2,5-Dimethyl-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
5-Fluoro-2-methyl-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
3-Methoxy-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
4-Methoxy-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
2-Methoxy-5-methyl-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
2-chloro-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -4-trifluoromethyl-benzenesulfonamide;
4-chloro-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -benzenesulfonamide;
N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -3-nitro-benzenesulfonamide;
Dimethylamine-1-sulfonic acid {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -phenyl} -amide;
5-Fluoro-2-methyl-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
2,4-difluoro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
5-chloro-thiophene-2-sulfonic acid 4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzylamide;
5-chloro-2-methoxy-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
2-chloro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -4-trifluoromethyl-benzenesulfonamide;
Thiophene-3-sulfonic acid 4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzylamide;

4-fluoro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
2-Fluoro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
3-Fluoro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
2-chloro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -5-trifluoromethyl-benzenesulfonamide;
N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -3-nitro-benzenesulfonamide;
4-chloro-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -4-nitro-benzenesulfonamide;
Dimethylamine-1-sulfonic acid 4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzylamide;
2-Methyl-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
2,5-Dimethyl-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
4-Methoxy-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
3-Methoxy-N- {4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
5-Fluoro-2-methyl-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide; 2,4-difluoro-N- {3- [ 5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
5-chloro-thiophene-2-sulfonic acid 3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzylamide;
5-chloro-2-methoxy-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
2-chloro-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -4-trifluoromethyl-benzenesulfonamide;
2,5-dimethoxy-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;

3-Methoxy-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
2-chloro-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -5-trifluoromethyl-benzenesulfonamide;
N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -3-nitro-benzenesulfonamide;
4-chloro-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -4-nitro-benzenesulfonamide;
C- (4-fluoro-phenyl) -N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -methanesulfonamide;
4-Methoxy-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
2,5-dimethyl-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
Pyrrolidine-1-sulfonic acid 3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzylamide;
Thiophene-2-sulfonic acid 3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzylamide;
Thiophene-3-sulfonic acid 3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzylamide;
2-Methyl-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide;
2-Fluoro-N- {3- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide; and 3-Fluoro-N- {3- [5- (2- Methyl-benzoyl) -thiazol-2-ylamino] -benzyl} -benzenesulfonamide.

・ Special table 2007-501824
Structural formula:

(here,
R1 is aryl, heterocyclyl, amino or alkoxy;
R2 is hydrogen, alkyl or halogen;
R3 is alkyl, halogen or trifluoromethyl;
A1 is C-R3 or nitrogen;
A2 is piperidine or pyrrolidine, wherein the nitrogen atoms of the piperidine and pyrrolidine rings are bound to A3;
A3 is -S (O) 2- or C (O)-;
n is 0, 1 or 2.)
And the pharmaceutically acceptable salts and esters thereof.

More specifically, the compounds represented by the above structural formulas selected from the following compounds and their pharmaceutically acceptable salts and esters:
(2-{[1- (thiophen-2-sulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (thiophen-3-sulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (5-chloro-thiophen-2-sulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (2-Fluoro-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (3-Fluoro-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (4-Fluorobenzenesulfonyl) -piperidin-4-ylmethyl] -amino] -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (2,4-difluoro-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (toluene-2-sulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (2,5-Dimethyl-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (5-Fluoro-2-methyl-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (3-Methoxy-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;

(2-{[1- (4-Methoxy-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
o-tolyl- (2-{[1- (4-trifluoromethoxy-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -methanone;
(2-{[1- (2-chloro-4-trifluoromethyl-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (4-chloro-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;

(2-{[1- (4-Nitro-benzenesulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2-{[1- (pyrrolidin-1-sulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
4-{[5- (2-methyl-benzoyl) -thiazol-2-ylamino] -methyl} -piperidine-1-sulfonic acid dimethylamide;
(2-{[1- (morpholine-4-sulfonyl) -piperidin-4-ylmethyl] -amino} -thiazol-5-yl) -o-tolyl-methanone;
(2- {2- [1- (thiophen-3-sulfonyl) -piperidin-2-yl] -ethylamino} -thiazol-5-yl) -o-tolyl-methanone;
(2- {2- [1- (3-Fluoro-benzenesulfonyl) -piperidin-2-yl] -ethylamino} -thiazol-5-yl) -o-tolyl-methanone;
(S) -2-{[5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -methyl} -pyrrolidine-1-carboxylic acid t-butyl ester;
(S) -2-{[5- (2-trifluoromethyl-benzoyl) -thiazol-2-ylamino] -methyl} -pyrrolidine-1-carboxylic acid t-butyl ester;
(S)-(2-Ethyl-phenyl)-(2-{[1- (thiophen-2-sulfonyl) -pyrrolidin-2-ylmethyl] -amino} -thiazol-5-yl) -methanone;

(S)-(2-{[1- (thiophen-2-sulfonyl) -pyrrolidin-2-ylmethyl] -amino} -thiazol-5-yl)-(2-trifluoromethyl-phenyl) -methanone;
(S)-(2-{[1- (naphthalene-1-sulfonyl) -pyrrolidin-2-ylmethyl] -amino} -thiazol-5-yl)-(2-trifluoromethyl-phenyl) -methanone;
4- [5- (2-ethyl-benzoyl) -thiazol-2-ylamino] -piperidine-1-carboxylic acid t-butyl ester;
4- [5- (2-methyl-benzoyl) -thiazol-2-ylamino] -piperidine-1-carboxylic acid t-butyl ester;

4- [5- (2-trifluoromethyl-benzoyl) -thiazol-2-ylamino] -piperidine-1-carboxylic acid t-butyl ester;
4- [5- (pyridin-2-carbonyl) -thiazol-2-ylamino] -piperidine-1-carboxylic acid t-butyl ester;
(2-Ethyl-phenyl)-{2- [1- (naphthalene-1-sulfonyl) -piperidin-4-ylamino] -thiazol-5-yl} -methanone;
(2-Ethyl-phenyl)-{2- [1- (thiophen-2-sulfonyl) -piperidin-4-ylamino] -thiazol-5-yl} -methanone;
(2-Ethyl-phenyl)-{2- [1- (2-methoxy-5-methyl-benzenesulfonyl) -piperidin-4-ylamino] -thiazol-5-yl} -methanone;
{2- [1- (naphthalene-1-sulfonyl) -piperidin-4-ylamino] -thiazol-5-yl} -pyridin-2-yl-methanone;

Pyridin-2-yl- {2- [1- (thiophen-2-sulfonyl) -piperidin-4-ylamino] -thiazol-5-yl} -methanone;
{2- [1- (2-Methoxy-5-methyl-benzenesulfonyl) -piperidin-4-ylamino] -thiazol-5-yl} -pyridin-2-yl-methanone;
{2- [1- (naphthalene-1-sulfonyl) -piperidin-4-ylamino] -thiazol-5-yl}-(2-trifluoromethyl-phenyl) -methanone;
{2- [1- (thiophen-2-sulfonyl) -piperidin-4-ylamino] -thiazol-5-yl}-(2-trifluoromethyl-phenyl) -methanone;
{2- [1- (2-Methoxy-5-methyl-benzenesulfonyl) -piperidin-4-ylamino] -thiazol-5-yl}-(2-trifluoromethyl-phenyl) -methanone;
{2- [1- (naphthalene-1-sulfonyl) -piperidin-4-ylamino] -thiazol-5-yl} -o-tolyl-methanone;
{2- [1- (thiophen-2-sulfonyl) -piperidin-4-ylamino] -thiazol-5-yl} -o-tolyl-methanone; and {2- [1- (2-methoxy-5-methyl- Benzenesulfonyl) -piperidin-4-ylamino] -thiazol-5-yl} -o-tolyl-methanone.

・ Special table 2010-523583
NPY receptor antagonists and modulators such as SR-120819-A, PD-160170, NGD-95-1, BIBP-3226, 1229-U-91, CGP-71683, BIBO-3304, CP-671906-01, J-115814 etc.

・ Special table 2011-509239
NPY antagonists (neuropeptide Y) such as naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino) methyl] cyclohexylmethyl} amide hydrochloride (CGP 71683A).

2) Inhibitors of NPY-YR axis that inhibit binding to Y1R subtype:
・ Special table 2007-531714
(A) (i) -X-Thr-Arg-X3-Arg-Tyr-C (= O) NR1R2 (wherein R1 and R1 are independently hydrogen or C1-C6 alkyl, and X is Val, Ile. , Leu or Ala, X3 is Gln or Asn), or Thr is replaced by His or Asn, and / or Tyr is replaced by Trp or Phe, and / or its conserved Arg is replaced by Lys. C-terminal Y-receptor recognition amino acid sequence represented by a chemical substitution variant, and (ii) H2N-X1-Pro-X2- (Glu or Asp)-(wherein X1 is absent or at any amino acid residue X2 is Leu or Ser), or a PP fold peptide or PP fold peptide mimetic having an N-terminal Y receptor recognition amino acid sequence represented by a conservative substitution of the Leu or Ser, or (b ) Comprising a C-terminal Y receptor recognition amino acid sequence as defined in (i) above, and optionally an N-terminal sequence beginning with the Y receptor recognition amino acid sequence as defined in (ii) above,
The C-terminal Y receptor recognition sequence is fused to an amphipathic amino acid sequence domain comprising at least one α-helix turn adjacent to the N-terminus of the hexapeptide sequence,
The turn is constrained in a helix shape by a covalent intramolecular linkage,
Y receptor agonists selective for Y2 and Y4 receptors over Y1 receptors

・ Special table 2007-535549
A compound represented by the following structural formula, or a pharmaceutically acceptable salt or solvate thereof:

here:
R1 is heteroaryl, N-arylaminocarbonyl, N-heteroarylaminocarbonyl, benzimidazolyl or benzothiazolyl, wherein said benzimidazolyl and benzothiazolyl are each, optionally, separately, unsubstituted or Or substituted with 1 to 5 substituents, and each substituent is independently selected from the group consisting of: halogen, alkyl, cycloalkyl, alkoxy, alkylsulfonyl, thio, alkoxyalkyl, Cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, -OR20, -CN, -NO2, -NR20R21, -C (O) R20, -C (O) OR20. , -C (O) NR20R21, -S (O) 0-2NR20R21, -CF3, -OCF3, -CF2CF3, -C (= N-OR20) R21, -N (R20) S (O) 0-2R21,-. N (R20) C (O) (R21), -N (R20) C (O) NR21R22, -C (O) N (R20) (R21), -SO2R20 and -SO2N (R20) (R21);

R20, R21 and R22 are independently alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl, where each alkyl, cycloalkyl. , Cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl and heteroaryl are unsubstituted or, if desired, substituted individually with 1 to 5 substituents. Where the substituents are the same or different and are independently selected from the group consisting of: halogen, -CF3, -CN, -COOH, -C (O) Oalkyl, -C (O) Ocyclo. Alkyl, -C (O) O-arylalkyl, -C (O) O-heteroarylalkyl, -C (O) NH2, -C (O) N (H) (alkyl), -C (O) N ( H) (arylalkyl), -C (O) N (H) (heteroarylalkyl), -C (O) N (H) (cycloalkyl), -C (O) N (H) (aryl),- C (O) N (H) (heteroaryl), -C (O) N (H) (arylalkyl), -C (O) N (H) (heteroarylalkyl), -C (O) N (alkyl ) (Alkyl), -C (O) N (alkyl) (aryl), -C (O) N (alkyl) (heteroaryl), -S-alkyl, -S-aryl, -S-arylalkyl, -S. -Heteroarylalkyl, -S (O) 2 (alkyl), -S (O) 2 (aryl), -S (O) 2 (arylalkyl), -S (O) 2 (heteroaryl), -S ( O) 2 (heteroarylalkyl), -S (O) 2 (cycloalkyl), -S (O) 2N (H) (heterocycloalkyl), -S (O) NH2, -S (O) N (alkyl ) (Alkyl), -S (O) N (H) (alkyl), -S (O) N (H) (aryl), -S (O) N (alkyl) (alkyl), -S (O) 2NH2. , -S (O) 2N (H) (alkyl), -S (O) 2N (H) (aryl), -S (O) 2N (H) (arylalkyl), -S (O) 2N (H). (Heteroarylalkyl), -S (O) 2N (H) (cycloalkyl), -S (O) 2N (alkyl) (aryl), -S (O) 2N (alkyl) (alkyl), OH, -O. (C1-C6) alkyl, -O-cycloalkyl, -O-heterocycloa Alkyl, -O-cycloalkylalkyl, -O-heterocycloalkylalkyl, -O-arylalkyl, -O-heteroarylalkyl, -O-aryl, -O-heteroaryl, -NH2, -N (H) ( Alkyl), -N (H) (aryl), -N (H) (heteroaryl), -N (H) arylalkyl, -N (H) (heteroarylalkyl), -N (alkyl) (alkyl), -N (arylalkyl) (arylalkyl), -N (heteroarylalkyl) (arylalkyl), -N (H) C (O) -alkyl, -N (H) C (O) -arylalkyl, -N (H) C (O) -heteroarylalkyl, -N (H) C (O) -heteroaryl, -N (H) C (O) -aryl, -N (H) C (O) NH2, -N. (H) C (O) N (H) (alkyl), -N (H) C (O) N (alkyl) (alkyl), -N (alkyl) C (O) N (H) (alkyl),- N (alkyl) C (O) N (alkyl) (alkyl), -N (H) S (O) 2-alkyl, -N (H) S (O) 2-arylalkyl, -N (H) S ( O) 2-heteroarylalkyl, -N (H) S (O) 2-aryl, -N (H) S (O) 2-heteroaryl, -N (H) S (O) 2N (H) (alkyl ), -N (H) S (O) 2N (alkyl) (alkyl), -N (alkyl) S (O) 2N (H) (alkyl) and -N (alkyl) S (O) 2N (alkyl) ( Alkyl);

X is -CH or N;
L is an aliphatic or heteroaliphatic linker chain, which chain is optionally linked separately with one or more selected from the group consisting of: alkyl, aryl, cycloalkyl , Spiroalkyl, heteroaryl and combinations thereof;
R15 is present or absent and, if present, is H, aryl, alkyl, arylalkyl, heterocycloalkyl or heteroarylalkyl;
R18 is H, halogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, -OR20, -CN, -NO2, -NR20R21,-. C (O) R20, -C (O) OR20, -C (O) NR20R21, -S (O) 0-2NR20R21, -CF3, -OCF3, -CF2CF3, -C (= N-OR20) R21, -N. (R20) S (O) 0-2R21, -N (R20) C (O) (R21), -N (R20) C (O) NR21R22, -C (O) N (R20) (R21), -SO2R20. Or SO2N (R20) (R21);
A is represented by the formula:

R14 is present or absent and, if present, H, aryl, alkyl, arylalkyl, carboxyl, alkylaryl, acyl, alkenyl, heteroarylalkyl, alkoxycarbonyl, heteroaryl, Cycloalkyl, alkenyl or arylcarbonyl; or R14 together with R16 or R16 ′ is heteroaryl, heterocycloalkyl, heterocycloalkenyl, heterocyclenyl, heteroarylcycloalkenyl, heteroarylalkyl, heteroarylalkenyl, Heterocycloalkenylaryl, heterocycloalkylaryl, heteroarylcycloalkyl, cycloalkylheteroaryl or heterocycloalkylheteroaryl;
R16 and R16 ′ are separately, either present or absent, identical or different, and separately selected from the group consisting of: H, aryl, alkyl, arylalkyl, heteroaryl, Carboxyl, substituted carboxyl, aroyl, heteroarylalkyl, cyclohexanyl, cycloalkyl, alkylthio, alkoxycarbonyl, cycloalkylalkyl, alkylaminocarbonyl, haloaryl, haloalkyl, phenylalkyl, alkoxy, acyl, aroyl, alkylcarboxyl, alkylcycloalkyl , Alkylamino, adamantyl, alkylthioether, biphenyl, alkanol, dialkyl isocyanate and alkylimidazole, provided that at least one of R16 and R16 ′ is present; or R16 and R16 ′ together Form a spiroalkyl group, a heterospiroalkyl group or = O;

Y is S, O, N or C, provided that (1) when Y is N, N is unsubstituted or alkyl, arylalkyl, heteroarylalkyl, alkenyl, arylcarbonyl, Substituted with an alkoxycarbonyl or a substituent selected from the group consisting of:
Or (2) when Y is N, the substituent of N is taken together with Z to form a heterocycloalkyl moiety, or (3) when Y is C, C is unsubstituted Or optionally substituted separately with one or two substituents, which are the same or different and are independently selected from the group consisting of: alkyl , Arylalkyl, heteroarylalkyl, aryl and heteroaryl;

Z is either present or absent, and if present, H, aryl, alkyl, alkoxy, arylalkyl, phenylalkyl, cycloalkyl, spiroalkyl, alkylaryl, Alkylaminocarbonyl, haloaryl, haloalkyl, (CH3) 2NC (O)-, alkylcarboxyl, acyl, heteroarylalkyl, alkoxycarbonyl, carboxyl, alkylcycloalkyl, alkylamino, alkylthioether, biphenyl, alkanol, dialkyl isocyanate, alkyl Imidazole or = O; or Z together with R16 is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclenyl, heterocycloalkyl, arylcycloalkenyl, heteroarylalkyl, heteroarylalkenyl, cycloalkenylaryl. , Arylcycloalkyl, cycloalkylaryl, heteroarylcycloalkyl or cycloalkylheteroaryl; or Z is heterocycloalkyl linked together with Y;
B is a 6-membered ring; and n is 1, 2 or 3;

Provided that when either condition (i) or condition (ii) is met, at least one of R16, R16 ', R18 and Z is present and is a substituent other than H;
Condition (i) is fulfilled when the compound of the above structural formula is:
Here, R1 is selected from the following structures:
q is 1 or 2;
p is an integer from 1 to 5; and S'is independently selected from the group consisting of: H, alkyl, halogen, methoxy, carboxyaminomethyl, alkoxycarbonyl and alkanoylaminomethyl;

Condition (ii) is fulfilled when the compound of the above structural formula is:
Where R1 is optionally substituted or unsubstituted and selected from the following structures:
m is an integer from 1 to 5; and S'is independently selected from the group consisting of: H, alkyl, halogen, methoxy, carboxyaminomethyl, alkoxy, carbonyl and alkanoylaminomethyl.

・ JP2007-77144
Structural formula:
[Wherein X is N or CR14;
R1 is H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1 To C6 alkyl-OR7, C1 to C6 cyanoalkyl, NR8R9, and C1 to C6 alkyl-NR8R9;
R2 is H,
C1-C6 alkyl, together with A or B, optionally forming a C3-C6 amino carbocycle or C2-C5 aminoheterocycle, each of which is optionally substituted with R7,
C3-C10 cycloalkyl, or (C3-C10 cycloalkyl) C1-C6 alkyl; or
R2 and R6, together with the two nitrogen atoms to which they are attached, form a C2-C5 aminoheterocycle optionally substituted with R7;

A is (CH2) m [where m is 1, 2 or 3] and at each carbon atom, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1 -C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, cyano, halogen, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7, C1-C6 cyanoalkyl, NR8R9, or optionally C1-C6 alkyl-NR8R9. Mono- or di-substituted, or
A and B together form a C3-C6 carbocycle optionally substituted at each carbon atom with R7, or
A and R2 taken together form a C3-C6 amino carbocycle optionally substituted at each carbon atom with R7;
B is (CH2) n [where n is 0, 1, 2 or 3], and at each carbon atom, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl ) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halogen, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7, C1-C6 cyanoalkyl, NR8R9, or C1-C6 alkyl-NR8R9. Optionally replaced, or
B and R2 taken together form a C3-C6 amino carbocycle optionally substituted at each carbon atom with R7, or
B and R6 taken together form a C3-C6 amino carbocycle which is optionally substituted at each carbon atom with R7;

R3 is H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1 ~ C6 alkyl-OR7, C1 to C6 cyanoalkyl, NR8R9, and C1 to C6 alkyl-NR8R9;
R4 is selected from aryl or heteroaryl, each of which in each case is C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1- C6 alkenyl, C1-C6 alkynyl, halogen, C1-C6 haloalkyl, trifluoromethylsulfonyl, OR7, C1-C6 alkyl-OR7, NR8R9, C1-C6 alkyl-NR8R9, CONR8R9, C1-C6 alkyl-CONR8R9, COOR7, C1 ~ C6 alkyl-COOR7, CN, C1-C6 alkyl-CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, and 3-, 4- or 5- (2-oxo-1,3-oxazolidinyl) independent Optionally substituted with 1 to 5 substituents selected as follows, provided that at least one of the ortho or para positions relative to the point of attachment of the aryl or heteroaryl ring to the pyrazole is substituted;

R5 and R6 are independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl;
R7 is H, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C3 haloalkyl, or heterocycloalkyl, C1-C8 alkylsulfonyl, Arylsulfonyl, heteroarylsulfonyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, each of which is halogen, C1-C6 haloalkyl, OR13, NR8R9. , C1-C6 alkyl-OR13, C1-C6 alkyl-NR8R9, CONR8R9, COOR13, CN, SO2NR8R9, SO2R13, each of which is optionally substituted with 1-5 substituents independently selected in each case, However, for SO2R13, R13 cannot be H;

R8 and R9 are in each case H, C1-C6 alkyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C3-C10 cycloalkenyl, C2-C6 alkynyl, heterocycloalkyl, C1-C8 alkanoyl, aroyl, Independently selected from heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, or R8 and R9 taken together in each case are C1-C6 alkyl, C3- C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C3 haloalkyl, or heterocycloalkyl, C1-C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-C8 alkanoyl, Aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, respectively, may form a C3-C6 amino carbocycle or C2-C5 aminoheterocycle, each optionally substituted;
R13 is in each case independently from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl. Selected, provided that R7 is SO2R13, then R13 cannot be H; and
R14 is H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, or CN, provided that R1 is If Me, R3 is Me, R4 is 2,4-Me2-Ph, R2 is H, A is CH (Me), B is (CH2) 3 and R5 and R6 are Et, then X is not N]
Or a pharmaceutically acceptable salt thereof.

The following patent documents are exemplified in Japanese Patent Publication No. 2010-509397:
(US Pat. Nos. 6,001,836, WO96 / 14307, WO01 / 23387, WO99 / 51600, WO01 / 85690, WO01 / 85098, WO01 / 85173, and WO01 / 89528). The compounds described therein are non-limiting examples of inhibitors of the NPY-YR axis that inhibit binding to the Y1R subtype; and in Tables 2010-509397, BIBP3226, J-115814, BIBO3304. , LY-357897, CP-671906, and GI-264879A; these compounds are non-limiting examples of inhibitors of the NPY-YR axis that inhibit binding to the Y1R subtype. Furthermore, the special table 2012-518637, the special table 2012-518638 and the special table 2012-525325 are mentioned. The compounds described therein are also non-limiting examples of inhibitors of the NPY-YR axis that inhibit binding to the Y1R subtype.

3) NPY-YR axis inhibitors that inhibit Y2R subtype binding:
・ Special table 2007-531713
(A) having a C-terminal Y2 receptor recognition amino acid sequence, and
Does not have a tyrosine residue corresponding to Tyr1 of NPY, and / or
Does not have a proline residue corresponding to Pro2 of NPY, and / or
Serine residue corresponding to Ser3 of NPY, asparagine residue, glutamine residue, threonine residue, leucine residue, isoleucine residue, valine residue, methionine residue, tryptophan residue , Has no tyrosine residue or phenylalanine residue,
It has neither a lysine residue nor an arginine residue corresponding to Lys4 of NPY, and / or
Has a residue other than leucine at a position corresponding to Leu24 of NPY, and / or
NPY has a residue other than arginine at the position corresponding to Arg25, and / or
NPY has a residue other than histidine at a position corresponding to His26, and / or
NPY has a residue other than isoleucine at the position corresponding to Ile28, and / or
Has a residue other than asparagine at a position corresponding to Asn29 of NPY, and / or
Have a residue other than leucine or methionine at the position corresponding to Leu30 of NPY
A PP-folding peptide or a PP-folding peptide mimetic selected from PYY, NPY, PYY mimics and NPY mimetics, or

(B) having a C-terminal Y2 receptor recognition amino acid sequence, and
Does not have proline in the position corresponding to PP Pro2, and / or
No leucine at the position corresponding to Leu3 in PP, and / or
Does not have glutamic acid at the position corresponding to Glu4 of PP
A PP folding peptide selected from PP and PP mimetics or a PP folding peptide mimetic, or (c) (i) comprising a C-terminal Y2 receptor recognition amino acid sequence fused at the N-terminus to an amphipathic amino acid sequence domain Wherein the amphipathic amino acid sequence domain comprises at least one α-helix turn flanking the N-terminus of the Y2 receptor recognition sequence, the turn constrained in a helix shape by a covalent intramolecular linkage, ii) Having one or more of the modifications listed in (a) above if it has an N-terminal structure similar to NPY or PYY, and above (b) if it has an N-terminal structure similar to PP. Have one or more of the modifications,
Y receptor agonists other than PYY3-36 that are selective for Y2 receptors over Y1 and Y4 receptors.

-Peptide YY (eg, PYY3-36), NPY13-36, [Leu31, Pro34] NPY, Ac-NPY (24-36) [Leu28, Leu31, which are analogs of NPY described in Re-Table 2006/132406. ].

-Batterham et al., Nature. 418: 650-654 (2003), as well as other Y2 agonists such as N-acetyl [Leu (28,31)] NPY24-36 (White-Smith and Potter, Neuropeptides). , 33: 526-33 (1999)), TASP-V (Malis et al., Br. J. Pharmacol., 126: 989-96 (1999)), cyclo- (28/32) -Ac- [Lys28-Glu32. ]-(25-36) -pNPY (Cabrele and Beck-Sickinger, J-Pept-Sci., 6: 97-122 (2000)). In addition, there are also the special tables 2011-500629, 2011-500632 and 2011-500633, and the compounds described therein are non-inhibitors of the NPY-YR axis which inhibit the binding with the Y2R subtype. This is a limited example.

-The NPY-2 receptor antagonists described in Table 2011-509239, for example as described in WO2007038943.

3) Inhibitor of NPY-YR axis that inhibits binding to Y4R subtype:
・ Special table 2007-529463
(A) (i) -X-Thr-Arg-X3-Arg-Tyr-C (= O) NR1R2 (wherein R1 and R1 are independently hydrogen or C1-C6 alkyl, and X is Val. , Ile, Leu or Ala, X3 is a residue other than Gln) or Thr is replaced by His or Asn, and / or Tyr is replaced by Trp or Phe, and / or Arg is replaced by Lys. C-terminal Y4 receptor recognition amino acid sequence represented by a conservative substitution variant thereof, and (ii) H2N-X1-Pro-X2- (Glu or Asp)-(wherein X1 is absent or arbitrary. An amino acid residue, X2 is Leu, Ile or Ser) or a PP fold peptide or PP fold peptide mimetic having an N-terminal Y receptor recognition amino acid sequence represented by a conservative substitution thereof, or ( b) comprising the C-terminal Y4 receptor recognition sequence defined in (i) above, and optionally the N-terminal sequence beginning with the Y4 receptor recognition amino acid sequence defined in (ii) above,
Said C-terminal Y4 receptor recognition sequence fused to an amphipathic amino acid sequence domain comprising at least one α-helix turn flanking the N-terminus of said hexapeptide sequence,
The turns are constrained in a helix shape by covalent intramolecular linkages, or (c) are covalently linked, each comprising the last four residues of the sequence defined in (i) above. Comprising two C-terminal Y4 receptor recognition amino acid sequences
Y4 receptor agonists other than PP that are selective for Y4 receptors over Y1 and Y2 receptors.

-Batterham et al., J. Appl. Clin. Endocrinol. Metab. , 88: 3989-3992 (2003), and other Y4 agonists (eg, 1229U91 (Raposinho et al., Neuroendocrinology., 71: 2-7 (2000)) with the Y4R subtype. 3 is a non-limiting example of an inhibitor of the NPY-YR axis that inhibits binding.

-The NPY-4 receptor antagonists described in Japanese Patent Publication No. 2011-509239, for example, described in WO2007038942.

4) Inhibitor of NPY-YR axis that inhibits binding to Y5R subtype:
・ Special table 2004-516267
Structural formula:
Or a prodrug thereof, or a pharmaceutically acceptable salt and / or hydrate of the compound or the prodrug, or, where applicable, geometric isomers or optical isomers or racemic mixtures thereof. ,

In the formula,
= A-B = is = C (R4) -C (R5) =, and -X = Y- is -C (R6) = N-, -N = C (R7)-, -N =. N- or -S-, or = AB- is = NC (R5) = and -X = Y- is -N = C (R7)-, -C (R6). ) = N-, -S- or -O-, or = AB- is = C (R4) -N = and -X = Y- is -C (R6) = N. -, -S- or -O-, or = AB- is = NN-, and -X = Y- is -S- or -O-, or = A-B = is = C (R4)-and -X = Y- is -S-N =, -N (R10) -N =, or = A-B = is- C (R4) = and -X = Y- is = NS-, or = NN (R10)-;

Z is
And
R1 is H or-(C1-C6) alkyl;
R2 is H,-(C1-C6) alkyl,-(C3-C7) cycloalkyl or-(C1-C6) alkyl (C3-C7) cycloalkyl;
R3 is

And

Q is -OR13, or -NR13R14;
j is 1 or 2;
k is 0, 1 or 2;
l is 0, 1 or 2;
m is 0, 1 or 2;
R4, R5, R6 and R7 can be the same or different and are H, -OH, halogen, polyhaloalkyl,-(C1-C6) alkyl,-(C3-C7) cycloalkyl,-(C1-C6) alkyl. (C3-C7) cycloalkyl, -CN, NR10R11, NR13R14, -O (C1-C6) alkyl, -O (C3-C7) cycloalkyl, -O (C1-C6) alkyl (C3-C7) cycloalkyl, Independently selected from the group consisting of -S (C1-C6) alkyl, -S (C3-C7) cycloalkyl or -S (C1-C6) alkyl (C3-C7) cycloalkyl;

R8 is 1 to 3 substituents, which may be the same or different, H, halogen, -OH, polyhaloalkyl, polyhaloalkoxy, -CN, -NO2,-(C1-C6) alkyl,-(C3 To C7) cycloalkyl,-(C1 to C6) alkyl (C3 to C7) cycloalkyl, NR10R11, NR13R14, -O (C1 to C6) alkyl, -O (C3 to C7) cycloalkyl, -O (C1 to C6). ) Independently selected from the group consisting of alkyl (C3-C7) cycloalkyl or CONR13R14;
R9 is -SO2 (C1-C6) alkyl, -SO2 (C3-C7) cycloalkyl, -SO2 (C1-C6) alkyl (C3-C7) cycloalkyl, -SO2 (C1-C6) polyhaloalkyl, -SO2. [Hydroxy (C2-C6) alkyl], -SO2 [amino (C2-C6) alkyl], -SO2 [alkoxy (C2-C6) alkyl], -SO2 [alkylamino (C2-C6) alkyl], -SO2 [ Dialkylamino (C2-C6) alkyl], -SO2 (aryl), -SO2 (heteroaryl), -SO2 [aryl (C1-C6) alkyl], -SO2NR13R14, -CO (C1-C6) alkyl, -CO ( C3-C7) cycloalkyl, -CO (C1-C6) alkyl (C3-C7) cycloalkyl, CO (C1-C6) polyhaloalkyl, -C (O) aryl, -C (O) heteroaryl, -CONR13R14- , C (S) NR13R14, aryl, heteroaryl,-(CH2) CONR13R14, -C (= NCN) alkylthio, -C (= NCN) NR13R14,-(C1-C6) alkyl,-(C3-C7) cycloalkyl. ,-(C1-C6) alkyl (C3-C7) cycloalkyl,-(C1-C6) alkylaryl,-(C1-C6) alkylheteroaryl or -COOR12;

R10 is H or alkyl;
R11 is H,-(C1-C6) alkyl,-(C3-C7) cycloalkyl,-(C1-C6) alkyl (C3-C7) cycloalkyl, aryl, heteroaryl, -SO2 (C1-C6) alkyl. , -SO2 (C3-C7) cycloalkyl, -SO2 (C1-C6) alkyl (C3-C7) cycloalkyl, -SO2 (C1-C6) polyhaloalkyl, -SO2 (aryl), -SO2 (heteroaryl), -CO (C1-C6) alkyl, -CO (C3-C7) cycloalkyl, -CO (C1-C6) alkyl (C3-C7) cycloalkyl, -C (O) aryl, -C (O) heteroaryl, -CONR13R14 or -COOR12;
R12 is (C1 to C6) alkyl, (C3 to C7) cycloalkyl, (C1 to C6) alkyl (C3 to C7) cycloalkyl,-(C1 to C6) alkylaryl,-(C1 to C6) alkylheteroaryl. , Aryl or heteroaryl;
R13 and R14 can be the same or different and are H,-(C1-C6) alkyl,-(C3-C7) cycloalkyl,-(C1-C6) alkyl (C3-C7) cycloalkyl,-(C1- C6) independently selected from alkylaryl, aryl or heteroaryl; and R15 is one or two substituents, which may be the same or different, and H,-(C1-C6) alkyl,-(C3 To C7) cycloalkyl,-(C1 to C6) alkyl (C3 to C7) cycloalkyl, aryl, heteroaryl, -CN, -CONR13R14, -COOR13, -OH, -O (C1 to C6) alkyl, -O ( C3-C7) cycloalkyl, -O (C1-C6) alkyl (C3-C7) cycloalkyl, -NR10R11, -NR13R14, or aryl, heteroaryl, hydroxy, alkoxy, -NR10R11, -NR13R14, -CONR13R14, or-. A compound independently selected from a-(C1-C6) alkyl group substituted with a COOR13 group, provided that substitution with R15 results in a chemically stable compound.

・ Special table 2005-500338
The following structural formula:

A compound represented by: or a pharmaceutically acceptable salt or solvate thereof, wherein
X is independently N or C;
Z is independently NR8 or CR3R9;
D is independently H, -OH, -alkyl or substituted alkyl, provided that when X is N, then D and X-D bonds are absent;
E is independently H, -alkyl or substituted alkyl, or D and E may be independently linked together via a-(CH2) p-bridge.
Q is independently H, -alkyl or substituted alkyl, or the carbon to which D, X, Q and Q are attached may be joined to form a 3- to 7-membered ring;

g, j, k, m and n can be the same or different and are independently selected;
g is 0-3, and when g is 0, the carbons shown to be bound by (CH2) g are no longer linked;
j and k are independently 0-3, so that the sum of j and k is 0, 1, 2 or 3; m and n are independently 0-3. , So that the sum of m and n is 1, 2, 3, 4 or 5.
p is 1 to 3;
R1 is 1-5 substituents which may be the same or different, and each R1 is independently hydrogen, hydroxyl, halogen, haloalkyl, -alkyl, substituted alkyl, -cycloalkyl, CN, alkoxy, cyclo. Alkoxy, alkylthio, cycloalkylthio, -NR5R6, -NO2, -CONR5R6, -NR5COR6, -NR5CONR5R6 (where the two R5 moieties can be the same or different), -NR6C (O) OR7, -C. (O) OR6, -SOR7, -SO2R7, -SO2NR5R6, selected from the group consisting of aryl and heteroaryl;
R2 is 1-6 substituents which may be the same or different, and each R2 is independently selected from the group consisting of hydrogen, -alkyl, substituted alkyl, alkoxy, and hydroxyl group, provided that X is When N and R2 is a hydroxyl group or an alkoxy, R2 is not directly bonded to the carbon adjacent to X;

R3 is independently hydrogen, -alkyl or substituted alkyl;
R4 is 1-6 substituents which may be the same or different, and each R4 is independently selected from hydrogen, -alkyl, substituted alkyl, alkoxy, and hydroxyl, provided that Z is NR8. Where, and R4 is a hydroxyl group or an alkoxy, R4 is not directly bonded to the carbon adjacent to NR8;
R5 and R6 are independently hydrogen, -alkyl, substituted alkyl or -cycloalkyl;
R7 is independently -alkyl, substituted alkyl or -cycloalkyl;
R8 is independently hydrogen, -alkyl, substituted alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroalkyl, -SO2R10, -SO2NR5R11, -C (O) R11, -C ( O) NR5R11 and —C (O) OR10;
R9 is independently hydrogen, -alkyl, substituted alkyl, hydroxyl, alkoxy, -NR5R11, aryl, or heteroaryl; or R3 and R9 are linked together and to the carbon to which they are attached. May form a carbocyclic or heterocyclic ring having from 3 to 7 ring atoms;
R10 is -alkyl, substituted alkyl, -cycloalkyl, -alkylcycloalkyl, aryl or heteroaryl;
And R11 is independently hydrogen, -alkyl, substituted alkyl, -cycloalkyl, aryl or heteroaryl.
A compound or a pharmaceutically acceptable salt or solvate thereof.

・ Special table 2005-532392
Structural formula:
A compound represented by: or a pharmaceutically acceptable salt or solvate thereof, wherein
m is a number from 1 to 3;
n is a number from 1 to 3;
m and n can be the same or different;

R1 is 0-5 substituents which may be the same or different and each is independently -OH, halogen, alkyl, haloalkyl, cycloalkyl, -CN, alkoxy, cycloalkoxy, alkylthio-. , Cycloalkylthio-, -NR5R6, -NO2, -C (O) NR5R6, -NR5C (O) R6, -NR5C (O) NR5R6 (wherein the two R5 moieties can be the same or different). , -NC (O) OR7, -C (O) OR5, -SOR5, -SO2R5, -SO2NR5R6, aryl or heteroaryl;
R2 is 0-2 substituents which may be the same or different and each is independently -OH, halogen, alkyl, haloalkyl, cycloalkyl, -CN, alkoxy, cycloalkoxy, alkylthio-. , Cycloalkylthio-, -NR5R6, -NO2, -C (O) NR5R6, -NR5C (O) R6, -NR5C (O) NR5R6 (wherein the two R5 moieties can be the same or different). , -NC (O) OR7, -C (O) OR5, -SOR5, -SO2R5, -SO2NR5R6, aryl or heteroaryl;

R3 is hydrogen or alkyl;
R4 is 0-6 substituents which may be the same or different and each is independently alkyl, alkoxy, heteroaryl, aralkyl-, heteroaralkyl-, haloalkyl or -OH;
R5 and R6 can be the same or different and each is independently hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl or cycloalkyl;
R7 is alkyl or cycloalkyl;
Z is NR8 or CR3R9;
R8 is hydrogen, alkyl, cycloalkyl, alkyl substituted with a cycloalkyl group, aryl, heteroaryl, aralkyl-, heteroaralkyl-, -SO2R10, -SO2NR5R11, -C (O) R11, -C (O) NR5R11. Or -C (O) OR10,
R9 is hydrogen, alkyl, -OH, alkoxy, -NR5R11, aryl, or heteroaryl; or R3 and R9 are joined together to form a 3-7 membered ring with the carbon to which they are attached. Possible;
R10 is alkyl, cycloalkyl, aryl or heteroaryl; and R11 is hydrogen, alkyl, cycloalkyl, aryl, or heteroaryl.
A compound or a pharmaceutically acceptable salt or solvate thereof.

・ Special table 2006-511529
Structural formula:
[Wherein, R1 is a hydrogen atom or (C1-C4) alkyl, and R2 is a hydrogen atom or C (O) R2a, -C (O)-(CH2) n-R2b or (CH2) m-R2c. Where n is 0, 1 or 2, m is 0, 1, 2 or 3, R2a is (C1-C4) alkyl or halo-substituted (C1-C4) alkyl, and R2b and R2C are -NH (C1 -C4) alkyl, -N ((C1-C4) alkyl) 2, pyridinyl, hydroxy (C1-C4) alkyl, phenyl or piperidinyl; R3 is (C1-C6) alkyl; and
X is carbonyl or methylene. ]
A pharmaceutically acceptable salt thereof, a prodrug of the compound or the salt, or a solvate or hydrate of the compound, the salt or the prodrug.

・ Special table 2006-511530
Structural formula:
[In the formula,
R1 is hydrogen or (C1-C4) alkyl;
R2 is hydrogen, (C1-C4) alkyl, aryl, or a 5-6 membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen or sulfur; and
R3 is hydrogen, (C1-C4) alkyl, or halo-substituted (C1-C4) alkyl;
Or R2 and R3 are taken together and are optionally substituted an aromatic 6-membered heterocycle, wherein said heterocycle has 1 to 2 ring nitrogen atoms, or an optionally substituted Form an aromatic 6-membered carbocycle]
A compound, a pharmaceutically acceptable salt thereof, a prodrug of the compound or salt, or a solvate or hydrate of the compound, salt or prodrug.

・ Special table 2007-506728
The NPY Y5 antagonist has the formula:

A compound represented by, or

Structural formula
[In the formula,
A is oxygen or hydrogen;
W, X, Y and Z are independently N or CR1 (wherein R1 is in each case hydrogen, halogen, hydroxy, nitro, cyano, amino, (C1-C6) alkyl, (C1-C6) alkoxy. , (C1-C6) alkoxy substituted with amino, mono- or di (C1-C6) alkylamino or (C1-C6) alkoxy, (C3-C7) cycloalkyl, (C3-C7) Cycloalkyl (C1-C4) alkyl, (C2-C6) alkenyl, (C3-C7) cycloalkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkynyl, halo (C1-C6) alkyl, halo (C1). -C6) alkoxy, mono- and di (C1-C6) alkylamino, amino (C1-C6) alkyl and mono- and di- (C1-C6) alkylamino (C1-C6) alkyl independently selected) Is]
Or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or

The following formula:
Or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

・ Special table 2007-506731
Structural formula:
Or a pharmaceutically acceptable salt, solvate or prodrug thereof or any of the foregoing;
In the formula, X is selected from the group consisting of chlorine, bromine, fluorine, iodine, trifluoromethyl, hydrogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C5 or C6 cycloalkyl, ester, amide, aryl and heteroaryl. To be done.

・ Special table 2008-514616
Structural formula:
[In the formula,
Ar1 is
Selected from the group consisting of (1) aryl and (2) heteroaryl, wherein the aryl and heteroaryl groups are unsubstituted or, if desired,
(A) halogen, (b) nitro, (c) lower alkyl, (d) halo (lower) alkyl, (e) hydroxy (lower) alkyl, (f) cyclo (lower) alkyl, (g) lower alkenyl, ( h) lower alkoxy, (i) halo (lower) alkoxy, (j) lower alkylthio, (k) carboxyl, (1) lower alkanoyl, (m) lower alkoxycarbonyl, (n) optionally substituted with oxo Optionally lower alkylene, and optionally substituted with a substituent selected from the group consisting of (o) -Q-Ar2;
Ar2 is selected from the group consisting of (1) aryl, and (2) heteroaryl, where the aryl and heteroaryl groups are unsubstituted or, if desired,
, (A) halogen, (b) cyano, (c) lower alkyl, (d) halo (lower) alkyl, (e) hydroxy (lower) alkyl, (f) hydroxy, (g) lower alkoxy, (h) halo. It may be substituted with a substituent selected from the group consisting of (lower) alkoxy, (i) lower alkylamino, (j) di-lower alkylamino, (k) lower alkanoyl, and (l) aryl;

n is 0 or 1;
Q is selected from the group consisting of a single bond or carbonyl;
T, U, V and W are each independently
Selected from the group consisting of (1) nitrogen and (2) methine, where the methine group is unsubstituted or, if desired,
, (A) halogen, (b) lower alkyl, (c) hydroxy, and (d) lower alkoxy, may be substituted with a substituent selected from the group consisting of:
Wherein at least two of T, U, V and W are methines;
X is
(1) nitrogen, and (2) selected from the group consisting of methine;
Y is
It is selected from the group consisting of (1) imino which may be unsubstituted or optionally substituted with lower alkyl, and (2) oxygen. ]
And a pharmaceutically acceptable salt and ester of the compound,

Specifically, (1) 3-oxo-N- (5-phenyl-2-pyrazinyl) -spiro [isobenzofuran-1 (3H), 4′-piperidine] -1′-carboxamide,
(2) 3-oxo-N- (7-trifluoromethylpyrido [3,2-b] pyridin-2-yl) spiro- [isobenzofuran-1 (3H), 4'-piperidine] -1'- Carboxamide,
(3) N- [5- (3-fluorophenyl) -2-pyrimidinyl] -3-oxospiro- [isobenzofuran-1 (3H), 4′-piperidine] -1′-carboxamide,
(4) trans-3′-oxo-N- (5-phenyl-2-pyrimidinyl) spiro [cyclohexane-1,1 ′ (3′H) -isobenzofuran] -4-carboxamide,
(5) trans-3′-oxo-N- [1- (3-quinolyl) -4-imidazolyl] spiro [cyclohexane-1 ′, 3′H) -isobenzofuran] -4-carboxamide,
(8) trans-3-oxo-N- (5-phenyl-2-pyrazinyl) spiro [4-azaisobenzofuran-1 (3H), l'-cyclohexane] -4'-carboxamide,

(8) trans-N- [5- (3-fluorophenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide,
(9) trans-N- [5- (2-fluorophenyl) -2-pyrimidinyl] -3-oxospiro [5-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide,
(10) trans-N- [1- (3,5-difluorophenyl) -4-imidazolyl] -3-oxospiro [7-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide,
(11) trans-3-oxo-N- (1-phenyl-4-pyrazolyl) spiro [4-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide,
(12) trans-N- [1- (2-fluorophenyl) -3-pyrazolyl] -3-oxospiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide,
(13) trans-3-oxo-N- (l-phenyl-3-pyrazolyl) spiro [6-azaisobenzofuran-1 (3H), 1'-cyclohexane] -4'-carboxamide, and (14) trans- A group consisting of 3-oxo-N- (2-phenyl-1,2,3-triazol-4-yl) spiro [6-azaisobenzofuran-1 (3H), 1′-cyclohexane] -4′-carboxamide. NPY5 antagonists selected from and pharmaceutically acceptable salts and esters of said NPY5 antagonists,

・ Special table 2010-517966
Structural formula:
[In the formula:
R is one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, aryl or heteroaryl optionally substituted by cyano;
W is -CZ1 or nitrogen;
Z1 is hydrogen, C1-C4 alkyl;
A is one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, 5-membered heteroaryl optionally substituted by cyano, pyrazine, pyrimidine or quinoline or quinazoline. And
B is hydrogen or one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, 5-10 membered aryl or heteroaryl optionally substituted by cyano. A and B may be linked via any atom;
Provided that when W is -CZ1, the compound of the above structural formula has trans stereochemistry.
Or a pharmaceutically acceptable salt or solvate thereof.

・ Special table 2010-517967
Structural formula:
[In the formula,
R is aryl or heteroaryl (which may be substituted by one or more halogen, C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 haloalkyl, C1 -C4 haloalkoxy, cyano) Good);
Z1 is H, C1-C4 alkyl or F;
Z is CH2, CH (C1-C4 alkyl), C (C1-C4 alkyl) 2 or a bond;
A is 5-membered heteroaryl (which may be substituted by one or more halogen, C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 haloalkyl, C1 -C4 haloalkoxy, cyano) Good);
B is hydrogen or is 5-6 membered heteroaryl or phenyl, which is one or more of halogen, C1 -C4 alkyl, C1 -C4 alkoxy, C1 -C4 haloalkyl, C1 -C4. Haloalkoxy, optionally substituted by cyano); A and B are attached via any atom]
Or a pharmaceutically acceptable salt or solvate thereof.

-Table 2010-509397 exemplifies the following documents:
US6,140,354, US6,191,160, US6,258,837, US6,313,298, US6,337,332, US6,329,395, US6,340,683, US6,326,375, US6. 335, 345, EP-01010691, EP-01044970, WO97 / 19682, WO97 / 20820, WO97 / 20821, WO97 / 20822, WO97 / 20823, WO98 / 27063, WO00 / 64880, WO00 / 68197, WO00 / 9849, WO01 /. 09120, WO01 / 85714, WO01 / 85730, WO01 / 07409, WO01 / 02379, WO01 / 02379, WO01 / 23388, WO01 / 23389, WO01 / 44201, WO01 / 62737, WO01 / 62738, WO01 / 09120, WO02 / 22592, WO0248152, WO02 / 49648, WO01 / 14376, WO04 / 110375, WO05 / 000217, and Norman et al., J. Am. Med. Chem. , 43: 4288-4312 (2000); the compounds described therein are non-limiting examples of inhibitors of the NPY-YR axis that inhibit binding to the Y5R subtype; and Table 2010- 509397 includes 152,804, GW-569180A, GW-594884A, GW-587081X, GW-548118X; FR226928, FR240662, FR252384; 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A. SR-120819A, as well as JCF-104 have been described; these compounds are non-limiting examples of inhibitors of the NPY-YR axis that inhibit binding to the Y5R subtype. Furthermore, re-table 2006/001318, WO2007 / 125952, WO2008 / 026563, WO2008 / 026564, WO2009 / 054434, WO2010 / 101246, WO2010 / 101247, JP2010-270114, JP2011-231050, JP2011-88833, JP 2012-167027 is mentioned. The compounds described therein are also non-limiting examples of inhibitors of the NPY-YR axis that inhibit binding to the Y5R subtype.

-L-152804 described in Japanese Patent Publication No. 2011-509239, or the NPY-5 receptor antagonist described in, for example, WO2006001318.

Preferred compounds include, for example:
-Inhibitors of the NPY-YR axis that inhibit binding to the Y1R subtype:
BIBP3226, BIBO3304, 1229U91, NGD95-1, CGP71683A, J-104870, and G1264879A, and


A compound represented by:

-Inhibitors of NPY-YR axis that inhibit binding with Y2R subtype:
BIIE0246,
-Inhibitors of NPY-YR axis that inhibit binding with Y2R subtype:
L-152.804 (CGP71683A), S-2367 (velneperit), and

These specific inhibitors are antagonists of neuropeptide Y, Goro Katsuura et al., “Obesity Research” vol8 No.1 84-85, 2002; Anti-obesity action of novel neuropeptide Y Y5 receptor antagonist S-2367, Yukioka Hijio, N. Pharmacol. 136.270-274, 2010.

In the present invention, the "antibody against NPY or a functional fragment or derivative thereof" as an inhibitor of the NPY-YR axis means an anti-NPY antibody-related substance that inhibits the NPY-YR axis.
In one aspect of the present invention, the antibody is preferably a human antibody in the sense that it is ultimately intended as a therapeutic drug. A method of making a human antibody involves administering the NPY antigen to a transgenic non-human animal that has been genetically modified to produce human antibodies rather than endogenous antibodies. Typically, the animal has been modified to inactivate endogenous heavy and / or kappa light chains in the genome so that these endogenous loci are immunized in response to antigens. The rearrangement necessary to produce the gene encoding the globulin is not possible. In addition, the animal stably has at least one human heavy chain locus and at least one human light chain locus in its genome and is responsive to the antigen administered thereby to this antigen. Human loci can be rearranged to provide genes encoding immunospecific human variable regions. A detailed description for constructing animals useful in this method is given, for example, in WO 94/02602.

  The immunoglobulin chain (s) and / or functional fragments and derivatives thereof corresponding to the antibodies of the invention may be prepared according to conventional techniques known in the art, eg deletion of amino acid (s), (1 or Insertion (s), substitution (s), addition (s) and / or recombination (s) and / or any other modification (s) known in the art. Can be used alone or in combination to be further modified and produced. Methods for introducing such modifications into the DNA sequence underlying the amino acid sequence of the immunoglobulin chain are well known to those of skill in the art. See, for example, Sambrook, Molecular Cloning A Laboratory Manual, Cold Spring Harbor Laboratory (1989) N.M. Y. checking ...

  By analogs of YR is meant structural analogs of YR that inhibit the binding of NPY to the six NPY receptors (YR), Y1R, Y2R, Y3R, Y4R, Y5R and Y6R subtypes. An analogue of YR means, for the purposes of the present invention, a functionally equivalent part, mutant or variant of YR, in particular the extracellular part of YR. The YR analogs according to the present invention also include fusion proteins containing YR or its analogs and other proteins or portions of proteins, preferably fusion proteins containing the Fc portion of an antibody (YR / Fc fusion protein). ..

In the present invention, the “antibody against YR or a functional fragment or derivative thereof” as an inhibitor of the NPY-YR axis means an anti-YR antibody-related substance that inhibits the NPY-YR axis.
In one aspect of the present invention, the antibody is preferably a human antibody in the sense that it is ultimately intended as a therapeutic drug. A method of making human antibodies comprises administering a YR antigen, particularly an extracellular region antigen, to a transgenic non-human animal genetically modified to produce human antibodies rather than endogenous antibodies. Including. Typically, the animal has been modified to inactivate endogenous heavy and / or kappa light chains in the genome so that these endogenous loci are immunized in response to antigens. The rearrangement necessary to produce the gene encoding the globulin is not possible. In addition, the animal stably has at least one human heavy chain locus and at least one human light chain locus in its genome and is responsive to the antigen administered thereby to this antigen. Human loci can be rearranged to provide genes encoding immunospecific human variable regions. A detailed description for constructing animals useful in this method is given, for example, in WO 94/02602.

  The immunoglobulin chain (s) and / or functional fragments and derivatives thereof corresponding to the antibodies of the invention may be prepared according to conventional techniques known in the art, eg deletion of amino acid (s), (1 or Insertion (s), substitution (s), addition (s) and / or recombination (s) and / or any other modification (s) known in the art. Can be used alone or in combination to be further modified and produced. Methods for introducing such modifications into the DNA sequence underlying the amino acid sequence of the immunoglobulin chain are well known to those of skill in the art. See, for example, Sambrook, Molecular Cloning A Laboratory Manual, Cold Spring Harbor Laboratory (1989) N.M. Y. checking ...

  The term “influenza virus infection” refers to the presence of an influenza (eg, influenza A or B virus) virus in a cell or subject, or a pathological condition resulting from invasion of a cell or subject by an influenza virus. In a specific embodiment, the term refers to respiratory illness caused by influenza virus. The term "infection" means the entry, multiplication and / or presence of a virus in a cell or subject. In one embodiment, the infection is an “active” infection, ie the virus is replicating in a cell or subject. Such infections are characterized by the spread of the virus from cells, tissues and / or organs that are initially infected by the virus to other cells, tissues and / or organs. The infection may be a latent infection, ie the virus is not replicating. In certain embodiments, infection refers to a pathological condition that results from the presence of a virus in a cell or subject, or by the invasion of a cell or subject by the virus.

In a preferred embodiment, the invention relates to a pharmaceutical composition wherein the influenza virus infection is a severe influenza virus infection. In the present invention, “severe” means, for example, the severity of influenza classified in “Adult Novel Influenza Treatment Guidelines (March 31, 2014)” issued by the Ministry of Health, Labor and Welfare. In other words, “severe” patients are those who need hospitalization management. Specifically, it is judged that patients who are seriously and at risk of life and those who are not at risk of life are hospitalized. Means a patient. More specifically, it means the following groups A-1 and A-2.

  “Treatment” as used herein refers to (1) delaying or preventing the onset of a disease or condition (eg, influenza virus infection); (2) slowing the progression, exacerbation, or worsening of symptoms of the disease or condition, or By (3) bringing about the amelioration of the symptoms of the disease or condition; or (4) by a method or process intended to cure the disease or condition. The treatment may be given before the onset of the disease or condition as a prophylactic measure, or alternatively the treatment may be given after the onset of the disease.

  A "pharmaceutical composition" as used herein comprises an effective amount of at least one NPY-YR axis inhibitor and at least one pharmaceutically acceptable carrier or excipient. The term “effective amount” as used herein refers to a compound or composition that is sufficient to meet its intended purpose, eg, a desired biological or pharmacological response in a cell, tissue, system, or subject. Means any amount. For example, in certain embodiments of the invention, the purpose is to have anti-influenza virus activity, prevent influenza virus infection, prevent the onset of influenza virus-related disease, progress of symptoms of influenza virus-related disease, It means to slow, reduce or stop the progression or worsening, to bring about the amelioration of the symptoms of the disease and / or to cure the influenza virus related disease.

  "Pharmaceutically acceptable carrier or excipient" refers to a carrier medium that does not interfere with the effectiveness of the biological activity of the active ingredient and is not overly toxic to the host at the concentrations it is administered. .. The term includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and adsorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art.

  Generally, the NPY-YR axis inhibitors or compositions of the invention are administered in an effective amount, ie, an amount sufficient to meet the intended purpose. The exact amount of NPY-YR axis inhibitor or pharmaceutical composition administered will depend on the age, sex, weight and general health of the subjects being treated, the desired biological or medical response among the subjects. (Eg, prevention of influenza virus infection or treatment of influenza virus-related brain disease).

  The NPY-YR axis inhibitors and compositions of the invention may be used in a variety of therapeutic or prophylactic methods. In particular, the invention provides a method for treating or preventing an influenza virus-related disease or condition in a subject, which provides the subject with an effective amount of a nucleolar morphology of the biological cells of the invention. Administering an inhibitor of the NPY-YR axis of the present invention or a composition thereof, which inhibits influenza virus from entering or infecting cells of a subject, thereby ameliorating a brain disease or condition in the subject, It may result in prevention or treatment.

  The present invention, in certain aspects, administers the NPY-YR axis inhibitor or composition of the present invention alone. In another aspect, the NPY-YR axis inhibitors or compositions of the invention are administered in combination with at least one additional therapeutic drug. The NPY-YR axis inhibitor or composition of the present invention can be administered before administration of the therapeutic drug, at the same time as the therapeutic drug, and / or after administration of the therapeutic drug.

  Therapeutic drugs that may be administered in combination with the NPY-YR axis inhibitors or compositions of the invention may have beneficial effects in treating, managing or preventing influenza virus infections, or influenza virus related diseases or conditions. It may be selected from among a wide variety of biologically active compounds known in the art. Such drugs include, among others, antiviral and anti-inflammatory drugs. Antiviral drugs include interferon (eg, interferon alpha, pegylated interferon alpha), anti-influenza virus (monoclonal or polyclonal) antibody, RNA polymerase inhibitor, protease inhibitor, IRES inhibitor, helicase inhibitor, antisense compound, ribozyme. , And any combination thereof. Anti-inflammatory agents include steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents such as COX2 inhibitors, specifically celecocib, IL-6 antibodies, specifically tocilizumab, TNF antibodies, specifically infliximab, and Including any combination thereof.

  The NPY-YR axis inhibitors of the invention are optionally formulated with one or more suitable pharmaceutically acceptable carriers or excipients and administered to a subject in need thereof at a desired dose. It can be administered by any suitable route. Various delivery systems are known and can be used to administer the NPY-YR axis inhibitors of the present invention, such as tablets, capsules, injections, encapsulation agents in liposomes, powders, Including microcapsules and the like. Methods of administration include transdermal, intradermal, intramuscular, intraperitoneal, intralesional, intravenous, subcutaneous, intranasal, pulmonary, epidural, intraocular and oral routes. Administration can be systemic or local.

  Administration of the NPY-YR axis inhibitors or compositions of the invention can be such that the amount delivered is effective for the purpose intended. The route of administration, formulation, and dosage will depend on the desired therapeutic effect, the severity of the influenza virus infection or influenza virus-related condition being treated (if it already exists), the presence of any other infection, the age, sex of the patient. , Weight, and overall health status and potency of NPY-YR axis inhibitors or compositions used, bioavailability and in vivo half-life, use (or unused) of combination therapies and other clinical factors. Can depend. These factors can be readily determined by the attending physician during the course of treatment. As studies are conducted using the NPY-YR axis inhibitors of the present invention, further information will be obtained regarding appropriate dose levels and treatment times.

  The treatment of the present invention may consist of a single dose or multiple doses. Thus, administration of the NPY-YR axis inhibitors of the invention, or compositions thereof, may be constant or periodic over a specified period and at specified intervals, such as once every few hours, once daily, or weekly. It may be once a month (eg time-release form). Alternatively, the delivery may be continuous delivery over a period of time, eg intravenous delivery.

  Generally, the amount of NPY-YR axis inhibitor administered is preferably about 1 ng / kg to about 100 mg / kg of the subject's body weight, eg, about 100 ng / kg to about 50 mg / kg of the subject's body weight; or It can range from about 1 μg / kg to about 10 mg / kg of the subject's body weight.

<Screening method>
As another aspect, the present invention provides a method for screening a substance for preventing and / or treating influenza virus infection, which method uses an inhibitory function for the NPY-YR axis as an index.
Specifically, the present invention provides a method of screening a substance for preventing and / or treating influenza virus infection, which comprises the following steps:
(A) preparing a system of NPY-YR axes containing biological cells expressing NPY and YR,
(B) contacting the system with a candidate compound of a substance for preventing and / or treating influenza virus infection,
(C) Whether the candidate compound exerts an inhibitory function in the NPY-YR axis system,
(D) A method of identifying the candidate compound as a substance for preventing and / or treating an influenza virus infection if the candidate compound exhibits an inhibitory function. Hereinafter, it will be described more specifically.

  The term “preventing and / or treating influenza virus infection” in the present invention is the same as above, to reduce, inhibit, block or prevent influenza virus replication, cell entry and / or cell influenza virus infection, results It means any effect that effectively suppresses or inhibits the life cycle of influenza virus and eliminates or reduces viral activity.

  The term “candidate compound” in the present invention refers to any natural or unnatural molecule, eg a biological macromolecule such as a nucleic acid, a polypeptide or a protein, an organic or inorganic molecule, or an organism to test for an activity of interest. It means a biological material such as an extract prepared from cells or tissues of bacteria, fungi, plants or animals (including mammals, especially humans). In the screening method of the present invention, candidate compounds are evaluated for their ability to have a predetermined anti-influenza virus activity. The libraries include, but are not limited to, natural and unnatural compound libraries, medicinal plant extracts, peptides, antibodies, nucleic acid libraries, etc. possessed by universities, companies and the like.

  The “biological cells” in the “NPY-YR axis system containing biological cells expressing NPY and YR” used in the screening method of the present invention refers to a cell population of substantially the same species, and preferably At least about 80%, and more preferably at least about 100% of the cells in the population are of the same cell type. Examples of cell types include, but are not limited to, platelets, lymphocytes, T cells, B cells, natural killer cells, endothelial cells, tumor cells, epithelial cells, granulocytes, monocytes, mast cells, nerve cells and the like. Preferably, human lung epithelial-derived A549 cells and canine renal tubular-derived MDCK cells, cultured cell lines and primary cultured cells derived from eukaryotes including mammals, and cells established from mosquitoes such as C6 / 36 cells. Is mentioned. "Biological cells" are preferably virus sensitive cells, more preferably phagocytic cells. Without being bound by any particular theory, it is important in the present invention that NPY derived from phagocytic cells including alveolar and interstitial macrophages and monocytes is important, not NPY derived from nerves.

  The “virus-sensitive cell” refers to any cell that has a receptor for the virus and can be infected with the virus, and includes, for example, brain cells, primary cells, dendritic cells, placental cells, endometrial cells, lymph node cells. , Lymphoid cells (B and T cells), peripheral blood mononuclear cells, skin cells, Langerhans cells, monocytes / macrophages and the like, but are not limited thereto.

  The cells used in the screening methods of the present invention may be prepared by techniques well known in the art, for example, the cells may be obtained by blood collection from a patient or healthy subject or by biopsy, or by immune and microbial suppliers such as May be purchased from American Type Culture Collection, Manassas, VA.

  The cells used in the present invention can be cultured according to standard cell culture techniques. For example, cells are grown in a suitable environment in an incubator containing a humidified 95% air-5% CO2 atmosphere in a sterile environment at 37 ° C. The vessel may contain agitated or stationary medium. A variety of cell culture media may be used, including media containing undefined biological fluids (eg, fetal calf serum) as well as fully defined media such as 293 SFM serum-free media (Invitrogen Corp., Carlsbad, CA). )including. Cell culture techniques are well known in the art and established protocols are available for culturing a variety of cell types (eg RI Freshney, "Culture of Animal Cells: A Manual of Basic Technique", 2nd Edition, 1987, Alan R. Liss, Inc.).

  The “line of NPY-YR axis containing biological cells expressing NPY and YR” used in the screening method of the present invention means a cell line in which the NPY-YR axis is functionally exerted.

  In a particular embodiment, the screening methods of the invention are carried out using cells contained in multiple wells of a multi-well assay plate. Such assay plates are commercially available, for example from Strategene Corp. (La Jolla, CA) and Corning Inc. (Acton, MA) and include, for example, 48-well, 96-well, 384-well, and 1536-well plates. ..

  The term “contact” means, for example, adding a candidate compound of an inhibitor of the NPY-YR axis adjusted to a predetermined concentration to cells contained in a plurality of wells of a multi-well assay plate. Then, the candidate compound is examined for a predetermined “anti-influenza virus activity”.

  Those skilled in the art can easily determine whether or not the candidate compound exerts an inhibitory function in the NPY-YR axis system. Specifically, using a GPCR ligand-binding assay system (Fluorescent G protein-coupled receptors (GPCRs) | Volume 8 No. 4), for example, a candidate compound binds to NPY and YR by a fluorescent labeled ligand for GPCR assay. It can be evaluated whether or not it has a function of competitively inhibiting.

  Screening the library according to the methods of the invention provides compounds with the desired, but not optimized, biological activity, commonly referred to as "hit" or "lead" compounds. The next step in developing useful drug candidates typically involves analysis of the relationship between the chemical structure of the hit compound and its biological or pharmacological activity. Molecular structure and biological activity can be correlated by observing the results of global structural modifications for a given biological index. The structure-activity relationship information available from the initial screen can then be used to generate a small compound library, which is then screened for compounds with higher affinity. The process of performing synthetic modifications of biologically active compounds to meet the stereoelectronic, physicochemical, pharmacokinetic and toxicological factors required for clinical utility is lead optimized. Candidate compounds identified by the screening method of the present invention are also applicable early in lead optimization. Drug candidates that have been chemically modified and improved by lead optimization can be included in the present invention in an appropriate range. A suitable range is a range that can be understood by those skilled in the art as a drug candidate compound that influences the morphology of the nucleolus of a biological cell according to the present invention has a certain range of chemical structures and exhibits similar activity.

  The screening method described herein can be a kit. For example, the biological cells disclosed herein can be packaged in various containers such as vials, tubes, microtiter well plates, bottles, etc., and other reagents can be included in separate containers to form a kit. Here, a positive control sample or compound, a negative control sample or compound, a buffer solution, a cell culture solution, a specific detection probe, and the like can be included in the kit as a whole.

<Biomarker related>
Another aspect of the present invention is a method for determining future severity of influenza virus infection,
(A1) a step of measuring the amount of NPY in the blood of the subject (test biomarker amount),
(B1) a step of comparing the amount of the test biomarker with the amount of NPY in the blood of a non-virus-infected sample (control biomarker amount), and (c1) the amount of the test biomarker is more than the control biomarker amount In the case of abundance, a method of determining that a subject is aggravated by an influenza virus infection is provided; a control biomarker amount means below a detection limit.
In this regard, in yet another aspect, the present invention provides a biomarker that is NPY in blood, which can determine future severity of influenza virus infection. Furthermore, the present invention provides the use of blood NPY as a bimarker with which future severity of influenza virus infection can be determined.

  The present inventors have found that NPY, which should originally be present in nerves, is below the detection limit in healthy people, but is circulated in the blood in influenza virus infection patients, particularly in severe influenza virus infection patients, For the first time, it was found that it was associated with influenza virus infections, especially severe influenza virus infections, and the use of the determination method, biomarker and blood NPY of the present invention was completed. If the severity of the subject can be determined in advance by using the determination method, biomarker, and blood NPY of the present invention, it becomes possible to predict in advance which patients will have severe influenza, thus preventing severe influenza virus infection. Extremely beneficial to By using the biomarker-related embodiment of the present invention, a subject whose blood NPY is elevated can be found. Therefore, by treating such a subject in advance, the severity of influenza in the subject can be improved. Can be suppressed.

  NPY is a fat cell of an obese patient (Singer, K. et al. Neuropeptide Y is produced by adipose tissue macrophages and regulates obesity-induced inflammation. PloS one 8, e57929, doi: 10.1371 / journal.pone.0057929 (2013)), Airway of asthmatic mice (Lu, Y. & Ho, RC An association between neuropeptide Y levels and leukocyte subsets in stress-exacerbated asthmatic mice. Neuropeptides 57, 53-58, doi: 10.1016 / j.npep. 2015.11.091 (2016) ) Has been reported to increase production. Influenza virus-infected patients with obesity and asthma have been reported to be susceptible to severe influenza (Clark, NM & Lynch, JP, 3rd. Influenza: epidemiology, clinical features, therapy, and prevention. Semin Respir Crit Care Med 32, 373-392, doi: 10.1055 / s-0031-1283278 (2011)). It is considered that this is involved in activation of the NPY-Y receptor axis, and it is considered that activation of the NPY-Y receptor axis may be used as a predictor of influenza severity and a biomarker.

  In particular, it is said that the elderly and cancer patients tend to have severe influenza, but no biomarker for the seriousness of influenza has been found so far. According to the present invention, it was found that NPY in blood is useful as a biomarker for the severity of influenza in the elderly.

  The amount of NPY in blood can be usually measured by an immunological method. For example, it can be measured by an ELISA method well known to those skilled in the art.

<Vaccine 1>
In another aspect, the present invention provides a host factor-targeted vaccine for the prevention and / or treatment of influenza virus infections, the vaccine comprising NPY conjugated to a pharmaceutically acceptable carrier.
The current vaccine as an effective method of protecting against influenza virus infection is immunotherapy against influenza virus. In this case, it is necessary to achieve a good match between the prevalent strain and the isolate contained in the vaccine, but such a match is often achieved due to the high mutation rate of the influenza virus. Have difficulty. First, the influenza virus is continuously mutated: the dominant strain of influenza virus is replaced by a mutant strain that has undergone sufficient antigen drift to avoid an existing antibody response. Therefore, the isolates to be included in the vaccine formulation must be selected annually based on the intensive surveillance efforts of the World Health Organization (WHO) Collaborative Research Center. Second, strains must be selected approximately 6 months before the start of the influenza season to allow sufficient time for vaccine production and distribution. Often, the Vaccine Strain Selection Committee's predictions are inaccurate, resulting in a significant reduction in vaccination efficacy.

  On the other hand, the vaccine of the present invention utilizes the immunological activity against NPY bound to a pharmaceutically acceptable carrier and does not depend on the type of influenza virus strain that is prevalent, and thus is extremely useful for medical practice and patients. is there. Specifically, a peptide vaccine using NPY peptide as an antigen, humoral immunity against NPY antigen expressed by a DNA plasmid to neutralize the action of NPY, thereby treating and / or severely treating influenza virus infection. It is a DNA vaccine that exerts a prophylactic effect against oxidization, or an RNA vaccine against NPY mRNA.

  The vaccine of the present invention, when bound to a carrier protein (or a protein containing a T cell epitope) and administered to a mammal, can significantly induce the production of antibodies directed against NPY. NPY in the vaccine of the present invention also includes some peptides of NPY and derivatives thereof capable of producing an antibody that inhibits the NPY-YR axis. The peptide of NPY in the vaccine of the present invention should not elicit an immunological response in a host that is not the same as the naturally occurring NPY but is reactive to the NPY peptide.

  The NPY in the vaccine of the present invention can be synthetically produced as a part of the isolated peptide or other peptide or polypeptide by a chemical synthesis method well known in the art. Alternatively, the NPY can be produced in a peptide-producing microorganism, then isolated and, if desired, further purified. Peptide variants can be in microorganisms such as bacteria, yeasts or fungi, in eukaryotic cells such as mammalian or insect cells, or in adenoviruses, poxviruses, herpesviruses, Semliki Forest virus, baculovirus, It can be produced in a recombinant viral vector such as a bacteriophage, Sindville virus or Sendai virus. Bacteria suitable for producing the compound / peptide include E. coli, Bacillus subtilis or any other bacterium capable of expressing the peptide. Suitable yeast types for expressing the compounds / peptides are Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida, Pichia pastoris or other capable of expressing peptides. Includes any yeast. Corresponding methods are well known in the art. Methods for isolating and purifying recombinantly produced peptides are also well known in the art and include, for example, gel filtration, affinity chromatography, ion exchange chromatography and the like.

  To facilitate isolation of the peptide, a fusion polypeptide may be made in which the peptide is translationally fused (covalently linked) into a heterologous polypeptide that allows isolation by affinity chromatography. Typical atypical polypeptides are His-Tag (eg His6; 6 histidine residues), GST-Tag (glutathione-S-transferase) and the like. The fusion polypeptide not only facilitates purification of the peptide, but may also prevent degradation of the peptide during purification. If it is desired to remove the variant polypeptide after purification, the fusion peptide may contain a cleavage site at the junction between the peptide and the variant polypeptide. The cleavage site consists of an amino acid sequence that is cleaved by an enzyme (eg, protease) specific for the amino acid sequence at that site.

  As used herein, "NPY bound to a pharmaceutically acceptable carrier" and "NPY bound to a carrier" refer to NPY fused or conjugated to a carrier. If the NPY of the invention is fused or conjugated to a carrier (eg, via a carboxyl, amino, sulfhydryl, hydroxyl, imidazolyl, guanidyl or indolyl group), a linker may be present between the NPY and the protein carrier.

  The NPY in the vaccine of the invention is bound to a carrier, especially a protein carrier. According to a preferred embodiment of the invention, the carrier is selected from the group consisting of keyhole limpet hemocyanin (KLH), tetanus toxoid (TT) or diphtheria toxoid (DT) or any other protein or peptide containing T cell epitopes.

  According to a preferred embodiment of the present invention, the NPY in the vaccine of the present invention comprises a pharmaceutically acceptable carrier, preferably KLH (Squash hemocyanin), tetanus toxoid, albumin binding protein, bovine serum albumin, dendrimer (MAP; Biol. Chem. 358: 581), as well as being linked to protein linkers (or flanking regions), as well as Singh et al., Nat. Biotech. 17 (1999), 1075-1081 (in particular Table 1 of this document). ), And O'Hagan et al., Nature Reviews, Drug Discovery 2 (9) (2003), 727-735 (especially the endogenous immunopotentiating compounds and delivery systems described therein). ) Are also linked to the adjuvant substrates described above or mixtures thereof. Conjugation chemistry (eg, via heterobifunctional compounds such as GMBS, and, of course, other compounds as described in “Bioconjugate Techniques”, Greg T. Hermanson) is known to those skilled in the art in this sense. Can be selected from among the reactions. In addition, the vaccine composition may be formulated with an adjuvant, preferably a low solubility aluminum composition, especially aluminum hydroxide. Of course, MF59 aluminum phosphate, calcium phosphate, cytokine (eg, IL-2, IL-12, GM-CSF), saponin (eg, QS21), MDP derivative, CpG oligomer, LPS, MPL, polophosphazene, emulsion (eg, Freund's, SAF), liposomes, virosomes, cochleates, PLG microparticles, poloxamer particles, virus-like particles, heat-labile enterotoxins (LT), cholera toxoids (CT), mutant toxoids (eg LTK63 and LTR72), micro Adjuvants such as particles and / or polymerized liposomes can also be used.

According to a preferred embodiment of the present invention, NPY in the vaccine of the present invention is formulated by an adjuvant, preferably adsorbed on alum.

  The vaccine of the present invention may be administered subcutaneously, intramuscularly, intracutaneously or intravenously (see, eg, "Handbok of Pharmaceutical Manufacturing Formulations", Sarfaraz Niazi, CRC Press Inc, 2004). Depending on the route of administration, the drug may contain respective carriers, adjuvants and / or inert additives.

  Vaccines according to the invention may be present in amounts of from 0.1 ng to 10 mg, preferably from 10 ng to 1 mg, in particular from 100 ng to 100 μg, or alternatively, from 100 fmol to 10 μmol, preferably 10 pmol to 1 μmol, in particular 100 pmol to 100 nmol. Contains a compound. The compound or protein of the invention is preferably administered to the mammal in an amount of 100 ng to 1 mg, more preferably 1 μg to 500 μg, even more preferably 10 μg to 100 μg, especially 20-40 or 30 μg per dose. Typically, the vaccine may also contain adjuvants such as buffers, stabilizers and the like.

<Vaccine 2>
In another aspect, the present invention provides a vaccine for preventing and / or treating influenza virus infection, which comprises a nucleic acid-based vaccine containing a polynucleotide encoding NPY.
Vaccine antigens are molecules, often polypeptides, which, by including the antigen, stimulate an immune response against target cells. Nucleic acid-based vaccines (eg DNA or RNA vaccines) are used to deliver antigen-encoding DNA or RNA to cells and generate the antigen of interest to elicit an immune response. DNA vaccines may include DNA vectors, including but not limited to naked or linear DNA, regular plasmids, mini circular vectors, or mini intron plasmids. The vector encoding a polypeptide antigen is administered in vivo and the antigen is expressed by the cell to elicit an immune response against the antigen.

  When delivered as a vaccine, plasmid DNA is taken up by antigen presenting cells and expressed within the antigen presenting cells to produce the antigen. Subsequently, the antigen is presented to T cells to elicit a cellular immune response. In particular, antigens produced within antigen presenting cells are displayed as peptide epitopes that bind to major histocompatibility complex (MHC) class I and class II molecules and are carried with the MHC molecules to the surface of antigen presenting cells. It Subsequently, these surface antigens are presented to immature T cells (CD8 + T cells) and CD4 + T cells that contain the transmembrane glycoprotein "cluster class 8".

  In some embodiments, the polynucleotide is in a plasmid vector. As used herein, the term "plasmid vector" is not limited to ordinary plasmid vectors, but is "engineered to lack the majority of the plasmid backbone," a mini-circular vector, complete within the intron upstream of the region encoding the antigen. Also included are "mini-intron plasmids" (MIPS), in which the plasmid backbone is located, or linear pieces of DNA.

  In some embodiments, the polynucleotide is RNA (eg mRNA). In some embodiments, RNA forms a complex with protamine and is protected from RNase. In some embodiments, RNA content is optimized for RNA stabilization. In some embodiments, nucleotides can be modified to protect the RNA from RNase.

  The nucleic acid-based vaccine of the present invention may be administered subcutaneously, intramuscularly, intradermally, or intravenously (see, for example, "Handbook of Pharmaceutical Manufacturing Formulations", Sarfaraz Niazi, CRC Press Inc, 2004). Depending on the route of administration, the drug may contain respective carriers, adjuvants and / or inert additives.

  The nucleic acid-based vaccine according to the present invention is present in an amount of 0.1 ng to 10 mg, preferably 10 ng to 1 mg, particularly 100 ng to 100 μg, or alternatively, 100 fmol to 10 μmol, preferably 10 pmol to 1 μmol, particularly 100 pmol to 100 nmol. Contains a compound of the invention. The compound or protein of the invention is preferably administered to the mammal in an amount of 100 ng to 1 mg, more preferably 1 μg to 500 μg, even more preferably 10 μg to 100 μg, especially 20-40 or 30 μg per dose. Typically, the vaccine may also contain adjuvants such as buffers, stabilizers and the like.

  Both the NPY-containing vaccine and the nucleic acid-based vaccine according to the present invention are preferably administered to a subject susceptible to severe disease. Typically, it is an influenza virus-infected patient with obesity or asthma, which has been reported to be susceptible to severe influenza. In short, a subject having elevated NPY in blood, that is, a high-risk patient can be administered with the vaccine containing the NPY or the nucleic acid-based vaccine according to the present invention, and is also administered in the sense of preventing aggravation. Should do.

  Hereinafter, the present invention will be described in detail with reference to Examples, but it should be noted that these do not limit the scope of the present invention and are merely examples.

The antibodies used in the examples are shown in Table 1.

Example 1
Enhancement of NPY synthesis in pulmonary phagocytic cells after influenza virus infection 1-1: Correlation between severe influenza virus infection pathology and NPY In order to investigate the function of NPY for the pathology of severe influenza virus infection, influenza virus H1N1 / PR8 strain The expression levels of NPY mRNA and protein in the lungs of a mouse model intratracheally infected with (Transferred from Professor Takaaki Nakaya of Kyoto Prefectural Medical University) were measured over time using real-time RT-PCR and ELISA, respectively. The lung lesions in this model closely resemble those of severe human influenza (23,24). Lung tissue was sampled at 0, 4 and 8 days post infection to examine NPY mRNA and protein levels. The results are shown in FIG. 1 for NPY mRNA and in FIG. 2 for proteins. Both NPY mRNA and protein expression levels increased significantly over time.

1-2: Expression of NPY in lung bone marrow cells infected and uninfected with influenza virus NPY-GFP mice (25) expressing GFP under the control of mouse Npy promoter, purchased from the US Jackson Laboratory, were used as influenza virus H1N1 / PR8. The strain was intratracheally infected, and lung tissues were stained with anti-GFP antibody (Ab) (MBL, Japan).
Cells in BAL fluid from uninfected and infected NPY-GFP mice were then analyzed by flow cytometry (26,27,28). The obtained results are shown in FIG. It was shown that the numbers of NPY-GFP positive alveolar macrophages (CD11c + Siglec-F +), stromal macrophages (CD11b + F4 / 80+) and monocytes (Ly6-C + CD11b +) were significantly increased after virus infection. On the other hand, neutrophils (CD11b + Ly6-G +), myeloid dendritic cells (mDCs) (CD11c + CD103 +), and T cells (CD3 +) show NPY-GFP signal under uninfected or infected conditions. Was not shown. Taken together, these results indicate that NPY is predominantly expressed in phagocytic cells including alveolar macrophages and stromal macrophages and monocytes in the lung after influenza virus infection.

1-3: Confirmation of the origin of NPY in the lung after influenza virus infection In order to eliminate the possibility that the increase in NPY level observed in the virus-infected lung originates in the sympathetic nerve (SNS), we used NPY-GFP mice. , Chemosympathectomy with 6-hydroxydopamine (6-OHDA) or reserpine, which impairs noradrenergic and dopaminergic neurons, was performed (30). First, we confirmed that chemosympathectomy using these chemicals efficiently reduced SNS-derived NPY production. Next, after administration of control (0.9% NaCl containing 10 ^-7 M ascorbic acid (saline)) or 6-OHDA, NPY-GFP mice were intratracheally infected with virus, and 6-OHDA treatment It was found that it did not affect the induction of NPY in the infected lung (Fig. 4). Furthermore, like NPY6-OHDA treatment, reserpine treatment did not alter NPY expression in virus-infected lungs (FIG. 4). The results indicate that the source of NPY observed in virus-infected lungs is unlikely to be the sympathetic nerve.

Example 2
Improvement of severe influenza virus infection by removal of NPY
It was confirmed whether the expression of NPY is actively involved in the pathophysiology of severe influenza virus infection. To test this, WT (wild-type) mouse (129X1 / SvJJmsSlc inbred mouse, purchased from Japan SLC) and NPY KO mouse (purchased from Jackson Laboratory, USA) were tested with two different 56.2 TCID50 and 250 TCID50. Titers of influenza virus H1N1 / PR8 strain were infected. The survival rate of each infected NPY KO mouse was significantly improved compared to WT (Fig. 5 (56.2 TCID50) and Fig. 6 (250 TCID50)). Consistent with this, there was less lung edema formation in NPY KO mice compared to WT mice (Figure 8) and histological analysis determined less tissue damage (Figure 7). Importantly, NPY KO mice showed poor viral replication as assessed by viral NP mRNA expression (Figure 9). Furthermore, mRNA expression of pro-inflammatory cytokines Cxcl1, Cxcl2 and Il-6 was lower in NPY KO lungs than in WT lungs, whereas mRNA expression of anti-inflammatory cytokine IL-10 was higher in NPY KO lungs than in WT lungs. (FIG. 10). Furthermore, flow cytometric analysis showed that the BAL fluid of virus-infected NPY KO mice had a significantly reduced number of phagocytic cells including alveolar and stromal macrophages and monocytes in BAL fluid compared to WT mice. (FIG. 11). These results suggest that NPY deficiency ameliorates the pathology of severe influenza virus infections.

The influenza virus H1N1 / PR8 strain has been shown to be able to infect macrophages or monocytes (Cline, TD, et. Al., The Journal of general virology 98, 2401-2412, doi: 10.1099 / jgv.0.000922. (2017); White, MR et al., Innate Immun 23, 77-88, doi: 10.1177 / 1753425916678470 (2017).).
It was investigated whether the above findings observed in NPY-KO mice were specific to the influenza virus H1N1 / PR8 strain and related to other viruses. Pandemic H1N1 / 2009 strain (A / California / 04/2009 H1N1) known to infect macrophages / monocytes (transferred from Dr. Yoshihiro Kawaoka, Institute of Medical Science, The University of Tokyo) at a virus titer of 100 FFU and WT and NPY KO mice were infected transtracheally. The obtained results are shown in FIG. Here again, NPY KO mice again show improved survival following viral infection, and the attenuated phenotype in NPY KO mice can infect not only influenza virus H1N1 / PR8 strains, but also macrophages and monocytes. It was also found in other viruses.

Example 3
Improvement of pathological condition of influenza virus infection by phagocytic cell-specific Y1 receptor deficiency 3-1: Induction of Y1R expression in pulmonary phagocytes after influenza virus infection
The NPY Y1 receptor (Y1R) has been shown to localize to immune cells including macrophages and neutrophils (14,32,33,34). Frozen lung sections from uninfected and infected WT mice were co-stained with Y1R Ab and CD11c, CD11b, Ly6-G, Ly6-C, CD103, CD3 or NK1.1 Ab to quantify image data. For quantification, Y1R and cells were used for the number of cells positive for each cell surface marker (CD11c, CD11b, Ly6-G, Ly6-C, CD103, CD3 or NK1.1) using images from 6 fields in each group. The ratio of the number of cells positive for both surface markers was calculated. (FIG. 13). In virus-infected lungs, Y1R was expressed on CD11c, CD11b or Ly6-C positive cells, but not on Ly6-G, CD103, CD3 or NK1.1 positive cells. These show that, like NPY, Y1R expression is induced in CD11c, CD11b or Ly6-C positive lung phagocytic cells after influenza virus infection.

3-2: Effect of Y1R deficiency in phagocytes on pathological conditions of severe influenza virus infection Next, in order to investigate the function of Y1R in phagocytes, M lysosome, which is known to selectively delete the Y1R gene in bone marrow cells, is known. Phagocytic cell-specific Y1R KO (Y1R ^PC-KO ) mice were generated using (LysM) -Cre mice (purchased from Jackson Laboratory, USA) (35). Subsequently, WT (Y1R ^PC-WT ) and Y1R ^PC-KO mice were infected with influenza virus.

Importantly, Y1R ^PC-KO mice showed better survival (FIG. 14) and lung histology (FIG. 15) compared to WT. Viral replication in lung tissue (FIG. 16) and expression of proinflammatory cytokines (FIG. 17) were lower in Y1R ^PC-KO mice compared to Y1R ^{PC- WT} mice. Furthermore, virus titers (FIG. 18) and IL-6 protein levels (FIG. 19) in the supernatant of infected phagocytic cells were lower in Y1R ^PC-KO than in Y1R ^PC-WT . These data indicate that Y1R deficiency in phagocytes attenuates viral replication and proinflammatory cytokine production, resulting in amelioration of severe influenza virus infection pathology.

Example 4
Effect of Y1 receptor inhibitor on survival rate of virus-infected mice
BIBO3304 (Tocris Bioscience), which is a Y1 receptor inhibitor, was intratracheally administered to WT mice at 20 mg / mouse or PBS as a control, and then H1N1 / PR8 strains were infected with 100 FFU of viral titer through the respiratory tract. The obtained results are shown in FIG. The Y1 receptor inhibitor treatment group improved the survival rate after viral infection.

Example 5
Changes in blood NPY concentration during virus infection
WT mice were infected with H1N1 / PR8 strain at a virus titer of 100 FFU via the respiratory tract, and changes in NPU concentration in blood were examined. The obtained results are shown in FIG. Blood NPY concentration increased with time after virus infection.

  Here we found that activation of the NPY-Y1 receptor axis induces SOCS3, which causes severe influenza. Expression of SOCS3 is elevated even in the highly toxic H5N1 influenza (Vijayakumar, P. et al. Analysis of the crow lung transcriptome in response to infection with highly pathogenic H5N1 avian influenza virus. Gene 559, 77-85, doi: 10.1016 / j .gene.2015.01.016 (2015)), an inhibitor of SOCS1 / 3 has been reported to improve the pathology of fatal severe influenza (Ahmed, CM, Dabelic, R., Bedoya, SK, Larkin, J., 3rd & Johnson, HMA SOCS1 / 3 Antagonist Peptide Protects Mice Against Lethal Infection with Influenza A Virus. Frontiers in immunology 6, 574, doi: 10.3389 / fimmu.2015.00574 (2015)). Since SOCS3 has been reported to enhance Ebola virus infection (Okumura A, Rasmussen AL, Halfmann P, Feldmann F, Yoshimura A, Feldmann H, Kawaoka Y, Harty RN, Katze MG. Suppressor of Cytokine Signaling 3 Is an Inducible Host Factor That Regulates Virus Egress during Ebola Virus Infection. J Virol. 2015 Oct; 89 (20): 10399-406. Doi: 10.1128 / JVI.01736-15. Epub 2015 Aug 5), NPY-Y1 acceptance Inhibition of body axis may have an effect on Ebola infection through decreased SOCS3 production.

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Literature cited in the examples:
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Claims (27)

  A pharmaceutical composition for preventing and / or treating influenza virus infection, which comprises an inhibitor of the NPY-YR axis.   The NPY-YR axis inhibitor is selected from among NPY analogs, antibodies against NPY or functional fragments or derivatives thereof, YR analogs, and antibodies against YR or functional fragments or derivatives thereof. The pharmaceutical composition described.   The pharmaceutical composition according to claim 2, wherein the inhibitor of the NPY-YR axis is a substance related to NPY.   The pharmaceutical composition according to claim 3, wherein the analogue of NPY is a compound that inhibits the binding of NPY to Y1R, Y2R, Y4R and Y5R subtypes. The pharmaceutical composition according to claim 4, wherein the compound is selected from the following:


  The pharmaceutical composition according to claim 1, wherein the inhibitor of the NPY-YR axis is selected from an antibody against NPY or a functional fragment or derivative thereof, and an antibody against YR or a functional fragment or derivative thereof.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the influenza virus infection is a severe influenza virus infection.   A method for screening a substance for preventing and / or treating an influenza virus infection, wherein the inhibitory function for the NPY-YR axis is used as an index.   The screening method according to claim 8, wherein the influenza virus infection is a severe influenza virus infection. A method of screening substances for the prevention and / or treatment of influenza virus infections, which comprises the following steps:
(A) preparing a system of NPY-YR axes containing biological cells expressing NPY and YR,
(B) contacting the system with a candidate compound of a substance for preventing and / or treating influenza virus infection,
(C) Whether the candidate compound exerts an inhibitory function in the NPY-YR axis system,
(D) A method of identifying the candidate compound as a substance for preventing and / or treating an influenza virus infection if the candidate compound exhibits an inhibitory function.   The screening method according to claim 10, wherein the influenza virus infection is a severe influenza virus infection.   The screening method according to claim 10 or 11, wherein the biological cells expressing NPY and YR are phagocytic cells. A method of determining future severity of an influenza virus infection, comprising:
(A1) a step of measuring the amount of NPY in the blood of the subject (test biomarker amount),
(B1) a step of comparing the amount of the test biomarker with the amount of NPY (the control biomarker amount) in the blood of a non-virus-infected sample, and (c1) the amount of the test biomarker is more than the control biomarker amount A method for determining that a subject has a severe influenza virus infection when the number is high.   The method according to claim 13, wherein the control biomarker amount is below the detection limit.   A biomarker that is NPY in blood that can determine future severity of influenza virus infections.   Use of blood NPY as a bimarker with which future severity in influenza virus infection can be determined.   A vaccine for preventing and / or treating influenza virus infections, which vaccine comprises NPY bound to a pharmaceutically acceptable carrier.   18. Vaccine according to claim 17, characterized in that the carrier is a protein carrier.   19. The vaccine of claim 18, wherein the protein carrier is selected from the group consisting of keyhole limpet hemocyanin (KLH), tetanus toxoid (TT) or diphtheria toxoid (DT).   20. The vaccine of any of claims 17-19, wherein NPY is formulated with an adjuvant.   21. Vaccine according to claim 20, characterized in that the adjuvant is alum.   The vaccine according to any one of claims 17 to 21, wherein the influenza virus infection is a severe influenza virus infection.   Use of NPY for the manufacture of a vaccine for the prevention and / or treatment of influenza virus infections.   A vaccine for preventing and / or treating influenza virus infection, comprising a nucleic acid-based vaccine comprising a polynucleotide encoding NPY.   The nucleic acid-based vaccine according to claim 24, wherein the polynucleotide is DNA and is a DNA vaccine.   The nucleic acid-based vaccine according to claim 24, wherein the polynucleotide is RNA and is an RNA vaccine.   27. The nucleic acid-based vaccine according to any of claims 24 to 26, wherein the polynucleotide is present in a plasmid vector.