KR101815193B1 - INHIBITOR FOR PPARγ PHOSPHORYLATION AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME - Google Patents

INHIBITOR FOR PPARγ PHOSPHORYLATION AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME Download PDF

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KR101815193B1
KR101815193B1 KR1020150188520A KR20150188520A KR101815193B1 KR 101815193 B1 KR101815193 B1 KR 101815193B1 KR 1020150188520 A KR1020150188520 A KR 1020150188520A KR 20150188520 A KR20150188520 A KR 20150188520A KR 101815193 B1 KR101815193 B1 KR 101815193B1
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phosphorylation
chemical formula
pparγ
inhibitor
ppar
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KR20170078212A (en
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박승범
배환
김희준
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(주)스파크바이오파마
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965Non-condensed pyrazines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

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Abstract

The present invention relates to a PPARy phosphorylation inhibitor and a pharmaceutical composition comprising the same. The PPAR? Phosphorylation inhibitor of the present invention is characterized in that it selectively inhibits only phosphorylation of Ser273 without showing transactivation, and strongly binds to PPAR? According to covalent binding, unlike the conventional PPARγ-targeted drugs. Therefore, it may be usefully used in related fields such as drugs for PPAR gamma-related diseases.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a PPAR [gamma] phosphorylation inhibitor and a pharmaceutical composition comprising the PPAR [gamma]

The present invention relates to a PPARy phosphorylation inhibitor and a pharmaceutical composition comprising the same.

Organisms lose their biocompatibility due to various internal / external factors and lose intracellular homeostasis, resulting in poor metabolism efficiency of sugars and fats. In addition, over-nutrition due to changes in dietary habits increases cardiovascular diseases such as obesity, hyperlipidemia, metabolic dysfunction such as diabetes, and hypertension and atherosclerosis, and these diseases are complicated diseases including genetic and nutritional factors I have the causes.

Peroxisome is one of the subcellular organelles responsible for these metabolic functions and has long been thought to play a minor role in cellular function. However, recent studies have shown that oxygen, glucose, lipid, hormone Metabolism, and so on. It has also been reported that peroxisome has a wide effect on the regulation of cell proliferation / differentiation and the regulation of inflammatory mediators.

Continued research in this area has shown evidence that nuclear hormone receptors, known as peroxisome proliferator-activated receptors (PPARs), may be good targets for pharmacological approaches to these diseases I put out.

There are three types of PPARs, PPARα, PPARβ / δ, and PPARγ, of which PPARγ is most abundant in adipose tissue and is found in endothelium, macrophages, and pancreatic β-cells. PPARγ regulates the differentiation of adipocytes and plays a crucial role in systemic lipid homeostasis. Furthermore, since PPARγ is closely linked to insulin sensitivity, PPARγ has been a major target for the development of therapeutic agents for obesity, diabetes, and the like.

Recently, studies have shown that inhibiting the phosphorylation of the Ser273 residue of PPARγ by Cyclin dependent kinase 5 (Cdk5) reduces the insulin resistance and is likely to treat diabetes (Non-Patent Documents 1 and 2). This study was conducted to investigate the relationship between PPARγ and obesity in obesity. When obesity develops, TNF-α, IL-6 and free fatty acids (FFAs) And activation of PPAR [gamma] -phosphorylation has been actively under way since it explains the mechanism by which the expression of genes capable of improving insulin resistance, such as adiponectin and adipsin, is reduced.

On the other hand, as a drug targeting PPARγ, a drug based on thiazolidinediones (TDZ) has been developed as a therapeutic agent for diabetes, but a problem has been reported that adverse effects such as increase in weight, edema and decrease in bone density have been reported. In January 1997, the US FDA approved troglitazone was recovered from the market due to hepatotoxicity. There is a report that the side effect is caused by the transactivation of PPARγ. Therefore, there is a need to develop a therapeutic agent that selectively inhibits PPARγ phosphorylation without causing transactivation of PPARγ .

1. Choi, J. H. et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature 466, 451-456, 2010. 2. Choi, J. H. et al. Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Nature 477, 477-481, 2011.

The present invention relates to a PPAR? Phosphorylation inhibitor capable of effectively inhibiting PPAR? Phosphorylation without causing transactivation of PPAR? (Specifically, inhibiting phosphorylation of Ser273 of PPAR?) And a pharmaceutical composition containing the same as an active ingredient The purpose is to provide.

In order to solve the above problems, the present invention provides a PPAR? Phosphorylation inhibitor comprising at least one compound selected from the group consisting of compounds represented by the following general formulas (1) to (3).

[Chemical Formula 1]

Figure 112015128256936-pat00001

(2)

Figure 112015128256936-pat00002

(3)

Figure 112015128256936-pat00003

In the above Formulas 1 to 3,

Wherein R 1 is - (CH 2 ) nA 1 -X- (CH 2 ) mA 2 -R 6 ,

A 1 is a cycloalkyl compound or an aromatic compound having 5 to 6 carbon atoms,

X is an oxygen atom, a sulfur atom or a nitrogen atom,

A 2 is an aromatic compound or a heteroaromatic compound,

N is an integer of 0 or 1,

M is an integer of 0 to 10,

R 6 is a hydrogen atom or - (CH 2 ) oA 3 - (CH- 2 ) p R 7 ,

A 3 is an oxygen atom, -NH-, -NH-C (= O) - or -C (= O) -NH-,

R 7 is a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group,

Each of o and p is an integer of 0 to 5,

In Formula 2, R 2 is hydrogen, an alkyl group having 1 to 3 carbon atoms, a substituted or unsubstituted phenyl group, or -NR 8 R 9 , wherein R 8 and R 9 may be the same or different from each other, An atom or an alkyl group having 1 to 3 carbon atoms,

R 3 and R 4 may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group,

In Formula 3, R 5 may be a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

In one embodiment, A 1 and A 2 are arromatic compounds, X is an oxygen atom, n is 0, and m is 1.

In another embodiment R < 1 >

Figure 112015128256936-pat00004
or
Figure 112015128256936-pat00005
Lt; / RTI >

In another embodiment, R < 6 > is a hydrogen atom,

Figure 112015128256936-pat00006
,
Figure 112015128256936-pat00007
,
Figure 112015128256936-pat00008
,
Figure 112015128256936-pat00009
,
Figure 112015128256936-pat00010
,
Figure 112015128256936-pat00011
,
Figure 112015128256936-pat00012
,
Figure 112015128256936-pat00013
,
Figure 112015128256936-pat00014
,
Figure 112015128256936-pat00015
, or
Figure 112015128256936-pat00016
Lt;

Wherein R 7 is -A 4 -R 10 , A 4 is a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,

R 10 represents a hydrogen atom, a methyl group,

Figure 112015128256936-pat00017
,
Figure 112015128256936-pat00018
, or
Figure 112015128256936-pat00019
ego,

R 11 may be a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

Another embodiment may include at least one compound selected from the group consisting of compounds represented by formulas (4) to (19).

[Chemical Formula 4]

Figure 112015128256936-pat00020

[Chemical Formula 5]

Figure 112015128256936-pat00021

[Chemical Formula 6]

Figure 112015128256936-pat00022

(7)

Figure 112015128256936-pat00023

[Chemical Formula 8]

Figure 112015128256936-pat00024

[Chemical Formula 9]

Figure 112015128256936-pat00025

[Chemical formula 10]

Figure 112015128256936-pat00026

(11)

Figure 112015128256936-pat00027

[Chemical Formula 12]

Figure 112015128256936-pat00028

[Chemical Formula 13]

Figure 112015128256936-pat00029

[Chemical Formula 14]

Figure 112015128256936-pat00030

[Chemical Formula 15]

Figure 112015128256936-pat00031

[Chemical Formula 16]

Figure 112015128256936-pat00032

[Chemical Formula 17]

Figure 112015128256936-pat00033

[Chemical Formula 18]

Figure 112015128256936-pat00034

[Chemical Formula 19]

Figure 112015128256936-pat00035

Further, the present invention provides a pharmaceutical composition for preventing or treating obesity, metabolic diseases or cardiovascular diseases, which comprises the PPARy phosphorylation inhibitor as an active ingredient.

In one embodiment, the metabolic disease is diabetes, hyperlipidemia, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, syndrome X or endothelial dysfunction, and the cardiovascular disease is cardiovascular disease Hypertension, precoagulant state, dyslipidemia or an atherosclerotic disease.

Another embodiment may further comprise a pharmacologically acceptable agent, cachet, or excipient.

The PPAR? Phosphorylation inhibitor of the present invention is characterized in that it selectively inhibits only phosphorylation of Ser273 without showing transactivation, and strongly binds to PPAR? According to covalent binding, unlike the conventional PPARγ-targeted drugs. Therefore, it may be usefully used in related fields such as drugs for PPAR gamma-related diseases.

Fig. 1 shows the structures of SB1405, SB1406, GW9662 and SB1404 according to the first embodiment.
Fig. 2 shows the results of confirming the inhibitory effect of the PPARγ Ser273 residue according to Experimental Example 1 on phosphorylation.
FIG. 3 shows X-ray crystal structures of SB1405 and SB1406 according to Experimental Example 1. FIG.
4 shows chemical structures of A to F according to Example 2. Fig.
FIG. 5 shows the results of confirming the inhibitory effect of the PPARγ Ser273 residue according to Experimental Example 2 on phosphorylation.
6 shows a design process of SB1405, SB1451 and SB1453 according to the third embodiment.
Fig. 7 shows the results of confirming the inhibitory effect of the PPARγ Ser273 residue according to Experimental Example 3 on phosphorylation.
Fig. 8 shows the results of confirming the inhibitory effect of the PPARγ Ser273 residue according to Experimental Example 4 on phosphorylation.
FIG. 9 shows the results of confirming the inhibitory effect of the PPARγ Ser273 residue according to Experimental Example 5 on phosphorylation.
10 shows the results of confirming the inhibitory effect of the PPARγ Ser273 residue according to Experimental Example 6 on phosphorylation.
Fig. 11 shows the results of confirming the inhibitory effect of the PPAR [gamma] Ser273 residue on the cells according to Experimental Example 7 against phosphorylation.
Fig. 12 shows the result of confirming the transcription activity effect according to Experimental Example 8. Fig.
FIG. 13 shows the result of confirming accumulated lipids through Oil Red O staining according to Experimental Example 9. FIG.
Fig. 14 shows the results of confirming the inhibitory effect of PPARγ Ser273 residue in vivo on the phosphorylation inhibition according to Experimental Example 10.
Fig. 15 shows the results of evaluation of expression of 17 genes regulated by PPARy phosphorylation according to Experimental Example 11. Fig.
FIG. 16 shows the expression evaluation results of 17 genes regulated by the transcriptional activity according to Experimental Example 12. FIG.
17 shows the results of glucose tolerance test according to Experimental Example 13. Fig.

The present invention relates to a PPARy phosphorylation inhibitor and a pharmaceutical composition comprising the same.

Hereinafter, the present invention will be described in detail.

The present invention provides a PPAR? Phosphorylation inhibitor comprising at least one compound selected from the group consisting of the compounds represented by the above-mentioned general formulas (1) to (3).

In the above Formulas 1 to 3,

Wherein R 1 is - (CH 2 ) nA 1 -X- (CH 2 ) mA 2 -R 6 ,

A 1 is a cycloalkyl compound or an aromatic compound having 5 to 6 carbon atoms,

X is an oxygen atom, a sulfur atom or a nitrogen atom,

A 2 is an aromatic compound or a heteroaromatic compound,

N is an integer of 0 or 1,

M is an integer of 0 to 10,

R 6 is a hydrogen atom or - (CH 2 ) oA 3 - (CH 2 ) p R 7 ,

A 3 is an oxygen atom, -NH-, -NH-C (= O) - or -C (= O) -NH-,

R 7 is a substituted or unsubstituted aromatic group or a substituted or unsubstituted heteroaromatic group,

Each of o and p is an integer of 0 to 5,

In Formula 2, R 2 is hydrogen, an alkyl group having 1 to 3 carbon atoms, a substituted or unsubstituted phenyl group, or -NR 8 R 9 , wherein R 8 and R 9 may be the same or different from each other, An atom or an alkyl group having 1 to 3 carbon atoms,

R 3 and R 4 may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group,

In Formula 3, R 5 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group.

In the above formula (1), the moiety excluding R 1 is a structure for covalent coupling with PPARγ. In R 1 , a moiety other than R 6 occupies a specific binding site of hydrophobicity to inhibit phosphorylation of PPARγ Ser273 residue - (CH 2 ) oA 3 - (CH 2 ) pR 7 , in which R 6 is not a hydrogen atom, has a structure for further enhancing the PPARγ phosphorylation inhibitory effect.

(2) is a modification of the structure for the PPARγ covalent bonding in order to improve solubility, and Formula (3) is a modification of the structure for the covalent inhibitor, while maintaining a high potency, which is a merit of the covalent inhibitor, Is a modification of the structure for covalent bonding in Formula 1 so as not to occur. In particular, the compound of formula (3) is characterized in that it can act as a reversible inhibitor.

As used herein, the cycloalkyl compounds include, but are not limited to, cyclopentyl, cyclohexyl, and the like.

The heteroaromatic group or the heteroaromatic compound includes at least one of an oxygen atom, a sulfur atom or a nitrogen atom, and the position of the oxygen atom, the sulfur atom or the nitrogen atom is not limited. For example, the heteroaromatic compounds include, but are not limited to, furan, thiophene, pyrrole, imidazole, and the like.

The alkyl group having 1 to 3 carbon atoms means a linear or branched alkyl group, and includes, for example, methyl, ethyl, n-propyl and i-propyl.

The alkyl group having 1 to 5 carbon atoms means a linear or branched alkyl group, and includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, It does not.

The position of X connected to A 1 is not limited. However, when A 1 is an aromatic compound, ortho or meta is preferable, and most preferred is ortho.

The position of R 6 connected to A 2 is also not limited, but ortho or meta is preferable when A 2 is an aromatic compound.

In the R 1 of Formula 1 to 3, wherein A 1 and A 2 is an Aro matic compound, wherein X is an oxygen atom, wherein n is O, the m may be 1.

For example, R < 1 &

Figure 112015128256936-pat00036
or
Figure 112015128256936-pat00037
Lt; / RTI >

In order to further enhance the PPAR? Phosphorylation inhibiting effect, the R 6 may have a hydrophobic portion and a hydrophilic portion on the basis of A 2 as shown in FIG. 6.

For example, R 6 is a hydrogen atom,

Figure 112015128256936-pat00038
,
Figure 112015128256936-pat00039
,
Figure 112015128256936-pat00040
,
Figure 112015128256936-pat00041
,
Figure 112015128256936-pat00042
,
Figure 112015128256936-pat00043
,
Figure 112015128256936-pat00044
,
Figure 112015128256936-pat00045
,
Figure 112015128256936-pat00046
,
Figure 112015128256936-pat00047
, or
Figure 112015128256936-pat00048
Lt;

Wherein R 7 is -A 4 -R 10 , A 4 is a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group

R 10 represents a hydrogen atom, a methyl group,

Figure 112015128256936-pat00049
,
Figure 112015128256936-pat00050
, or
Figure 112015128256936-pat00051
ego,

R 11 may be a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

More specifically, the inhibitor may include at least one member selected from the group consisting of compounds represented by formulas (4) to (19).

[Chemical Formula 4]

Figure 112015128256936-pat00052

[Chemical Formula 5]

Figure 112015128256936-pat00053

[Chemical Formula 6]

Figure 112015128256936-pat00054

(7)

Figure 112015128256936-pat00055

[Chemical Formula 8]

Figure 112015128256936-pat00056

[Chemical Formula 9]

Figure 112015128256936-pat00057

[Chemical formula 10]

Figure 112015128256936-pat00058

(11)

Figure 112015128256936-pat00059

[Chemical Formula 12]

Figure 112015128256936-pat00060

[Chemical Formula 13]

Figure 112015128256936-pat00061

[Chemical Formula 14]

Figure 112015128256936-pat00062

[Chemical Formula 15]

Figure 112015128256936-pat00063

[Chemical Formula 16]

Figure 112015128256936-pat00064

[Chemical Formula 17]

Figure 112015128256936-pat00065

[Chemical Formula 18]

Figure 112015128256936-pat00066

[Chemical Formula 19]

Figure 112015128256936-pat00067

The present invention also provides a pharmaceutical composition for preventing or treating obesity, metabolic diseases or cardiovascular diseases, which comprises a PPAR? Phosphorylation inhibitor as an active ingredient.

Since it is well known in the art that obesity, metabolic diseases, cardiovascular diseases and the like are influenced by the PPARgamma activation, the composition inhibits PPARy phosphorylation and is effective for preventing or treating diabetes, obesity, metabolic diseases or cardiovascular diseases More specifically, it inhibits the phosphorylation of PPARγ Ser273 and thus has the effect of preventing or treating the above-mentioned diabetes, obesity, metabolic diseases or cardiovascular diseases.

Specifically, the hypercholesterolemia among the metabolic diseases is low HDL-cholesterol, high LDL-cholesterol or hypertriglyceridemia, and the cardiovascular disease is hypertension, precoagulant state, dyslipidemia or atheromatous But it is not particularly limited thereto.

As the active ingredient in the pharmaceutical composition according to the present invention, the content of the inhibitor including at least one compound selected from the group consisting of the compounds represented by the formulas (1) and (3) The kind of the symptom, and the hardness, and may be 0.001 to 99.9% by weight, 0.1 to 99% by weight, or 1 to 50% by weight based on the weight of the composition, but is not limited thereto.

The dosage of the pharmaceutical composition according to the present invention can be determined in consideration of the administration method, the age, sex, the severity of the patient, the condition, the degree of absorption of the active ingredient in the body, the inactivation rate, Kg body weight to 500 mg / kg body weight, 0.1 mg / kg body weight to 400 mg / kg body weight or 1 mg / kg body weight to 300 mg / kg body weight, (Body weight), and may be administered once or several times, but the present invention is not limited thereto.

The pharmaceutical compositions of the present invention can be administered to mammals, including humans, in a variety of routes. The mode of administration may be any conventionally used route and may be administered, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injection. The pharmaceutical composition of the present invention can be administered orally or parenterally in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, transdermal preparations, suppositories and sterilized injection solutions Can be used.

The pharmaceutical composition of the present invention may contain, in addition to the active ingredient, a pharmaceutically suitable and physiologically acceptable carrier, an auxiliary agent, and an auxiliary agent such as a diluent. Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are usually used can be used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, Lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Examples of liquid formulations for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, have. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, transdermal preparations and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Witepsol, macrogol, Tween 61, cacao paper, laurin, glycerogelatin and the like may be used as a base for suppositories.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are provided to illustrate the present invention, and the present invention is not limited by the following examples, but may be variously modified and changed.

Example  One. PPAR gamma Ser273 Residue  Production of inhibitors that inhibit phosphorylation (Irreversible) 1

It was confirmed that the ligand inhibiting phosphorylation of the PPAR gamma Ser273 residue occupied a specific binding site of hydrophobicity in common. The covalent inhibitors that are expected to effectively occupy the specific binding site are designated as SB1405 (Formula 4) and SB1406 (Formula 5) based on the previously known covalent ligands GW9662 and the PPARγ crystal structure, And the SB1404 (Formula 21), which is expected to not occupy at all, was also fabricated, and the structure thereof is shown in Fig.

[Reaction Scheme 1]

Figure 112015128256936-pat00068

(GW9662)

Figure 112015128256936-pat00069

(SB1404, 2-chloro-N-methyl-5-nitrobenzamide)

Figure 112015128256936-pat00070

(SB1405, N- (2- (benzyloxy) phenyl) -2-chloro-5-nitrobenzamide)

Figure 112015128256936-pat00071

1 H NMR (400 MHz, CDCl 3) δ 8.78 (brs, 1H), 8.64 (d, J = 2.8 Hz, 1H), 8.48 (dd, J = 7.6, 1.2 Hz, 1H), 8.16 (dd, J = 8.8, 2.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.41-7.34 (m, 5H), 7.10 (d, J = 7.6, 1.6 Hz, 1H), 7.05-7.00 (m, 2H ), 5.11 (s, 2 H); 13 C NMR (100 MHz, CDCl 3 ) δ 161.5, 147.8, 146.7, 137.5, 136.2, 136.0, 131.7, 128.8, 128.6, 128.0, 127.3, 126.1, 125.9, 125.0, 121.6, 120.6, 111.8, 71.2; LRMS (ESI) m / z calcd for C 20 H 16 ClN 2 O 4 [M + H] +: 383.08; Found: 382.91.

(SB1406, N- (3- (benzyloxy) phenyl) -2-chloro-5-nitrobenzamide)

Figure 112015128256936-pat00072

1 H NMR (400 MHz, CDCl 3) δ 8.52 (s, 1H), 8.20 (dd, J = 8.8, 2.4 Hz, 1H), 7.99 (s, 1H), 7.60 (d, J = 9.2 Hz, 1H) , 7.45-7.24 (m, 7H), 7.09 (d, J = 8.4 Hz, 1H), 6.81 (dd, J = 8.4, 2.0 Hz, 1H), 5.07 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 162.4, 159.5, 146.7, 138.2, 137.7, 136.8, 136.6, 131.7, 130.1, 128.7, 128.2, 127.7, 126.1, 125.3, 112.8, 112.2, 107.2 70.2; LRMS (ESI) m / z calcd for C 20 H 16 ClN 2 O 4 [M + H] +: 383.08; Found: 382.87.

Experimental Example  One. PPAR gamma Ser273 Residue  Identification of inhibition of phosphorylation 1

The phosphorylation inhibitory effect of the PPARγ Ser273 residue of the inhibitor prepared in Example 1 was confirmed using an in vitro Cdk5 assay (Cell Signaling Technology, USA) according to the manufacturer's instructions.

Specifically, 0.5 [mu] g of purified PPAR [gamma] LBD (Ligand Binding Domain) was reacted with active Cdk5 / p35 (Millipore, USA) at 30 [deg.] C for 30 minutes to effect phosphorylation. Assays were performed under the following conditions:

25 uM ATP, 25 mM Tris-HCl, pH 7.5, 5 mM β-glycerophosphate, 2 mM DTT, 0.1 mM Na 3 VO 4 , 10 mM MgCl 2 .

To confirm the inhibitory effect of the inhibitor, PPARγ LBD and inhibitor were first reacted at 30 ° C. 30 minutes before the assay. To confirm that the inhibitor did not act directly on Cdk5, the substrate was incubated with Rb peptide (residues 773 -928, Millipore) and the same assay was performed (the Rb peptide is one of the well-known substrates of Cdk5). The degree of phosphorylation of the substrate was confirmed by Western blotting using an aniti-phospho-Ser Cdk substrate antibody (Cell Signaling Technology, USA). The results are shown in Fig. Assays were also performed for Rosiglitazone (Rosi) and SR1664, also known as antidiabetic PPARγ ligands.

(Rosiglitazone)

Figure 112015128256936-pat00073

(SR1664)

Figure 112015128256936-pat00074

As shown in FIG. 2, it was confirmed that only SB1405 was the same as the antidiabetic PPARγ ligands Rosiglitazone and SR1664, the only covalent inhibitor.

In addition, X-ray crystallography confirmed the binding site. Unlike SB1406, SB1405 accurately occupied the specific binding site, thereby effectively inhibiting phosphorylation of the PPARγ Ser273 residue (see FIG. 3).

Example  2. PPAR gamma Ser273 Residue  Production of inhibitors that inhibit phosphorylation (Irreversible) 2

Based on the results of Experimental Example 1, various inhibitors were prepared as shown in the following Reaction Scheme 2 based on the structure of SB1405. The inhibitors prepared were A (Formula 6), C (Formula 7) D (Formula 8), E (Formula 9), and F (Formula 10).

[Reaction Scheme 2]

Figure 112015128256936-pat00075

 (A, 2-chloro-5-nitro-N- (2-phenoxyphenyl) benzamide)

Figure 112015128256936-pat00076

1 H NMR (400 MHz, CDCl 3) δ 8.63 (s, 1H), 8.61 (s, 1H), 8.59 (d, J = 7.2 Hz, 1H), 8.23 (dd, J = 7.2, 2.0 Hz, 1H) , 7.60 (d, J = 6.8 Hz, 1H), 7.36 (t, J = 6.4 Hz, 2H), 7.17-7.10 (m, 3H), 7.02 (d, J = 6.4 Hz, 2H), 6.92 (d, J = 6.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 161.8, 156.3, 146.7, 146.1, 137.4, 136.3, 131.6, 130.0, 129.0, 125.9, 125.7, 125.2, 124.2, 124.1, 121.3, 118.5, 118.0; LRMS (ESI) m / z calcd for C 19 H 14 ClN 2 O 4 [M + H] +: 369.06; Found: 369.05.

(C, 2-chloro-5-nitro-N- (2-phenethoxyphenyl) benzamide)

Figure 112015128256936-pat00077

1 H NMR (400 MHz, CDCl 3) δ 8.54 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.36 (s, 1H), 8.26 (dd, J = 8.4, 2.8 Hz, 1H) , 7.64 (d, J = 8.8 Hz, 1H), 7.18-7.10 (m, 6H), 7.04 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 161.7, 147.4, 146.8, 137.8, 137.7, 136.9, 131.7, 128.8, 128.6, 127.3, 126.7, 125.6, 125.5, 125.0, 121.6, 120.4, 111.6, 69.1, 35.6; LRMS (ESI) m / z calcd for C 21 H 18 ClN 2 O 4 [M + H] +: 397.10; Found: 397.15.

(D, 2-chloro-N- (2-ethoxyphenyl) -5-nitrobenzamide)

Figure 112015128256936-pat00078

1 H NMR (400 MHz, CDCl 3) δ 8.77 (brs, 1H), 8.72 (d, J = 2.8 Hz, 1H), 8.50 (dd, J = 8.0, 1.2 Hz, 1H), 8.25 (dd, J = 8.8, 2.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.13 (dd, J = 8.0, 1.2 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 4.14 (q, J = 6.8 Hz, 2H), 1.45 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 161.5, 147.7, 146.9, 137.5, 136.5, 131.9, 127.1, 126.2, 126.0, 125.0, 121.2, 120.3, 111.1, 64.4, 15.0; LRMS (ESI) m / z calcd for C 15 H 14 ClN 2 O 4 [M + H] +: 321.06; Found: 321.15.

(E, 2-chloro-N- (2- (hexyloxy) phenyl) -5-nitrobenzamide)

Figure 112015128256936-pat00079

1 H NMR (400 MHz, CDCl 3) δ 8.76 (brs, 1H), 8.72 (d, J = 2.8 Hz, 1H), 8.50 (dd, J = 8.0, 1.2 Hz, 1H), 8.25 (dd, J = 8.8, 2.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.13 (t, J = 8.0, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 4.06 (t , J = 6.8 Hz, 2H), 1.81 (m, 2H), 1.45 (m, 2H), 1.32 (m, 4H), 0.87 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 161.5, 147.9, 146.9, 137.5, 136.5, 131.8, 127.1, 126.2, 126.0, 125.0, 121.2, 120.3, 111.1, 68.9, 31.6, 29.3, 25.9, 22.7, 14.1; LRMS (ESI) m / z calcd for C 19 H 22 ClN 2 O 4 [M + H] +: 377.13; Found: 377.20.

2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -5-nitrobenzamide [

Figure 112015128256936-pat00080

1 H NMR (400 MHz, CDCl 3) δ 9.31 (brs, 1H), 8.64 (d, J = 2.8 Hz, 1H), 8.45 (dd, J = 8.0, 1.6 Hz, 1H), 8.26 (dd, J = 8.4, 2.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.13 (dd, J = 8.0, 1.6 Hz, 1H), 7.08 (dd, J = 8.0, 1.2 Hz, 1H), 6.98 ( dd, J = 8.0, 1.2 Hz , 1H), 4.19 (t, J = 5.6 Hz, 2H), 2.72 (t, J = 5.6 Hz, 2H), 2.50-2.43 (m, 8H), 2.16 (s, 3H ); 13 C NMR (100 MHz, CDCl 3) δ 162.1, 148.1, 146.7, 138.0, 137.2, 131.7, 128.2, 125.9, 125.7, 125.3, 122.1, 121.2, 113.4, 66.9, 57.2, 54.8, 53.3, 46.0; LRMS (ESI) m / z calcd for C 20 H 24 ClN 4 O 4 [M + H] +: 419.15; Found: 419.06.

Experimental Example  2. PPAR gamma Ser273 Residue  Confirmation of phosphorylation inhibition effect 2

Assays A, B, C, D, E, and F prepared in Examples 1 and 2 were performed in the same manner as Experimental Example 1, and the results are shown in FIG.

As shown in Fig. 5, F having a hydrophilic functional group at the R group did not inhibit the phosphorylation of the PPARγ Ser273 residue at all, but the compounds having a hydrophobic functional group at the R group were found to inhibit phosphorylation generally. In particular, it was confirmed that B (SB1405) having benzyl group as R group is the most effective structure for inhibiting phosphorylation.

Example  3. PPAR gamma Ser273 Residue  Production of inhibitors that inhibit phosphorylation (Irreversible) 3

SB1451 (Formula 11) and SB1453 (Formula 12) were prepared as shown in Reaction Scheme 3 based on the crystal structure as shown in Fig. 6 to improve physical properties as an inhibitor.

 [Reaction Scheme 3]

Figure 112015128256936-pat00081

Methyl) benzyl) oxy) phenyl) -5-nitrobenzamide (hereinafter referred to as "SB1451", 2-chloro-N- )

Figure 112015128256936-pat00082

1 H NMR (400 MHz, DMSO- d 6) δ 10.09 (s, 1H), 8,99 (t, J = 5.6 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.26 (dd, J = 8.4, 2.8 Hz, 1H ), 7.85 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 6.8 Hz, 1H), 7.39-7.24 (m, 6H), 7.20 (t, J = 8.4 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 5.34 (s, 2H), 4.58 ( d, J = 5.6 Hz, 2H), 3.48 (s, 2H), 2.34 (brs, 8H), 2.15 (s, 3H); 13 C NMR (100 MHz, DMSO- d 6) δ 166.1, 163.1, 150.5, 146.0, 141.8, 137.9, 137.7, 137.2, 134.2, 132.8, 131.3, 128.5, 128.2, 128.1, 127.1, 126.8, 126.29, 126.26, 125.5 , 124.7, 124.0, 120.5, 113.1, 67.9, 61.6, 54.7, 52.5, 45.7; LRMS (ESI) m / z calcd for C 34 H 35 ClN 5 O 5 [M + H] + : 628.23; Found: 628.30.

 Methyl) benzyl) oxy) phenyl) -5-nitrobenzamide (hereinafter referred to as " SB1453, 2-chloro-N- )

Figure 112015128256936-pat00083

1 H NMR (400 MHz, DMSO- d 6) δ 10.07 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.30 (dd, J = 8.8, 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 4H), 7.43-7.31 (m, 5H), 7.26 (d, J = 7.6 Hz, 1H), 7.17-7.14 7.01-6.97 (m, 1H), 5.19 (s, 2H), 4.46 (d, J = 6.0 Hz, 2H), 3.49 (s, 2H), 2.34 (brs, 8H), 2.14 (s, 3H); 13 C NMR (100 MHz, DMSO- d 6 )? 166.0, 163.0, 150.6, 146.0, 141.8, 139.9, 137.7, 137.2, 137.0, 133.0, 131.3, 128.6, 128.4, 127.2, 126.6. 126.33, 126.28, 125.9, 125.6, 124.7, 124.1, 120.5, 113.2, 69.8, 61.6, 54.7, 52.6, 45.7, 42.5; LRMS (ESI) m / z calcd for C 34 H 35 ClN 5 O 5 [M + H] + : 628.23; Found: 628.41.

Experimental Example  3. PPAR gamma Ser273 Residue  Confirm phosphorylation inhibition effect 3

Assays were carried out in the same manner as in Experimental Example 1 except that the concentrations of SB1451 and SB1453 prepared in Example 3 were varied (0.1 uM, 1 uM, and 10 uM), and the results are shown in Fig.

As shown in Fig. 7, SB1451 and SB1453 effectively inhibited the phosphorylation of the PPARγ Ser273 residue in a concentration-dependent manner.

Example  4. PPAR gamma Ser273 Residue  Production of inhibitors that inhibit phosphorylation (Irreversible) 4

SB1450 and SB1452 were prepared in a similar manner to Scheme 3.

(SB1450)

Figure 112015128256936-pat00084

(SB1452)

Figure 112015128256936-pat00085

Experimental Example  4. PPAR gamma Ser273 Residue  Confirm phosphorylation inhibition effect 4

Assays were carried out in the same manner as in Experimental Example 1 for comparison with the inhibitors prepared in Examples 1 to 4, and the results are shown in FIG.

As shown in Fig. 8, SB1450 and SB1452 effectively inhibited PPARy phosphorylation, but the degree of inhibition was slightly lower than that of SB1451 and SB1453.

Example  5. PPAR gamma Ser273 Residue  Production of inhibitors that inhibit phosphorylation (Irreversible) 5

Compound A (Formula 15), Compound B (Formula 16), Compound C (Formula 17), and Compound D (Formula 18) in which the structure of the covalent bonding site is modified to improve the solubility Respectively.

[Reaction Scheme 4]

Figure 112015128256936-pat00086

(Compound A)

Figure 112015128256936-pat00087

1 H NMR (400 MHz, CDCl 3) δ 8.31 (s, 1H), 7.87 (brs, 1H), 6.76 (brs, 1H), 3.02 (d, J = 6.0 Hz, 3H), 3,01 (d, J = 5.6 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 165.3, 162.3, 157.8, 155.0, 108.1, 28.2, 26.6; LRMS (ESI) m / z calcd for C 7 H 9 ClN 4 O [M + H] + : 201.05; Found: 201.10.

(Compound B)

Figure 112015128256936-pat00088

1 H NMR (400 MHz, CDCl 3) δ 8.45 (brs, 1H), 8.34 (s, 1H), 7.62 (brs, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.21 (t, J = 7.6 Hz, 1H), 3.04 (d, J = 4.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 162.9, 162.2, 158.0, 155.0, 136.7, 129.2, 125.5, 120.6, 108.8, 28.3; LRMS (ESI) m / z calcd for C 12 H 11 ClN 4 O [M + H] + : 263.06; Found: 263.10.

(Compound C)

Figure 112015128256936-pat00089

1 H NMR (400 MHz, CDCl 3) δ 9.12 (brs, 1H), 8.43 (d, J = 7.6 Hz, 1H), 8.32 (s, 1H), 8.09 (brs, 1H), 7.40-7.34 (m, 5H), 7.12 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 2H), 5.12 (s, 2H), 3.03 (d, J = 4.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 162.8, 162.7, 157.9, 155.3, 147.8, 135.7, 128.8, 128.6, 128.0, 127.1, 124.9, 121.3, 120.5, 111.6, 108.3, 71.2, 28.3; LRMS (ESI) m / z calcd for C 19 H 17 ClN 4 O 2 [M + H] +: 369.10; Found: 369.20.

(Compound D)

Figure 112015128256936-pat00090

1 H NMR (400 MHz, CDCl 3) δ 8.34 (s, 1H), 8.32 (brs, 1H), 7.63 (brs, 1H), 7.45-7.28 (m, 7H), 7.09 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.08 (s, 2H), 3.04 (d, J = 4.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 162.9, 162.3, 159.4, 158.1, 155.1, 137.9, 136.6, 129.9, 128.6, 128.0, 127.5, 112.9, 111.9, 108.6, 107.3, 70.1, 28.3; LRMS (ESI) m / z calcd for C 19 H 17 ClN 4 O 2 [M + H] +: 369.10; Found: 369.10.

Experimental Example  5. PPAR gamma Ser273 Residue  Confirm phosphorylation inhibition effect 5

Assays were carried out in the same manner as in Experimental Example 1, except that Compound A, Compound B, Compound C and Compound prepared in Example 4 were used at a concentration of 10 uM. The results are shown in FIG.

As shown in Fig. 9, it was confirmed that compound C (Formula 17) effectively inhibited PPAR [gamma] phosphorylation. From these results, it can be seen that Formulas 1 and 2 having the same R 1 show the same activity in PPARγ phosphorylation inhibition.

Example  6. PPAR gamma Ser273 Residue  Production of inhibitors that inhibit phosphorylation (reversible) 6

BH273 (Chemical Formula 19) was prepared by modifying the structure of the covalent bonding site as a reversible inhibitor which does not cause nonspecific binding while maintaining a high potency which is an advantage of a covalent inhibitor.

(BH273)

Figure 112015128256936-pat00091

Experimental Example  6. PPAR gamma Ser273 Residue  Confirm phosphorylation inhibition effect 6

The assay was carried out in the same manner as in Experimental Example 1, except that the concentration (0.1 uM, 1 uM, 10 uM) of BH273 prepared in Example 5 was used, and the results are shown in Fig.

As shown in Fig. 10, BH273 showed a similar level of Ser273 phosphorylation inhibition as rosiglitazone, an antidiabetic PPARγ ligand.

Experimental Example  7. Cellular PPAR gamma Ser273 Residue  Identification of inhibition of phosphorylation

The phosphorylation inhibitory effect of PPARy Ser273 residues of SB1451 and SB1453 prepared in Example 3 above was confirmed on HEK-293 cells.

Specifically, HEK-293 cells expressing PPARy were treated with phorbol 12-myristate 13-acetate for 30 minutes and then incubated at 4 ° C with FLAG M2 agarose (Sigma Aldrich, USA). Immunoprecipitate was analyzed using a phosphor-specific antibody or an anti-PPARγ antibody of PPARγ Ser273, and the results are shown in FIG.

As shown in Fig. 11, it was confirmed that both SB1451 and SB1453 effectively inhibited phosphorylation of PPARγ on the cell surface.

Experimental Example  8. Confirm transcriptional activity

It was tested whether SB1451 and SB1453 produced in Example 3 cause transactivation.

Specifically, HEK-293T cells were inoculated into 96-well plates at a density of 7000 cells / well before transfection. Then, the cells were transfected with pDR-1 luciferase reporter plasmid, PPARγ RXRα and pRL-renillin using the calcium phosphate transfection method. After transfection, rosiglitazone, SR1664, SB1451 and SB1453 were treated for 24 hours. Cells were cultured and reporter gene assay (Promega, USA) was performed using a dual-luciferase kit. The activity of luciferase was measured using a Bio-Tek microplate reader (ELx800TM, Bio-Tek Instruments Inc., USA) and normalized to Renilla activity, and the resulting Fold The change is shown in Fig.

As shown in Fig. 12, it was confirmed that SB1451 and SB1453 had little effect on the transcriptional activity of PPARy, unlike Rosiglitazone.

Experimental Example  9. 3 T3L1  Adipocyte Differentiation Promotion Test

3T3L1 adipose precursor cells were grown on a 6-well plate to a confluency of 100%, and then 1 uM dexamethasone, 850 nM insulin, and 10 uM inhibitor (included in DMEM containing 10% FBS) Respectively. Then, DMEM and 850 nM insulin containing 10% FBS were continuously treated while being treated and replaced. On the eighth day of culture, lipids accumulated in 3T3L1 cells were confirmed by Oil Red O staining, and the results are shown in Fig.

FIG. 13 shows the result of confirming the accumulated lipids through Oil Red O staining.

As shown in Fig. 13, while Rosiglitazone promoted adipogenesis and differentiated 3T3L1 cells into mature adipocytes, SB1451 and SB1453 did not show lipid production promotion results.

Experimental Example  10. PPAR gamma Ser273 Residue  Inhibition of phosphorylation) vivo )

SB1451 and SB14533 were administered to obesity-induced mice (DIO mice) at a dose of 10 mg / kg / day for 7 days, and the inhibitory effect of the PPARγ Ser273 residue on the phosphorylation inhibition was confirmed in the same manner as in Experimental Example 1, Is shown in Fig.

As shown in Fig. 14, SB1451 and SB1453 inhibited PPAR [gamma] phosphorylation in DIO mice. In particular, SB1453 inhibited PPARγ phosphorylation at a level similar to that of Rosiglitazone in DIO mice.

Experimental Example  11. PPAR Expression of genes regulated by phosphorylation of?

Using the DIO mice in Experimental Example 10, 17 genes that were significantly affected by PPARy phosphorylation were evaluated for their expression:

<Target gene>

Adiponectin, Cd24a, Txnip, Nr1d1, Peg10, Acyl, Cidec, Rarres2, Car3, Selenbp1, Aplp2, Nr3c1, Cyp2f2, Nr1d2, Ddx17, Rybp

 Specifically, qPCR was performed by separating RNA from adipose tissue, and the degree of expression of the genes by the inhibitor treatment is shown in Fig.

As shown in FIG. 15, in the case of DIO mice treated with SB1453, expression of the target genes was significantly increased.

Experimental Example  12. Expression of genes regulated by transcriptional activity

Using the DIO mice in Experimental Example 10, expression levels of 17 genes significantly affected by transcription activity by conventional PPARγ activation were evaluated:

<Target gene>

Aph2, Cycs, Idh3a, Ppcs, Fdx1, Fgfrl1, Pdk4, Cib2, Fmr1, Pim3, Lasl, Abhd12, Nadk, Arhgap5, Lass4, Plin2, Phospho1

The specific experimental method was the same as that of Experimental Example 12, and the results are shown in FIG.

As shown in FIG. 16, the expression level of 17 target genes in Rosiglitazone-treated DIO mice was greatly increased, but the treatment with SB1453 did not show a statistically significant difference when compared with Control.

Experimental Example  13. To pay  The glucose tolerance test

For glucose tolerance test, rosiglitazone, SB1453, and vehicle were administered by intraperitoneal injection to DIO mice at 10 mg / kg daily. After the administration of 1.5 g / kg of D-glucose to the fasting mice, blood was drawn from the tail vein at regular time intervals and glucose concentration was measured with a Truetrack glucometer (Nipro Diagnostics, Japan) Respectively.

As shown in FIG. 17, it was confirmed that mice administered with SB1453 or rosiglitazone effectively lowered blood glucose concentration as compared with vehicle control.

Claims (8)

delete delete delete delete A compound represented by the following formula (4) or a compound represented by the following formula (14).
[Chemical Formula 4]
Figure 112017060727352-pat00111

[Chemical Formula 5]
Figure 112017060727352-pat00112

[Chemical Formula 6]
Figure 112017060727352-pat00113

(7)
Figure 112017060727352-pat00114

[Chemical Formula 8]
Figure 112017060727352-pat00115

[Chemical Formula 9]
Figure 112017060727352-pat00116

[Chemical formula 10]
Figure 112017060727352-pat00117

(11)
Figure 112017060727352-pat00118

[Chemical Formula 12]
Figure 112017060727352-pat00119

[Chemical Formula 13]
Figure 112017060727352-pat00120

[Chemical Formula 14]
Figure 112017060727352-pat00121
A pharmaceutical composition for preventing or treating obesity, metabolic diseases or cardiovascular diseases, which comprises the compound of claim 5 as an active ingredient. The method of claim 6,
The metabolic diseases are diabetes, hyperlipidemia, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, syndrome X or endothelial dysfunction,
Wherein said cardiovascular disease is cardiovascular disease is hypertension, precoagulant state, dyslipidemia or atherosclerotic disease.
The method of claim 6,
A pharmaceutical composition further comprising a pharmacologically acceptable agent, carrier or excipient.
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