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WO2025170275A1 - Nouvel agoniste eif2b et composition pour la prévention ou le traitement de maladies métaboliques le comprenant - Google Patents

Nouvel agoniste eif2b et composition pour la prévention ou le traitement de maladies métaboliques le comprenant

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Publication number
WO2025170275A1
WO2025170275A1 PCT/KR2025/001480 KR2025001480W WO2025170275A1 WO 2025170275 A1 WO2025170275 A1 WO 2025170275A1 KR 2025001480 W KR2025001480 W KR 2025001480W WO 2025170275 A1 WO2025170275 A1 WO 2025170275A1
Authority
WO
WIPO (PCT)
Prior art keywords
acetamido
eif
propiolamide
chlorophenyl
chlorophenoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2025/001480
Other languages
English (en)
Korean (ko)
Inventor
최예린
안홍찬
박영혜
김소영
강성은
장민아
한재석
쿠수마페드호
이나라
박소영
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Industry Academy Cooperation Foundation of Soonchunhyang University
Daegu Gyeongbuk Medical Innovation Foundation
Original Assignee
Industry Academy Cooperation Foundation of Soonchunhyang University
Daegu Gyeongbuk Medical Innovation Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Industry Academy Cooperation Foundation of Soonchunhyang University, Daegu Gyeongbuk Medical Innovation Foundation filed Critical Industry Academy Cooperation Foundation of Soonchunhyang University
Publication of WO2025170275A1 publication Critical patent/WO2025170275A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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Definitions

  • the purpose of the present invention is to provide a novel compound that modulates the activity of downstream regulators involved in the integrated stress response.
  • Another object of the present invention is to provide a composition for treating metabolic diseases comprising the above compound.
  • the present invention provides a compound selected from a diamide derivative represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
  • n’, n”, m’ and m may be the same or different and are one of 0 to 2,
  • L is one of (C3-C10)cycloalkyl, (C5-C10)spirocycloalkyl and (C5-C10)bicycloalkyl,
  • a 1 and A 2 may be the same or different and are -CONH- or -NHCO-,
  • M’ and M may be the same or different and are one of (C1-C5)alkyl, (C2-C5)alkene, (C2-C5)alkyne; and heteroalkyl of 2 to 5 members containing one or more heteroatoms selected from O and S,
  • Ar 1 and Ar 2 may be the same or different, and are one of an unsubstituted or substituted (C5-C10)aryl and an unsubstituted or substituted 5 to 12-membered heteroaryl comprising one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted (C5-C10)aryl or the substituted 5 to 12-membered heteroaryl may be substituted with one or more of (C1-C5)alkyl, (C1-C5)alkoxy, halogen, trifluoromethyl, difluoromethyl and difluoroethyl.
  • the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising the above compound as an active ingredient.
  • the present invention provides a reagent composition for activating eIF2B comprising the above compound as an active ingredient.
  • novel compound according to the present invention can directly and significantly activate eIF2B, a protein that mediates integrated stress response signaling.
  • Figure 1 illustrates the mechanism of the Puromycin incorporation assay method used to verify the in vivo efficacy of a novel compound synthesized according to the present invention.
  • Figures 2a and 2b show the activity of a novel compound measured using the method of Figure 1.
  • Figure 3 shows the activity of the novel compound as a function of relative fluorescence intensity.
  • Figure 5 shows the results of enzyme activity analysis of the novel compound.
  • Figure 7 shows the experimental design and results for confirming the in vivo activity of a novel compound using an animal model.
  • Figure 8 shows the liver toxicity of the novel compound confirmed by ALT and AST levels.
  • Figure 9 shows the liver toxicity of the novel compound confirmed by histological changes.
  • Figure 10 shows the effect of a novel compound on macrophages.
  • the present inventors synthesized a novel compound that significantly activates eIF2B based on the fact that inhibition of protein synthesis by eIF2 ⁇ phosphorylation operates by inhibiting the activity of a GDP/GTP exchange enzyme called eIF2B, and further confirmed that the compound is effective in treating metabolic diseases related to eIF2B, thereby completing the present invention.
  • the present invention provides a novel compound selected from a diamide derivative represented by the following chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
  • n', n”, m’ and m may be the same or different and are one of 0 to 2
  • L is one of (C3-C10)cycloalkyl, (C5-C10)spirocycloalkyl and (C5-C10)bicycloalkyl
  • a 1 and A 2 may be the same or different and are -CONH- or -NHCO-
  • M’ and M” may be the same or different and are one of (C1-C5)alkyl, (C2-C5)alkene, (C2-C5)alkyne; and 2 to 5 membered heteroalkyl containing one or more heteroatoms selected from O and S
  • Ar 1 and Ar 2 may be the same or different and are one of unsubstituted or substituted (C5-C10)aryl and unsubstituted or substituted 5 to 12 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S.
  • substituted (C5-C10)aryl or substituted heteroaryl having 5 to 12 atoms may be substituted with one or more of (C1-C5)alkyl, (C1-C5)alkoxy, halogen, trifluoromethyl, difluoromethyl and difluoroethyl.
  • the compound is a compound in which n', n", m' and m" in the above chemical formula 1 may be the same or different and are 0 or 1
  • L is one of (C3-C7)cycloalkyl, (C6-C8)spirocycloalkyl and (C5-C8)bicycloalkyl
  • M' and M" may be the same or different and are one of (C2-C3)alkene, (C2-C3)alkyne; and one of 2 to 4 membered heteroalkyls containing one or more heteroatoms selected from O and S
  • Ar 1 and Ar 2 may be the same or different, and are one of unsubstituted or substituted (C5-C7)aryl and unsubstituted or substituted 5 to 10 membered heteroaryls containing one or more heteroatoms selected from the group consisting of N, O and S, and the substituted (C5-C7)aryl or the substituted 5 to 10 membered Heteroaryl may be substitute
  • the compound is a compound in which L in the above formula 1 is one of (C4-C6)cycloalkyl, spirocycloheptyl and bicyclopentyl, M' and M" may be the same or different, and are one of ethylene, acetylene and 2 to 4 membered heteroalkyl containing one heteroatom of O or S, Ar 1 and Ar 2 may be the same or different, and are one of unsubstituted or substituted phenyl and unsubstituted or substituted 5 to 10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted phenyl is substituted with one or more and three or less of trifluoromethyl, chlorine, fluorine, methoxy, methyl, ethyl and tert-butyl, and the substituted 5 to 10 membered heteroaryl is substituted with one or more and three or more of fluorine, methoxy, trifluor
  • the above 5 to 10-membered heteroaryl is one of pyridine, quinoline, thiazole, pyrimidazole, coumarone, 7-azaindole, benzimidazole, naphthyl, indazole, thionaphthene, benzothiazole, pyrimidine and pyrazole, and the above substituted 5 to 10-membered heteroaryl may be substituted with one of fluorine, methoxy, trifluoromethyl, difluoromethyl and difluoroethyl.
  • the diamide derivative represented by the above chemical formula 1 may be any one selected from the following group of compounds:
  • the above compound can activate eIF2B.
  • eIF2B eukaryotic initiation factor 2B
  • eIF2B eukaryotic initiation factor 2B
  • the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases, comprising as an active ingredient a compound selected from a diamide derivative represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the above metabolic disease may be selected from the group consisting of obesity, diabetes, arteriosclerosis, hyperlipidemia, fatty liver, and liver fibrosis, and preferably, the composition may be for anti-obesity use.
  • the pharmaceutical composition according to the present invention can be prepared according to conventional methods in the pharmaceutical field.
  • the pharmaceutical composition can be combined with an appropriate pharmaceutically acceptable carrier depending on the formulation, and, if necessary, can be prepared by further including excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc.
  • the appropriate carriers, etc., which do not inhibit the activity and properties of the compound according to the present invention, can be selected differently depending on the dosage form and formulation.
  • the pharmaceutical composition according to the present invention can be applied in any dosage form, and more specifically, it can be formulated and used as an oral dosage form, an external preparation, a suppository, and a parenteral dosage form of a sterile injection solution according to a conventional method.
  • the pharmaceutical composition can be administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not causing adverse effects.
  • the effective dosage level of the pharmaceutical composition may vary depending on the intended use, the patient's age, sex, weight, and health condition, the type and severity of the disease, the activity and sensitivity of the drug, the method of administration, the time of administration, the route of administration, and the excretion rate, the duration of treatment, the drugs used in combination or concurrently, and other factors well known in the medical field.
  • it may generally be administered once or several times daily at a dosage of 0.001 to 1000 mg/kg, preferably 0.01 to 100 mg/kg.
  • the above dosage does not limit the scope of the present invention in any way.
  • the pharmaceutical composition according to the present invention can be administered to any animal that may develop a metabolic disease, particularly obesity, and the animal may include, for example, humans and primates, as well as livestock such as cows, pigs, horses, and dogs.
  • the pharmaceutical composition according to the present invention can be administered via an appropriate route of administration depending on the formulation form, and can be administered via various routes, either oral or parenteral, as long as it can reach the target tissue.
  • the method of administration is not particularly limited, and can be administered by conventional methods such as oral, rectal, intravenous, intramuscular, or skin application, respiratory inhalation, intrauterine epidural, or intracerebroventricular injection.
  • the pharmaceutical composition according to the present invention can be used alone for the prevention or treatment of metabolic diseases, or can be used in combination with surgery or other drug treatments.
  • the present invention provides a health food composition for preventing or improving metabolic diseases, which comprises as an active ingredient a compound selected from a diamide derivative represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the above metabolic disease may be selected from the group consisting of obesity, diabetes, arteriosclerosis, hyperlipidemia, fatty liver, and liver fibrosis, and preferably, the composition may be for anti-obesity use.
  • the health food composition according to the present invention may be manufactured into powder, granules, tablets, capsules, syrup, or beverages for the purpose of preventing or improving metabolic diseases.
  • the form the health food may take, and it may be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods.
  • the above health food composition may be manufactured by further including food additives (food additives) commonly used in the industry and other appropriate auxiliary ingredients.
  • food additives food additives
  • suitability as a food additive may be determined by the specifications and standards for the relevant item, as stipulated in the General Provisions and General Test Methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety.
  • the above health food composition has the advantage of not having side effects that may occur with long-term use of general medicines as it uses food as a raw material, and is highly portable, so it can be taken as a supplement for preventing or improving metabolic diseases.
  • the present invention provides a reagent composition for activating eIF2B, which comprises as an active ingredient a compound selected from a diamide derivative represented by the above chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the above compound can enhance the expression or activity of eIF2B.
  • tert -Butyl (6-(2-(4-chlorophenoxy)acetamido)spiro[3.3]heptan-2-yl)carbamate] was dissolved in 20% TFA/CH 2 Cl 2 and the solution was stirred at room temperature for 4 h. The solution was evaporated under reduced pressure and the crude product was used in the next step without further purification.
  • tert -Butyl (6-(2-(pyridin-2-yloxy)acetamido)spiro[3.3]heptan-2-yl)carbamate] (50 mg, 0.14 mmol) was diluted with 20% TFA/CH 2 Cl 2 (1 mL, 0.14 M) and the solution was stirred at room temperature for 2 h. The organic solvent was removed under reduced pressure and the crude product was used in the next step without further purification.
  • tert -Butyl ( E )-(3-(3-(4-chlorophenyl)acrylamido)cyclobutyl)carbamate [ tert -Butyl ( E )-(3-(3-(4-chlorophenyl)acrylamido)cyclobutyl)carbamate] (130 mg, 0.37 mmol) was stirred in 10% TFA/CH 2 Cl 2 at room temperature for 4 h. The organic solvent was removed under reduced pressure and the crude product was used in the next step without further purification.
  • tert -Butyl (3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl) carbamate [ tert -butyl (3-(2-((2,6-dichlorobenzyl)thio)acetamido)cyclobutyl) carbamate] (100 mg, 0.24 mmol) was diluted in 20% TFA/CH 2 Cl 2 (1.2 mL, 0.2 M) and the solution was stirred at room temperature for 4 h. The organic solvent was removed under reduced pressure and the crude product was used in the next step without further purification.
  • the mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • tert-butyl (3-(2-(mesityloxy)acetamido)cyclobutyl)carbamate] (1.0 equiv., 111 mg, 0.306 mmol) was diluted in 20% TFA/DCM (255 ⁇ l/ 1.28 ml) at room temperature. After stirring for 4 h, the reaction mixture was evaporated without further purification.
  • N -(3-aminocyclobutyl)-2-(mesityloxy)acetamide 1.0 equiv., 80 mg, 0.305 mmol
  • DMF 1.5 ml
  • 2-(mesityloxy)acetic acid 1.1 equiv., 65 mg, 0.335 mmol
  • DIPEA 5.0 equiv., 266 ⁇ l, 1.525 mmol
  • HATU 2.0 equiv., 232 mg, 0.610 mmol
  • the reaction was diluted with EtOAc, and the organic phase was washed three times with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was suspended in a minimum amount of ethyl acetate and treated with hexane. The formed precipitate was purified to obtain 90 mg (82%) of the product as a pale yellow solid.
  • N -(3-aminocyclobutyl)-3-(2-chlorophenoxy)propanamide 1.0 equiv., 60 mg, 0.223 mmol
  • DMF 1.1 ml
  • 3-(2-chlorophenoxy)propanoic acid 1.1 equiv., 49 mg, 0.246 mmol
  • DIPEA 5.0 equiv., 195 ⁇ l, 1.116 mmol
  • HATU 2.0 equiv., 170 mg, 0.447 mmol
  • tert -butyl (3-(3-(2-fluorophenoxy)propanamido)cyclobutyl)carbamate (1.0 equiv., 40 mg, 0.108 mmol) was diluted in 20% TFA/DCM (255 ⁇ l/1.23 ml) at room temperature. After stirring for 4 h, the reaction mixture was evaporated without further purification.
  • N -(3-aminocyclobutyl)quinoline-3-carboxamide 1.0 equiv dissolved in CH 2 Cl 2 were added 2-(4-chlorophenoxy)acetyl chloride (1.5 equiv) and triethylamine (5 equiv).
  • the reaction mixture was stirred at room temperature, diluted with ethyl acetate, and washed with 10% aqueous lithium chloride (X3) and brine.
  • the organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure.
  • N -((1 r ,4 r )-4-aminocyclohexyl)-2-methoxyisonicotinamide 1.0 equiv
  • 2-(4-chlorophenoxy)acetyl chloride 1.5 equiv
  • triethylamine 5 equiv
  • N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide [ N -((1 r ,4 r )-4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide] (1.0 equiv), quinoline-3-carboxylic acid (1.2 equiv), N , N -diisopropylethylamine (2.5 equiv), EDCI (1.5 equiv), and HOBt (1.5 equiv) dissolved in DMF was stirred at room temperature overnight.
  • reaction mixture was diluted with ethyl acetate and washed with 10% aqueous lithium chloride (X3) and brine.
  • the organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure.
  • the residue was purified through filtration (EtOAc/ n -hexane) to obtain compound 13 (EIF-013) , N -((1 r ,4 r )-4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)quinoline-3-carboxamide, as a white solid with 99% purity.
  • N -(3-(aminomethyl)cyclobutyl)-3-(4-chlorophenyl)propiolamide 1.0 equiv., 22 mg, 0.084 mmol
  • DMF 449 ⁇ l
  • 3-(4-chlorophenyl)propiolic acid 1.1 equiv., 16 mg, 0.092 mmol
  • DIPEA 5.0 equiv., 78 ⁇ l, 0.449 mmol
  • HATU 2.0 equiv., 68.2 mg, 0.179 mmol.
  • N -(3-(aminomethyl)cyclobutyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide 1.0 equiv., 22 mg, 0.085 mmol
  • DMF 424 ⁇ l
  • 2-((5-fluoropyridin-2-yl)oxy)acetic acid 1.1 equiv., 15 mg, 0.085 mmol
  • DIPEA 3.0 equiv., 45 ⁇ l, 0.255 mmol
  • HATU 2.0 equiv., 64.6 mg, 0.170 mmol.
  • tert-butyl (3-(aminomethyl)cyclopentyl)carbamate [ tert -butyl (3-(aminomethyl)cyclopentyl)carbamate] in DMF (1.0 ml)
  • 2-((5-fluoropyridin-2-yl)oxy)acetic acid 1.1 equiv., 35.1 mg, 0.205 mmol
  • DIPEA 3.0 equiv., 98 ⁇ l, 0.560 mmol
  • HATU 2.0 equiv., 142 mg, 0.373 mmol.
  • tert-butyl (3-((2-((5-fluoropyridin-2-yl)oxy) acetamido )methyl)cyclopentyl)carbamate] (1.0 equiv., 30 mg, 0.082 mmol) was diluted with 20% TFA/DCM (68 ⁇ l/ 340 ⁇ l) at room temperature. After stirring for 3 h, the reaction mixture was evaporated without further purification.
  • N -((3-aminocyclopentyl)methyl)-2-((5-fluoropyridin-2-yl)oxy)acetamide (1.0 equiv., 20 mg, 0.075 mmol) in DMF (374 ⁇ l) was added 2-((5-fluoropyridin-2-yl)oxy)acetic acid (1.1 equiv., 14 mg, 0.082 mmol), DIPEA (3.0 equiv., 39 ⁇ l, 0.224 mmol), and HATU (2.0 equiv., 56.9 mg, 0.150 mmol).
  • N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide [ N -(3-aminocyclobutyl)-3-(4-chlorophenyl)propiolamide] in DMF (505 ⁇ l)
  • 3-(4-chlorophenyl)propiolic acid 1.1 equiv., 20.1 mg, 0.111 mmol
  • DIPEA 3.0 equiv., 53 ⁇ l, 0.303 mmol
  • HATU 2.0 equiv., 77 mg, 0.202 mmol
  • N -((1 r ,4 r )-4-aminocyclohexyl)pivalamide 1.0 equiv., 50 mg, 0.252 mmol
  • DMF 1.3 ml
  • 3-(4-chlorophenyl)propiolic acid 1.1 equiv., 50 mg, 0.277 mmol
  • DIPEA 3.0 equiv., 132 ⁇ l, 0.756 mmol
  • HATU 2.0 equiv., 192 mg, 0.504 mmol.
  • the reaction mixture was stirred at room temperature overnight.
  • the mixture was diluted with EtOAc, and the organic phase was washed three times with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was diluted with hexane and the formed precipitate was filtered and collected to obtain 73 mg (80%) of a white solid product.
  • the activity of the novel compound was measured using a method called Puromycin incorporation assay, as shown in Fig. 1.
  • the integrated stress response is initiated by the phosphorylation of eIF2 ⁇ , and phosphorylated eIF2 ⁇ inhibits protein synthesis.
  • the inhibition of protein synthesis by eIF2 ⁇ phosphorylation works by inhibiting the activity of a GDP/GTP exchange enzyme called eIF2B.
  • eIF2B a GDP/GTP exchange enzyme
  • Thapsigargin is a drug that inhibits SERCA calcium channels, altering calcium concentration in the endoplasmic reticulum (ER), thereby inducing the integrated stress response. It is widely used in research on the integrated stress response.
  • the enzyme assay involves loading GDP conjugated with BODIPY (a fluorescent substance) onto the eIF2 enzyme complex, then adding this to a sample containing eIF2B.
  • BODIPY a fluorescent substance
  • the process of BODIPY-conjugated GDP being released by the activity of eIF2B can be observed through fluorescence (Fig. 4).
  • the EC 50 for the new compounds was also confirmed. Referring to Fig. 6, while the negative control compound 35 showed no effect on GEF activity at all, ISRIB and compounds 43 showed similar activation of eIF2B. In addition, the EC 50 of ISRIB was approximately 20 nM, which is similar to the previously reported EC 50 , and compound 43 also showed an EC 50 of approximately 24 nM, which is comparable to that of ISRIB.
  • mice were fed a high-fat diet for a total of 8 weeks, during which time ISRIB was treated as a positive control and DMSO as a negative control.
  • body weight changes were investigated.
  • novel compounds 43 and 52 when administered to high-fat diet-fed obese mice, exhibited effects comparable to those of the control drug ISRIB.
  • the ALT and AST levels which indicate the degree of liver damage, were checked.
  • ALT and AST levels did not change significantly due to ISRIB, and novel compounds 43 and 52 also did not induce changes in ALT and AST levels in the liver after in vivo administration.

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Abstract

La présente invention concerne un nouvel agoniste de eIF2B et une composition pour la prévention ou le traitement de maladies métaboliques le comprenant. Plus particulièrement, la présente invention concerne un nouveau dérivé de diamide, un stéréoisomère, un solvate ou un sel pharmaceutiquement acceptable de celui-ci qui active eIF2B. Le nouveau composé selon la présente invention active directement et significativement eIF2B, une protéine qui médie la signalisation de réponse au stress intégrée, et peut ainsi être utilisé en tant que composition thérapeutique efficace pour des maladies métaboliques associées à eIF2B.
PCT/KR2025/001480 2024-02-05 2025-01-24 Nouvel agoniste eif2b et composition pour la prévention ou le traitement de maladies métaboliques le comprenant Pending WO2025170275A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014144952A2 (fr) * 2013-03-15 2014-09-18 Peter Walter Modulateurs de la voie eif2 alpha
KR20190031203A (ko) * 2016-05-05 2019-03-25 칼리코 라이프 사이언시스 엘엘씨 통합 스트레스 경로의 조정제
KR20200096918A (ko) * 2017-11-02 2020-08-14 칼리코 라이프 사이언시스 엘엘씨 통합된 스트레스 경로의 조절제
KR20210134351A (ko) * 2019-02-25 2021-11-09 프락시스 바이오테크 엘엘씨 통합 스트레스 반응 경로의 억제제

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PT1928454E (pt) 2005-05-10 2014-12-04 Intermune Inc Derivativos da piridona para modulação do sistema de proteína quinase ativada pelo stress

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2014144952A2 (fr) * 2013-03-15 2014-09-18 Peter Walter Modulateurs de la voie eif2 alpha
KR20190031203A (ko) * 2016-05-05 2019-03-25 칼리코 라이프 사이언시스 엘엘씨 통합 스트레스 경로의 조정제
KR20200096918A (ko) * 2017-11-02 2020-08-14 칼리코 라이프 사이언시스 엘엘씨 통합된 스트레스 경로의 조절제
KR20210134351A (ko) * 2019-02-25 2021-11-09 프락시스 바이오테크 엘엘씨 통합 스트레스 반응 경로의 억제제

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HEARN, B. R. ET AL.: "Structure-activity studies of bis-O-arylglycolamides: Inhibitors of the integrated stress response", CHEMMEDCHEM, vol. 11, 2016, pages 870 - 880, XP055383675, DOI: 10.1002/cmdc.201500483 *

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