WO2017115914A1 - Inhibiteur de la phosphorylation de ppary et composition pharmaceutique le comprenant - Google Patents

Inhibiteur de la phosphorylation de ppary et composition pharmaceutique le comprenant Download PDF

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WO2017115914A1
WO2017115914A1 PCT/KR2016/001513 KR2016001513W WO2017115914A1 WO 2017115914 A1 WO2017115914 A1 WO 2017115914A1 KR 2016001513 W KR2016001513 W KR 2016001513W WO 2017115914 A1 WO2017115914 A1 WO 2017115914A1
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formula
pparγ
group
substituted
phosphorylation
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PCT/KR2016/001513
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English (en)
Korean (ko)
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박승범
배환
김희준
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서울대학교산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic 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
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • the present invention relates to a PPAR ⁇ phosphorylation inhibitor and a pharmaceutical composition comprising the same.
  • Peroxysomes are one of the organelles that cause these metabolic disorders, and have been considered to play a minor role in cellular function for many years. It has been found to play an important role in metabolism. In addition, peroxysomes have been reported to have a wide range of effects on regulation of cell proliferation / differentiation and regulation of inflammatory mediators.
  • peroxisome proliferator-activated receptors also called "PPARs”
  • PPARs There are three types of PPARs, PPAR ⁇ , PPAR ⁇ / ⁇ , and PPAR ⁇ , of which PPAR ⁇ is most frequently found in adipose tissue and is found in vascular endothelial cells, macrophages, and pancreatic ⁇ -cells.
  • PPAR ⁇ regulates the differentiation of fat cells and plays a critical role in systemic lipid homeostasis. Furthermore, since PPAR ⁇ is closely related to insulin sensitivity, PPAR ⁇ has been a major target in the development of therapeutics such as obesity and diabetes.
  • Non-Patent Documents 1 and 2 In relation to the relationship between PPAR ⁇ and obese diabetes, the study found that obesity increased the inflammatory factors TNF- ⁇ , IL-6 and free fatty acids (FFAs), resulting in phosphorylation of Ser273 of PPAR ⁇ in adipocytes.
  • TNF- ⁇ , IL-6 and free fatty acids (FFAs) inflammatory factors
  • FFAs free fatty acids
  • the present invention provides a PPAR ⁇ phosphorylation inhibitor that can effectively inhibit PPAR ⁇ phosphorylation (specifically, inhibits Ser273 phosphorylation of PPAR ⁇ ) without causing transactivation of PPAR ⁇ , and a pharmaceutical composition containing the same as an active ingredient. It aims to provide.
  • the present invention provides a PPAR ⁇ phosphorylation inhibitor comprising at least one selected from the group consisting of compounds represented by the following formula (1) to compound represented by 3.
  • 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 ) pR 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,
  • O and p are each an integer of 0 to 5
  • 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 as or different from each other, and each hydrogen An atom or an alkyl group having 1 to 3 carbon atoms,
  • R 3 and R 4 may be the same as or different from each other, and each is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group,
  • 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.
  • a 1 and A 2 are an aromatic compound
  • X is an oxygen atom
  • n is O
  • m may be 1.
  • R 1 is or It may be
  • R 6 is a hydrogen atom, , , , . , , , , , or Is,
  • R 7 is -A 4 -R 10 , wherein A 4 is a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,
  • R 10 is a hydrogen atom, a methyl group, , , or ego,
  • R 11 may be a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • Another embodiment may include one or more selected from the group consisting of a compound represented by Formula 4 to a compound represented by 19.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of obesity, metabolic disease or cardiovascular disease, characterized in that it contains the PPAR ⁇ phosphorylation inhibitor as an active ingredient.
  • the metabolic disease is diabetes, hyperlipidemia, hyperinsulinemia, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (syndrome X) or endothelial dysfunction, wherein the cardiovascular disease is a cardiovascular disease Hypertension, precoagulant state, dyslipidemia or atherosclerosis disease.
  • Another embodiment may further comprise a pharmacologically acceptable medicament, diluent or excipient.
  • the PPAR ⁇ -phosphorylation inhibitor effectively inhibits only phosphorylation of Ser273 without transactivation, and is characterized by strong binding with PPAR ⁇ .
  • FIG. 1 shows the structures of SB1405, SB1406, GW9662 and SB1404 according to Example 1.
  • FIG. 1 shows the structures of SB1405, SB1406, GW9662 and SB1404 according to Example 1.
  • Figure 2 shows the results of confirming the phosphorylation inhibitory effect of the PPAR ⁇ Ser273 residue according to Experimental Example 1.
  • FIG. 3 shows X-ray crystal structures of SB1405 and SB1406 according to Experimental Example 1.
  • FIG. 4 shows the chemical structures of A to F according to Example 2.
  • FIG. 6 shows a design process of SB1405, SB1451 and SB1453 according to the third embodiment.
  • Figure 7 shows the results confirm the phosphorylation inhibitory effect of the PPAR ⁇ Ser273 residue according to Experimental Example 3.
  • Figure 9 shows the results of confirming the phosphorylation inhibitory effect of the PPAR ⁇ Ser273 residue according to Experimental Example 5.
  • Figure 10 shows the results confirming the phosphorylation inhibitory effect of the PPAR ⁇ Ser273 residue according to Experimental Example 6.
  • Figure 11 shows the results of confirming the phosphorylation inhibitory effect of PPAR ⁇ Ser273 residue on the cell according to Experimental Example 7.
  • Figure 13 shows the result of confirming the lipid accumulated through Oil Red O staining according to Experimental Example 9.
  • FIG. 14 shows the results of confirming the effect of inhibiting phosphorylation of PPAR ⁇ Ser273 residues in vivo according to Experimental Example 10.
  • FIG. 15 shows expression evaluation results of 17 genes regulated by PPAR ⁇ phosphorylation according to Experimental Example 11.
  • Figure 17 shows the sugar load test results according to Experimental Example 13.
  • the present invention relates to a PPAR ⁇ phosphorylation inhibitor and a pharmaceutical composition comprising the same.
  • the present invention provides a PPAR ⁇ phosphorylation inhibitor comprising at least one member selected from the group consisting of compounds represented by Formula 1 to compounds represented by 3.
  • 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 ) pR 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,
  • O and p are each an integer of 0 to 5
  • 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 as or different from each other, and each hydrogen An atom or an alkyl group having 1 to 3 carbon atoms,
  • R 3 and R 4 may be the same as or different from each other, and each is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted phenyl group,
  • 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.
  • the part except R 1 is a structure for covalently binding PPAR ⁇ , and the part except R 6 in R 1 occupies a hydrophobic specific binding site to inhibit phosphorylation of PPAR ⁇ Ser273 residue.
  • R 6 is-(CH 2 ) oA 3- (CH 2 ) pR 7 instead of a hydrogen atom, R 6 is a structure having in order to further increase the PPAR ⁇ phosphorylation inhibitory effect.
  • Formula 2 is a modification of the structure for covalently binding PPAR ⁇ in Formula 1 to improve solubility
  • Formula 3 is a non-specific binding while maintaining the high potency of the covalent inhibitor (Covalent inhibitor)
  • the structure for covalent bonding is modified in Chemical Formula 1.
  • the formula (3) is characterized in that it can act as a reversible inhibitor.
  • cycloalkyl compounds include, but are not limited to, cyclopentyl, cyclohexyl, and the like.
  • the heteroaromatic group or heteroaromatic compound includes at least one oxygen atom, sulfur atom or nitrogen atom, and is not limited to the position of the oxygen atom, sulfur atom or nitrogen atom.
  • the heteroaromatic compound includes, but is not limited to, furan, thiophene, pyrrole, imidazole, and the like.
  • An alkyl group having 1 to 3 carbon atoms means a straight or branched alkyl group and includes, for example, methyl, ethyl, n-propyl, i-propyl.
  • An alkyl group having 1 to 5 carbon atoms means a straight or branched alkyl group, and examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the like. It doesn't work.
  • the position of X linked to A 1 is not limited, but when A 1 is an aromatic compound, ortho or meta is preferable, and most preferably, ortho may be ortho.
  • R 6 connected to A 2 is not limited, but when A 2 is an aromatic compound, ortho or meta is preferable.
  • a 1 and A 2 are an aromatic compound, X is an oxygen atom, n is O, and m may be 1.
  • R 1 is or It may be
  • R 6 may have a structure of forming a part having hydrophobicity and a part having hydrophilicity on the basis of A 2 .
  • R 6 is a hydrogen atom, , , , . , , , , , or Is,
  • R 7 is -A 4 -R 10 , wherein A 4 is a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group,
  • R 10 is a hydrogen atom, a methyl group, , , or ego,
  • R 11 may be a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
  • the inhibitor may include one or more selected from the group consisting of compounds represented by Formula 4 to compounds represented by 19.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of obesity, metabolic diseases or cardiovascular diseases, characterized in that it contains a PPAR ⁇ phosphorylation inhibitor as an active ingredient.
  • the composition inhibits PPAR ⁇ phosphorylation to prevent or treat diabetes, obesity, metabolic diseases or cardiovascular diseases. It is characterized in that, more specifically inhibits the phosphorylation of PPAR ⁇ Ser273 exhibits the prevention or treatment of the diabetes, obesity, metabolic disease or cardiovascular disease.
  • hypercholesterolemia among the metabolic diseases is low HDL-cholesterolemia, high LDL-cholesterolemia or hypertriglyceridemia, and the cardiovascular disease is hypertension, precoagulant state, dyslipidemia or atherosclerosis. It may be a sclerotic disease, but is not particularly limited thereto.
  • the amount of the inhibitor including at least one selected from the group consisting of the compound represented by Formula 1 to the compound represented by Formula 3 is in the form and purpose of use, patient condition It may be appropriately adjusted according to the kind and severity of symptoms, 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 method of administration, the age, sex of the patient, the severity, the condition of the patient, the absorption of the active ingredient in the body, the inactivation rate and the drug used in combination, 0.1 mg / 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 based on ingredients It may be administered in (body weight), it may be administered once or divided into several, but is not limited thereto.
  • the pharmaceutical composition of the present invention can be administered to a mammal including a human by various routes.
  • the mode of administration can be any of the routinely used methods and can be administered, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine epidural or intracerebroventricular injection.
  • the pharmaceutical compositions of the present invention may be prepared in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral dosage forms, transdermals, suppositories, and sterile injectable solutions in accordance with conventional methods. Can be formulated and used.
  • the pharmaceutical composition of the present invention may further contain an adjuvant such as a pharmaceutically suitable and physiologically acceptable carrier, excipient and diluent in addition to the active ingredient.
  • Carriers, excipients and diluents which may be included in the pharmaceutical compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid form forms at least one excipient such as starch, calcium carbonate, sucrose or It may be prepared by mixing lactose, gelatin and the like.
  • lubricants such as magnesium styrate talc are also used.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, transdermal agents and the like.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • base of the suppository Whitepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • SB1405 (Formula 4) and SB1406 (Formula 5) are selected from the covalent inhibitors expected to occupy the specific binding sites as described in Scheme 1 below based on the GW9662 and PPAR ⁇ crystal structure, which are known covalent ligands.
  • SB1404 (Formula 21), which is expected to not be occupied at all, was also manufactured, and the structure thereof is shown in FIG. 1.
  • phosphorylation was performed by reacting 0.5 ⁇ g of purified PPAR ⁇ LBD (Ligand Binding Domain) at 30 ° C. for 30 minutes with active Cdk5 / p35 (Millipore, USA), and the assay was performed under the following conditions:
  • PPAR ⁇ LBD and the inhibitor were first reacted at 30 ° C. 30 minutes before the assay, and the substrate was Rb peptide (residues 773) to confirm that the inhibitor did not directly act on Cdk5. -928, Millipore) followed by the same assay (Rb peptide is one of the well known substrates of Cdk5).
  • the degree of phosphorylation of the substrate was confirmed by Western blotting using aniti-phospho-Ser Cdk substrate antibody (Cell Signaling Technology, USA), and the results are shown in FIG. 2.
  • Rosiglitazone (Rosi) and SR1664, which are known as antidiabetic PPAR ⁇ ligands were assayed in the same manner.
  • SB1451 (Scheme 11) and SB1453 (Scheme 12) were prepared as shown in Scheme 3 based on the crystal structure as described in FIG. 6.
  • SB1451 and SB1453 was found to effectively inhibit the phosphorylation of PPAR ⁇ Ser273 residues in a concentration-dependent manner.
  • SB1450 and SB1452 effectively inhibited PPAR ⁇ phosphorylation, but the degree of inhibition was slightly lower than that of SB1451 and SB1453.
  • BH273 (Formula 19) was modified in which the structure of the covalent binding site was modified.
  • the assay was performed in the same manner as in Experiment 1 with different concentrations (0.1 uM, 1 uM, 10 uM) of BH273 prepared in Example 5, and the results are shown in FIG. 10.
  • BH273 showed Ser273 phosphorylation inhibition similar to that of rosiglitazone, an antidiabetic PPAR ⁇ ligand.
  • HEK-293 cells expressing PPAR ⁇ were treated with PMA (phorbol 12-myristate 13-acetate) for 30 minutes and then incubated in FLAG M2 agarose (Sigma Aldrich, USA) at 4 ° C. Immunoprecipitate was analyzed using phosphor-specific or anti-PPAR ⁇ antibodies of PPAR ⁇ Ser273 and the results are shown in FIG. 11.
  • PMA phorbol 12-myristate 13-acetate
  • HEK-293T cells were seeded in 96-well plates at a density of 7000 cells / well before transfection. Then, the cells were transfected with pDR-1 luciferase reporter plasmid, PPAR ⁇ RXR ⁇ and pRL-renillin using calcium phosphate transfection. After transfection, rosiglitazone, SR1664, SB1451, and SB1453 were treated for 24 hours, and after culturing the cells, a reporter gene assay (Promega, USA) was performed using the Dual-luciferase kit.
  • Luciferase activity was measured using a Bio-Tek microplate reader (ELx800TM, Bio-Tek Instruments Inc., USA) and normalized to Renilla activity, resulting in Fold based on DMSO-treated cells. The change is shown in FIG. 12.
  • SB1451 and SB1453 had little effect on the transcriptional activity of PPAR ⁇ , unlike Rosiglitazone.
  • 3T3L1 adipocytes were grown to 100% confluency in 6-well plates, followed by 1 uM dexamethasone, 850 nM insulin and 10 uM inhibitor (in DMEM containing 10% FBS) for 2 days. Treated. Since then, 10% FBS containing DMEM and 850 nM insulin was continuously cultured while treating and replacing. On day 8 of the culture, lipids accumulated in 3T3L1 cells were confirmed by Oil Red O staining, and the results are shown in FIG. 13.
  • Figure 13 shows the result of confirming the lipid accumulated through the Oil Red O staining.
  • SB1451 and SB1453 did not show the result of promoting lipid formation, whereas Rosiglitazone promoted adiogenesis and differentiated 3T3L1 cells into mature adipocytes.
  • SB1451 and SB14533 were administered at 10 mg / kg / day for 7 days in obese-induced obese mice (DIO mice) to confirm the effect of inhibiting the phosphorylation of PPAR ⁇ Ser273 residues in the same manner as in Experiment 1, and the results 14 is shown.
  • SB1451 and SB1453 was confirmed to inhibit PPAR ⁇ phosphorylation in DIO mice.
  • SB1453 was found to inhibit PPAR ⁇ phosphorylation at a level similar to Rosiglitazone in DIO mice.
  • rosiglitazone, SB1453, and vehicle were intraperitoneally injected at 10 mg / kg daily in DIO mice. Thereafter, 1.5 g / kg of D-glucose was administered to fasting mice, and blood was drawn at regular intervals from the tail vein to measure glucose concentration using a Truetrack glucometer (Nipro Diagnostics, Japan). Shown in
  • mice administered SB1453 or rosiglitazone effectively reduced blood glucose levels as compared to vehicle control.

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Abstract

La présente invention concerne un inhibiteur de la phosphorylation de PPARγ et une composition pharmaceutique le comprenant. L'inhibiteur de la phosphorylation de PPARγ de la présente invention est caractérisé en ce qu'il inhibe uniquement, et efficacement, la phosphorylation de Ser273, de façon sélective et sans présenter de transactivation, à la différence des médicaments classiques ciblant PPARγ, et en ce qu'il se lie fortement à PPARγ par une liaison covalente. Par conséquent, il est attendu que l'inhibiteur de la phosphorylation de PPARγ soit utile pour des domaines apparentés, tels que celui des médicaments ciblant des maladies liées à PPARγ.
PCT/KR2016/001513 2015-12-29 2016-02-15 Inhibiteur de la phosphorylation de ppary et composition pharmaceutique le comprenant WO2017115914A1 (fr)

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KR1020150188520A KR101815193B1 (ko) 2015-12-29 2015-12-29 PPARγ 인산화 저해제 및 이를 포함하는 약학적 조성물
KR10-2015-0188520 2015-12-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109836378A (zh) * 2017-11-25 2019-06-04 上海华汇拓医药科技有限公司 一类鞘磷脂合酶抑制剂、其制备方法及其应用
WO2023172846A1 (fr) * 2022-03-08 2023-09-14 Flare Therapeutics Inc. Agonistes inverses de pparg et leurs utilisations

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002539185A (ja) * 1999-03-16 2002-11-19 グラクソ グループ リミテッド 核内受容体アリール化化合物
US20030134859A1 (en) * 2000-04-28 2003-07-17 Sankyo Company, Limited PPAR-gamma modulator
JP2003201271A (ja) * 2001-10-25 2003-07-18 Sankyo Co Ltd 脂質モジュレーター
KR20030064852A (ko) * 2000-12-22 2003-08-02 이시하라 산교 가부시끼가이샤 아닐린 유도체 또는 그의 염 및 이들을 함유하는사이토카인 생산 억제제
US20150361100A1 (en) * 2014-06-17 2015-12-17 Chiesi Farmaceutici S.P.A. Indolizine derivatives as phoshoinositide 3-kinases inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002539185A (ja) * 1999-03-16 2002-11-19 グラクソ グループ リミテッド 核内受容体アリール化化合物
US20030134859A1 (en) * 2000-04-28 2003-07-17 Sankyo Company, Limited PPAR-gamma modulator
KR20030064852A (ko) * 2000-12-22 2003-08-02 이시하라 산교 가부시끼가이샤 아닐린 유도체 또는 그의 염 및 이들을 함유하는사이토카인 생산 억제제
JP2003201271A (ja) * 2001-10-25 2003-07-18 Sankyo Co Ltd 脂質モジュレーター
US20150361100A1 (en) * 2014-06-17 2015-12-17 Chiesi Farmaceutici S.P.A. Indolizine derivatives as phoshoinositide 3-kinases inhibitors

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109836378A (zh) * 2017-11-25 2019-06-04 上海华汇拓医药科技有限公司 一类鞘磷脂合酶抑制剂、其制备方法及其应用
CN109836378B (zh) * 2017-11-25 2022-09-30 上海华汇拓医药科技有限公司 一类鞘磷脂合酶抑制剂、其制备方法及其应用
WO2023172846A1 (fr) * 2022-03-08 2023-09-14 Flare Therapeutics Inc. Agonistes inverses de pparg et leurs utilisations

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