ES2742503T3 - Derivados de FGF21 y sus usos - Google Patents
Derivados de FGF21 y sus usos Download PDFInfo
- Publication number
- ES2742503T3 ES2742503T3 ES15817847T ES15817847T ES2742503T3 ES 2742503 T3 ES2742503 T3 ES 2742503T3 ES 15817847 T ES15817847 T ES 15817847T ES 15817847 T ES15817847 T ES 15817847T ES 2742503 T3 ES2742503 T3 ES 2742503T3
- Authority
- ES
- Spain
- Prior art keywords
- ethoxy
- amino
- fgf21
- oxo
- ethylamino
- 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.)
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- 108090000376 Fibroblast growth factor 21 Proteins 0.000 title claims abstract description 384
- 102000003973 Fibroblast growth factor 21 Human genes 0.000 title claims abstract description 384
- 101000846529 Homo sapiens Fibroblast growth factor 21 Proteins 0.000 claims abstract description 74
- 102000056713 human FGF21 Human genes 0.000 claims abstract description 74
- 239000000126 substance Substances 0.000 claims abstract description 59
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 58
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 57
- 239000004606 Fillers/Extenders Substances 0.000 claims abstract description 50
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 18
- 150000001408 amides Chemical class 0.000 claims abstract description 10
- 150000002148 esters Chemical class 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000011593 sulfur Substances 0.000 claims abstract description 6
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract 7
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 363
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 291
- -1 11-carboxyundecanoylamino Chemical group 0.000 claims description 140
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 136
- 150000001875 compounds Chemical class 0.000 claims description 113
- 238000000034 method Methods 0.000 claims description 112
- 125000005647 linker group Chemical group 0.000 claims description 72
- 238000011282 treatment Methods 0.000 claims description 70
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 60
- 150000001413 amino acids Chemical class 0.000 claims description 47
- 239000002253 acid Substances 0.000 claims description 46
- 230000002265 prevention Effects 0.000 claims description 26
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 20
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 19
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 18
- 206010012601 diabetes mellitus Diseases 0.000 claims description 16
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- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 10
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- 150000002632 lipids Chemical class 0.000 claims description 7
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 6
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- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 6
- 229940126086 compound 21 Drugs 0.000 claims description 6
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 6
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 5
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 5
- 239000005711 Benzoic acid Substances 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 208000002249 Diabetes Complications Diseases 0.000 claims description 5
- 206010012655 Diabetic complications Diseases 0.000 claims description 5
- 208000030814 Eating disease Diseases 0.000 claims description 5
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 5
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 5
- 235000010233 benzoic acid Nutrition 0.000 claims description 5
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- 235000014632 disordered eating Nutrition 0.000 claims description 5
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 4
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- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 3
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 claims description 3
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 claims description 3
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 claims description 3
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 claims description 3
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- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 claims description 2
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- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 claims description 2
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- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 claims description 2
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- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 claims description 2
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- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
- C07K14/50—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP14199935 | 2014-12-23 | ||
| PCT/EP2015/080969 WO2016102562A1 (en) | 2014-12-23 | 2015-12-22 | Fgf21 derivatives and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2742503T3 true ES2742503T3 (es) | 2020-02-14 |
Family
ID=52130150
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES15817847T Active ES2742503T3 (es) | 2014-12-23 | 2015-12-22 | Derivados de FGF21 y sus usos |
Country Status (24)
| Country | Link |
|---|---|
| US (3) | US9744213B2 (https=) |
| EP (1) | EP3236991B1 (https=) |
| JP (1) | JP6727210B2 (https=) |
| KR (1) | KR102427527B1 (https=) |
| CN (1) | CN107108709B (https=) |
| AR (1) | AR103246A1 (https=) |
| AU (1) | AU2015371056B2 (https=) |
| DK (1) | DK3236991T3 (https=) |
| ES (1) | ES2742503T3 (https=) |
| HK (1) | HK1246156B (https=) |
| HR (1) | HRP20191292T1 (https=) |
| HU (1) | HUE044783T2 (https=) |
| IL (1) | IL252438B (https=) |
| MX (1) | MX377044B (https=) |
| MY (1) | MY181181A (https=) |
| PL (1) | PL3236991T3 (https=) |
| PT (1) | PT3236991T (https=) |
| RS (1) | RS59154B1 (https=) |
| RU (1) | RU2729011C2 (https=) |
| SA (1) | SA517381673B1 (https=) |
| SI (1) | SI3236991T1 (https=) |
| TW (2) | TWI708781B (https=) |
| WO (1) | WO2016102562A1 (https=) |
| ZA (1) | ZA201703768B (https=) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109414471A (zh) | 2016-05-24 | 2019-03-01 | 诺和诺德股份有限公司 | Mic-1化合物及其用途 |
| CN106421753A (zh) * | 2016-10-19 | 2017-02-22 | 哈尔滨医科大学 | 重组人成纤维细胞生长因子‑21在制备预防和治疗缺血性心律失常药物中的应用 |
| TWI710377B (zh) * | 2017-05-23 | 2020-11-21 | 丹麥商諾佛 儂迪克股份有限公司 | Ｍｉｃ－１化合物及其用途 |
| JP6852939B2 (ja) * | 2017-09-04 | 2021-03-31 | ８９バイオ リミテッド８９Ｂｉｏ Ｌｔｄ． | 変異体ｆｇｆ−２１ペプチドコンジュゲート及びその使用 |
| CA3104686A1 (en) | 2018-07-03 | 2020-01-09 | Bristol-Myers Squibb Company | Fgf-21 formulations |
| US11427623B1 (en) | 2019-05-28 | 2022-08-30 | 89Bio Ltd. | Methods of treatment using mutant FGF-21 peptide conjugates |
| CN115322794B (zh) | 2020-01-11 | 2025-09-19 | 北京质肽生物医药科技有限公司 | Glp-1和fgf21的融合蛋白的缀合物 |
| EP4337680A1 (en) | 2021-05-11 | 2024-03-20 | Cytoki Pharma ApS | Therapeutic derivatives of interleukin-22 |
| EP4089108A1 (en) | 2021-05-11 | 2022-11-16 | CytoKi Pharma ApS | Therapeutic derivatives of interleukin-22 |
| KR102631925B1 (ko) * | 2021-06-10 | 2024-02-01 | 토드제약 주식회사 | 신규 fgf21 변이체 개발 및 이의 생산기법과 용도 |
| CA3224743A1 (en) | 2021-07-14 | 2023-01-19 | Beijing Ql Biopharmaceutical Co., Ltd. | Fusion polypeptides for metabolic disorders |
| US20240376168A1 (en) * | 2021-09-08 | 2024-11-14 | Leto Laboratories Co., Ltd | Fgf21 mutant protein and use thereof |
| AR129879A1 (es) * | 2022-07-08 | 2024-10-09 | Novo Nordisk As | Compuestos de isvd altamente potentes capaces de sustituir al fviii(a) |
| MA71385A (fr) | 2022-07-08 | 2025-04-30 | Novo Nordisk A/S | Composés isvd hautement puissants capables de remplacer fviii(a) |
| PE20252745A1 (es) | 2023-03-30 | 2025-12-05 | Novo Nordisk As | Compuestos de fusion y usos de estos |
| AR132645A1 (es) * | 2023-05-12 | 2025-07-16 | Novo Nordisk As | Antagonista de acción prolongada del receptor de la hormona del crecimiento y uso del mismo |
| TW202511291A (zh) | 2023-09-11 | 2025-03-16 | 丹麥商諾佛 儂迪克股份有限公司 | 抗ｉｌ－６結構域之抗體 |
| CN118307684B (zh) * | 2024-06-11 | 2024-10-18 | 北京志道生物科技有限公司 | 一种经脂肪酸链修饰的glp-1-fgf21融合蛋白及其制备方法和应用 |
| WO2026012311A1 (zh) * | 2024-07-08 | 2026-01-15 | 浙江道尔生物科技有限公司 | Fgf21衍生物及其用途 |
Family Cites Families (39)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5424286A (en) | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
| IL128332A0 (en) | 1996-08-30 | 2000-01-31 | Novo Nordisk As | GLP-1 derivatives |
| WO2003011213A2 (en) | 2001-07-30 | 2003-02-13 | Eli Lilly And Company | Method for treating diabetes and obesity |
| EP1329227A1 (en) | 2002-01-22 | 2003-07-23 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Diagnostic conjugate useful for intercellular imaging and for differentiating between tumor- and non-tumor cells |
| MXPA05013565A (es) | 2003-06-12 | 2006-03-09 | Lilly Co Eli | Proteinas de fusion analogas al glp-1. |
| JP2007537981A (ja) | 2003-09-19 | 2007-12-27 | ノボ ノルディスク アクティーゼルスカブ | 新規の血漿タンパク質親和性タグ |
| KR101241862B1 (ko) | 2003-09-19 | 2013-03-13 | 노보 노르디스크 에이/에스 | 신규 ｇｌｐ-1 유도체 |
| CN1890371A (zh) | 2003-12-10 | 2007-01-03 | 伊莱利利公司 | 成纤维细胞生长因子的21突变蛋白 |
| JP2007537142A (ja) | 2003-12-18 | 2007-12-20 | ノボ ノルディスク アクティーゼルスカブ | アルブミン様物質に結合した新規のｇｌｐ−１類似物 |
| CA2557782A1 (en) | 2004-03-17 | 2005-10-06 | Eli Lilly And Company | Glycol linked fgf-21 compounds |
| SI1751184T1 (sl) | 2004-05-13 | 2010-01-29 | Lilly Co Eli | Fgf-21 fuzijski proteini |
| GB0412181D0 (en) | 2004-06-01 | 2004-06-30 | Celltech R&D Ltd | Biological products |
| MXPA06015049A (es) | 2004-07-08 | 2007-02-08 | Novo Nordisk As | Marcadores prolongadores de polipeptidos que comprenden una porcion tetrazol. |
| EA011390B1 (ru) | 2004-09-02 | 2009-02-27 | Эли Лилли Энд Компани | Мутантные белки (мутеины) фактора роста фибробластов 21 |
| WO2006028714A1 (en) | 2004-09-02 | 2006-03-16 | Eli Lilly And Company | Muteins of fibroblast growth factor 21 |
| US20080176790A1 (en) | 2004-10-29 | 2008-07-24 | Defrees Shawn | Remodeling and Glycopegylation of Fibroblast Growth Factor (Fgf) |
| US7655627B2 (en) | 2004-12-14 | 2010-02-02 | Eli Lilly And Company | Muteins of fibroblast growth factor 21 |
| WO2006078463A2 (en) | 2005-01-21 | 2006-07-27 | Eli Lilly And Company | Method for treating cardiovascular disease |
| TWI372629B (en) | 2005-03-18 | 2012-09-21 | Novo Nordisk As | Acylated glp-1 compounds |
| WO2008087190A2 (en) | 2007-01-18 | 2008-07-24 | Novo Nordisk A/S | Use of peptides in combination with surgical intervention for the treatment of obesity |
| CA2682147C (en) | 2007-03-30 | 2017-08-08 | Ambrx, Inc. | Modified fgf-21 polypeptides and their uses |
| CN101663046B (zh) | 2007-03-30 | 2017-07-28 | Ambrx公司 | 经修饰fgf‑21多肽和其用途 |
| CA2693504A1 (en) | 2007-08-03 | 2009-02-12 | Eli Lilly And Company | Treatment for obesity |
| US20100261637A1 (en) | 2007-09-05 | 2010-10-14 | Novo Nordisk A/S | Peptides derivatized with a-b-c-d- and their therapeutical use |
| US20100317057A1 (en) | 2007-12-28 | 2010-12-16 | Novo Nordisk A/S | Semi-recombinant preparation of glp-1 analogues |
| CN100587073C (zh) | 2008-03-24 | 2010-02-03 | 吉林农大生物反应器工程有限公司 | 人成纤维细胞生长因子-21的重组表达 |
| EP2296690B1 (en) * | 2008-06-04 | 2016-11-30 | Amgen, Inc | Fgf21 mutants and uses thereof |
| JP5878757B2 (ja) * | 2008-10-10 | 2016-03-08 | アムジエン・インコーポレーテツド | Ｆｇｆ２１変異体およびその使用 |
| WO2010065439A1 (en) | 2008-12-05 | 2010-06-10 | Eli Lilly And Company | Variants of fibroblast growth factor 21 |
| BRPI1007313A2 (pt) | 2009-01-23 | 2016-02-10 | Novo Nordisk As | derivados de fgf21 com ligante de albumina a-b-c-d-e e seu uso. |
| EP2427207B1 (en) * | 2009-05-05 | 2017-08-16 | Amgen, Inc | Fgf21 mutants and uses thereof |
| HRP20240135T1 (hr) | 2009-05-05 | 2024-04-12 | Amgen Inc. | Fgf21 mutanti i njihove upotrebe |
| US20120035099A1 (en) | 2009-06-11 | 2012-02-09 | Novo Nordisk A/S | Fgf21 analogues and derivatives |
| WO2011154349A2 (en) * | 2010-06-08 | 2011-12-15 | Novo Nordisk A/S | Fgf21 analogues and derivatives |
| EP2440235A1 (en) | 2009-06-11 | 2012-04-18 | Novo Nordisk A/S | Glp-1 and fgf21 combinations for treatment of diabetes type 2 |
| EP2595647A1 (en) * | 2010-07-20 | 2013-05-29 | Novo Nordisk A/S | N-terminal modified fgf21 compounds |
| MX2014002260A (es) * | 2011-08-31 | 2014-08-18 | Amgen Inc | Factor de crecimiento de fibroblasto 21 para usar en el tratamiento de diabetes tipo 1. |
| WO2014037373A1 (en) * | 2012-09-07 | 2014-03-13 | Sanofi | Fusion proteins for treating a metabolic syndrome |
| MX383664B (es) * | 2012-12-27 | 2025-03-14 | Ngm Biopharmaceuticals Inc | Uso de un péptido para modular la homeostasis de los ácidos biliares o tratamiento de una enfermedad relacionada con los ácidos biliares. |
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2015
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- 2015-12-22 TW TW108144310A patent/TWI708781B/zh active
- 2015-12-22 EP EP15817847.5A patent/EP3236991B1/en active Active
- 2015-12-22 RS RSP20191106 patent/RS59154B1/sr unknown
- 2015-12-22 JP JP2017533789A patent/JP6727210B2/ja active Active
- 2015-12-22 MY MYPI2017701848A patent/MY181181A/en unknown
- 2015-12-22 KR KR1020177017682A patent/KR102427527B1/ko active Active
- 2015-12-22 AU AU2015371056A patent/AU2015371056B2/en active Active
- 2015-12-22 PL PL15817847T patent/PL3236991T3/pl unknown
- 2015-12-22 HK HK18105587.8A patent/HK1246156B/en unknown
- 2015-12-22 HU HUE15817847 patent/HUE044783T2/hu unknown
- 2015-12-22 RU RU2017125050A patent/RU2729011C2/ru active
- 2015-12-22 CN CN201580069436.9A patent/CN107108709B/zh active Active
- 2015-12-22 ES ES15817847T patent/ES2742503T3/es active Active
- 2015-12-22 DK DK15817847.5T patent/DK3236991T3/da active
- 2015-12-22 PT PT15817847T patent/PT3236991T/pt unknown
- 2015-12-22 WO PCT/EP2015/080969 patent/WO2016102562A1/en not_active Ceased
- 2015-12-22 SI SI201530859T patent/SI3236991T1/sl unknown
- 2015-12-22 MX MX2017007458A patent/MX377044B/es active IP Right Grant
- 2015-12-22 TW TW104143111A patent/TWI681966B/zh active
- 2015-12-22 HR HRP20191292TT patent/HRP20191292T1/hr unknown
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2017
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- 2017-05-22 IL IL252438A patent/IL252438B/en unknown
- 2017-06-01 ZA ZA2017/03768A patent/ZA201703768B/en unknown
- 2017-06-06 SA SA517381673A patent/SA517381673B1/ar unknown
- 2017-07-07 US US15/643,543 patent/US9895417B2/en active Active
- 2017-12-21 US US15/849,920 patent/US10124039B2/en active Active
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