ES2916998T3 - Análogos del EGF(A) con sustituyentes de ácidos grasos - Google Patents
Análogos del EGF(A) con sustituyentes de ácidos grasos Download PDFInfo
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- ES2916998T3 ES2916998T3 ES17701078T ES17701078T ES2916998T3 ES 2916998 T3 ES2916998 T3 ES 2916998T3 ES 17701078 T ES17701078 T ES 17701078T ES 17701078 T ES17701078 T ES 17701078T ES 2916998 T3 ES2916998 T3 ES 2916998T3
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- Prior art keywords
- ethoxy
- peptide
- egf
- amino
- acetyl
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- 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
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
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- 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
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- 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
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- 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
- C07K14/485—Epidermal growth factor [EGF], i.e. urogastrone
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- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
Landscapes
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
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| PCT/EP2017/050668 WO2017121850A1 (en) | 2016-01-13 | 2017-01-13 | Egf(a) analogues with fatty acid substituents |
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| EA034898B1 (ru) | 2016-01-13 | 2020-04-03 | Грюненталь Гмбх | Производные 8-амино-2-оксо-1,3-диазаспиро[4,5]декана |
| HUE049134T2 (hu) | 2016-01-13 | 2020-08-28 | Gruenenthal Gmbh | 3-(karboximetil)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-dekán származékok |
| RU2747877C2 (ru) | 2016-01-13 | 2021-05-17 | Ново Нордиск А/С | Аналоги эфр(а) с заместителями - жирными кислотами |
| CN108602777B (zh) | 2016-01-13 | 2022-05-03 | 格吕伦塔尔有限公司 | 3-((杂-)芳基)-烷基-8-氨基-2-氧代-1,3-氮杂-螺-[4.5]-癸烷衍生物 |
| JP2020527159A (ja) * | 2017-07-19 | 2020-09-03 | ノヴォ ノルディスク アー/エス | Egf(a)類似体、その製造、製剤および使用 |
| US11130794B2 (en) | 2017-07-19 | 2021-09-28 | Novo Nordisk A/S | Bifunctional compounds |
| US11358994B2 (en) * | 2017-07-27 | 2022-06-14 | Saint Louis University | Fatty acid modified human epidermal growth factor |
| JOP20190150A1 (ar) | 2018-06-21 | 2019-12-21 | Merck Sharp & Dohme | مركبات مناهضة لـ pcsk9 |
| JP7434299B2 (ja) * | 2018-10-05 | 2024-02-20 | ノヴォ ノルディスク アー/エス | インスリンペプチドおよびegf(a)ペプチドを含む二官能性化合物 |
| US11633632B2 (en) | 2019-03-22 | 2023-04-25 | 3M Innovative Properties Company | Fall-protection system with monitoring system |
| CN110357969B (zh) * | 2019-05-27 | 2022-03-08 | 北京志道生物科技有限公司 | 一种GLP1-EGFa异源二聚体蛋白、功能及方法 |
| PE20220486A1 (es) | 2019-08-07 | 2022-04-04 | Novo Nordisk As | Composiciones solidas que comprenden un derivado de egf(a) y una sal de acido n-(8-(2-hidroxibenzoil)amino)caprilico |
| CN114641275A (zh) | 2019-11-07 | 2022-06-17 | 诺和诺德股份有限公司 | 包含pcsk9抑制剂和n-(8-(2-羟基苯甲酰基)氨基)辛酸的盐的固体组合物 |
| EP4334235A4 (en) | 2021-07-02 | 2024-11-06 | 3M Innovative Properties Company | AIR LIFT LOCKED WITH A FALL PROTECTION SAFETY DEVICE |
| WO2023012263A1 (en) | 2021-08-04 | 2023-02-09 | Novo Nordisk A/S | Solid oral peptide formulations |
Family Cites Families (27)
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| EP1922336B1 (en) | 2005-08-11 | 2012-11-21 | Amylin Pharmaceuticals, LLC | Hybrid polypeptides with selectable properties |
| WO2009022006A1 (en) | 2007-08-15 | 2009-02-19 | Novo Nordisk A/S | Insulins with an acyl moiety comprising repeating units of alkylene glycol containing amino acids |
| EP2296694B1 (en) | 2008-04-23 | 2015-08-05 | Amgen Inc. | Neutralizing proprotein convertase subtilisin kexin type 9 (pcsk9) variants and uses thereof |
| US8673850B2 (en) | 2008-05-30 | 2014-03-18 | Institut De Recherches Cliniques De Montreal | PCSK9 inhibitors and methods of use thereof |
| TWI445716B (zh) | 2008-09-12 | 2014-07-21 | Rinat Neuroscience Corp | Pcsk9拮抗劑類 |
| CN101993485B (zh) | 2009-08-20 | 2013-04-17 | 重庆富进生物医药有限公司 | 促胰岛素分泌肽类似物同源二聚体及其用途 |
| JPWO2012017774A1 (ja) | 2010-08-02 | 2013-10-03 | 日本電気株式会社 | 偏光子及び発光装置 |
| CN102153652A (zh) | 2010-12-10 | 2011-08-17 | 浙江大学 | 一种融合蛋白的表达方法及用途 |
| JP2014510516A (ja) | 2011-02-15 | 2014-05-01 | ノヴォ ノルディスク アー/エス | 長時間作用性il−1受容体アンタゴニスト |
| BR112013032667A2 (pt) * | 2011-06-20 | 2017-12-12 | Genentech Inc | polipeptídeo de ligação a pcsk9, ácido nucleico isolado, vetor, célula hospedeira, método para produzir o polipeptídeo, composição farmacêutica, método de redução do nível de colesterol ldl em um sujeito, método de tratamento de disfunção relacionada ao colesterol em um sujeito, método de tratamento de hipercolesterolemia em um sujeito, método de inibição da ligação de pcsk9 a ldlr e método de detecção da proteína pcsk9 em uma amostra |
| CN104093735B (zh) * | 2011-09-23 | 2018-07-06 | 诺沃—诺迪斯克有限公司 | 新的胰高血糖素类似物 |
| US9458214B2 (en) | 2011-09-26 | 2016-10-04 | Novartis Ag | Dual function fibroblast growth factor 21 proteins |
| WO2013093009A1 (en) * | 2011-12-21 | 2013-06-27 | Novo Nordisk A/S | N -terminally modified insulin derivatives |
| WO2013170636A1 (zh) | 2012-05-18 | 2013-11-21 | 爱德迪安(北京)生物技术有限公司 | 用于糖尿病治疗的蛋白、蛋白缀合物及其应用 |
| AR092076A1 (es) | 2012-08-22 | 2015-03-18 | Lilly Co Eli | Proteinas homodimericas |
| BR112015004734A2 (pt) | 2012-09-07 | 2017-11-21 | Sanofi Sa | proteínas de fusão para tratar uma síndrome metabólica |
| WO2014170496A1 (en) * | 2013-04-18 | 2014-10-23 | Novo Nordisk A/S | Stable, protracted glp-1/glucagon receptor co-agonists for medical use |
| US10323076B2 (en) | 2013-10-03 | 2019-06-18 | Modernatx, Inc. | Polynucleotides encoding low density lipoprotein receptor |
| EP3107937A4 (en) | 2014-02-21 | 2017-11-15 | MedImmune, LLC | Anti-pcsk9~glp-1 fusions and methods for use |
| US10570184B2 (en) * | 2014-06-04 | 2020-02-25 | Novo Nordisk A/S | GLP-1/glucagon receptor co-agonists for medical use |
| CN104558198A (zh) | 2014-07-25 | 2015-04-29 | 成都贝爱特生物科技有限公司 | GLP-1类似物和amylin类似物的融合蛋白制备及其用途 |
| WO2016147162A1 (en) * | 2015-03-19 | 2016-09-22 | Institut De Cardiologie De Montreal | Grp94 derived polypeptides for inhibiting pcsk9 and methods of use |
| CN105367884A (zh) | 2015-11-02 | 2016-03-02 | 陈薇 | 一种绝缘耐火抗辐射的屏蔽电缆材料及其制备方法 |
| RU2747877C2 (ru) | 2016-01-13 | 2021-05-17 | Ново Нордиск А/С | Аналоги эфр(а) с заместителями - жирными кислотами |
| US11130794B2 (en) | 2017-07-19 | 2021-09-28 | Novo Nordisk A/S | Bifunctional compounds |
| JP2020527159A (ja) | 2017-07-19 | 2020-09-03 | ノヴォ ノルディスク アー/エス | Egf(a)類似体、その製造、製剤および使用 |
-
2017
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- 2017-01-13 BR BR112018013820-7A patent/BR112018013820A2/pt not_active Application Discontinuation
- 2017-01-13 MY MYPI2018702319A patent/MY195199A/en unknown
- 2017-01-13 HR HRP20220720TT patent/HRP20220720T1/hr unknown
- 2017-01-13 AU AU2017207862A patent/AU2017207862B2/en not_active Ceased
- 2017-01-13 KR KR1020187022105A patent/KR102417487B1/ko active Active
- 2017-01-13 HU HUE17701078A patent/HUE058647T2/hu unknown
- 2017-01-13 JP JP2018536444A patent/JP6797926B2/ja active Active
- 2017-01-13 PE PE2018001257A patent/PE20181376A1/es unknown
- 2017-01-13 MX MX2018008681A patent/MX2018008681A/es unknown
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- 2017-01-13 CN CN201780006783.6A patent/CN108473550B/zh active Active
- 2017-01-13 RS RS20220538A patent/RS63298B1/sr unknown
- 2017-01-13 LT LTEPPCT/EP2017/050668T patent/LT3402811T/lt unknown
- 2017-01-13 CA CA3010756A patent/CA3010756A1/en not_active Withdrawn
- 2017-01-13 ES ES17701078T patent/ES2916998T3/es active Active
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2018
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- 2018-07-16 CO CONC2018/0007440A patent/CO2018007440A2/es unknown
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2020
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- 2020-11-17 JP JP2020190846A patent/JP2021035989A/ja not_active Withdrawn
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