CA2886228A1 - Insulin analog dimers - Google Patents
Insulin analog dimers Download PDFInfo
- Publication number
- CA2886228A1 CA2886228A1 CA2886228A CA2886228A CA2886228A1 CA 2886228 A1 CA2886228 A1 CA 2886228A1 CA 2886228 A CA2886228 A CA 2886228A CA 2886228 A CA2886228 A CA 2886228A CA 2886228 A1 CA2886228 A1 CA 2886228A1
- Authority
- CA
- Canada
- Prior art keywords
- chain
- insulin
- seq
- amino acid
- polypeptide
- 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.)
- Abandoned
Links
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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
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- 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
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- 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
- A61K47/55—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
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- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
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- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
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- Toxicology (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Emergency Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Obesity (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261705834P | 2012-09-26 | 2012-09-26 | |
| US61/705,834 | 2012-09-26 | ||
| PCT/US2013/061676 WO2014052451A2 (en) | 2012-09-26 | 2013-09-25 | Insulin analog dimers |
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| CA2886228A1 true CA2886228A1 (en) | 2014-04-03 |
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|---|---|---|---|
| CA2886228A Abandoned CA2886228A1 (en) | 2012-09-26 | 2013-09-25 | Insulin analog dimers |
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| EP (2) | EP2900255B1 (enExample) |
| JP (1) | JP6387008B2 (enExample) |
| CN (2) | CN108383902A (enExample) |
| AU (1) | AU2013323669B2 (enExample) |
| CA (1) | CA2886228A1 (enExample) |
| WO (1) | WO2014052451A2 (enExample) |
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| CA2800173C (en) | 2010-05-21 | 2019-05-14 | Ulrik Nielsen | Bi-specific fusion proteins |
| MX2015005662A (es) * | 2012-11-05 | 2015-08-20 | Univ Case Western Reserve | Analogos de insulina de una sola cadena de larga accion. |
| CR20170208A (es) | 2014-11-21 | 2017-07-17 | Merck Sharp & Dohme | Agonistas parciales del receptor de insulina |
| KR101669140B1 (ko) * | 2015-04-28 | 2016-10-26 | (주)케어젠 | 항비만 및 항당뇨 효능을 갖는 펩타이드 및 이의 용도 |
| AR105616A1 (es) | 2015-05-07 | 2017-10-25 | Lilly Co Eli | Proteínas de fusión |
| CN115960249A (zh) | 2015-10-02 | 2023-04-14 | 银溪制药股份有限公司 | 用于组织修复的双特异性治疗性蛋白质 |
| EP3448417B1 (en) * | 2016-04-26 | 2025-11-12 | Merck Sharp & Dohme LLC | Insulin dimer-incretin conjugates |
| WO2017205191A1 (en) * | 2016-05-24 | 2017-11-30 | Merck Sharp & Dohme Corp. | Insulin receptor partial agonists and glp-1 analogues |
| EP3463413A4 (en) * | 2016-05-25 | 2020-03-04 | Merck Sharp & Dohme Corp. | INSULIN RECEPTOR PART AGONISTS |
| WO2017210077A1 (en) * | 2016-06-02 | 2017-12-07 | Indiana University Research And Technology Corporation | Single chain insulin prodrugs |
| KR101887577B1 (ko) * | 2016-10-19 | 2018-09-10 | (주)케어젠 | 항비만 및 항당뇨 효능을 갖는 펩타이드 및 이의 용도 |
| EP3645713A4 (en) * | 2017-06-27 | 2021-06-30 | Codexis, Inc. | PENICILLIN-G ACYLASES |
| AU2018317810A1 (en) | 2017-08-17 | 2020-03-19 | Novo Nordisk A/S | Novel acylated insulin analogues and uses thereof |
| EP3956355B1 (en) * | 2019-04-19 | 2025-11-26 | The Trustees of Indiana University | Stabilization of prandial or basal insulin analogues by an internal diselenide bridge |
| US12435116B2 (en) | 2019-10-16 | 2025-10-07 | Clarence Hurt | Compounds, compositions, methods, and uses for treating insulin resistance, type 2 diabetes and metabolic syndrome |
| CN113801236A (zh) * | 2020-06-11 | 2021-12-17 | 宁波鲲鹏生物科技有限公司 | 一种赖脯胰岛素的制备方法 |
| CN113801235A (zh) * | 2020-06-11 | 2021-12-17 | 宁波鲲鹏生物科技有限公司 | 一种赖脯胰岛素衍生物及其应用 |
| EP4228675A1 (en) | 2020-10-13 | 2023-08-23 | Betavive Ltd. | Method and compounds for treating diabetes and associated metabolic diseases |
| WO2022081794A1 (en) * | 2020-10-15 | 2022-04-21 | Tavotek Biotherapeutics (Hong Kong) Limited | Shielded biologics with masking domains to shield antigen binding capability of biologics and uses thereof |
| MX2024004398A (es) * | 2021-10-12 | 2024-07-09 | Betavive Ltd | Peptidos y fragmentos para tratar diabetes y enfermedades metabolicas asociadas. |
| WO2024137820A1 (en) * | 2022-12-20 | 2024-06-27 | The Board Of Trustees Of The Leland Stanford Junior University | Insulin receptor antagonist |
Family Cites Families (82)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3740385A (en) | 1970-05-07 | 1973-06-19 | M Ondetti | N-terminal derivatives of secretin |
| US4450150A (en) | 1973-05-17 | 1984-05-22 | Arthur D. Little, Inc. | Biodegradable, implantable drug delivery depots, and method for preparing and using the same |
| US4275152A (en) | 1977-02-03 | 1981-06-23 | Eastman Kodak Company | Hydrolysis of protein-bound cholesterol esters |
| DK119785D0 (da) | 1985-03-15 | 1985-03-15 | Nordisk Gentofte | Insulinpraeparat |
| PH25772A (en) | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
| PT83613B (en) | 1985-10-28 | 1988-11-21 | Lilly Co Eli | Process for the selective chemical removal of a protein amino-terminal residue |
| US4741897A (en) | 1986-07-08 | 1988-05-03 | Baxter Travenol | Thyroxine analogs and reagents for thyroid hormone assays |
| US4876242A (en) | 1987-09-21 | 1989-10-24 | Merck & Co., Inc. | Human insulin-like growth factor analoges with reduced binding to serum carrier proteins and their production in yeast |
| GB8728561D0 (en) | 1987-12-07 | 1988-01-13 | Glaxo Group Ltd | Chemical compounds |
| US5514646A (en) | 1989-02-09 | 1996-05-07 | Chance; Ronald E. | Insulin analogs modified at position 29 of the B chain |
| US6225449B1 (en) | 1991-10-04 | 2001-05-01 | Washington University | Hormone analogs with multiple CTP extensions |
| EP0469084B1 (en) | 1989-04-20 | 1995-04-05 | Mount Sinai School Of Medicine Of The City University Of New York | Hepatospecific insulin analogues |
| US5268453A (en) | 1991-08-08 | 1993-12-07 | Scios Inc. | Tissue-selective insulin analogs |
| FI953001A7 (fi) * | 1992-12-18 | 1995-06-16 | Lilly Co Eli | Insuliinianalogeja |
| EP0688364A4 (en) | 1993-03-09 | 1997-10-15 | Abbott Lab | ENZYMES PRODUCED BY GENETIC ENGINEERING AND CONJUGATES OF SAID ENZYMES FOR DIAGNOSTIC ANALYSIS |
| US5359030A (en) | 1993-05-10 | 1994-10-25 | Protein Delivery, Inc. | Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same |
| US6476290B1 (en) | 1995-04-19 | 2002-11-05 | Dalhousie University | Transgenic tilapia comprising a humanized insulin gene |
| EP0741188A3 (en) | 1995-05-05 | 1999-07-14 | Eli Lilly And Company | Single chain insulin with high bioactivity |
| US6180767B1 (en) | 1996-01-11 | 2001-01-30 | Thomas Jefferson University | Peptide nucleic acid conjugates |
| IL128828A0 (en) | 1996-09-09 | 2000-01-31 | Zealand Pharmaceuticals As | Peptide prodrugs containing an alpha-hydroxy acid linker |
| UA65549C2 (uk) | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція |
| EP1053752A1 (en) | 1998-02-10 | 2000-11-22 | Yoshitomi Pharmaceutical Industries, Ltd. | Preparations with controlled release |
| SK12412000A3 (sk) | 1998-02-23 | 2002-05-09 | Neurocrine Biosciences, Inc. | Metódy liečenia diabetu použitím peptidových analógov inzulínu |
| IL138214A0 (en) | 1998-03-09 | 2001-10-31 | Zealand Pharmaceuticals As | Pharmacolgically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
| US20030236190A1 (en) | 1998-09-02 | 2003-12-25 | Renuka Pillutla | Isulin and IGF-1 receptor agonists and antagonists |
| US6875741B2 (en) | 1998-09-02 | 2005-04-05 | Renuka Pillutla | Insulin and IGF-1 receptor agonists and antagonists |
| GB2344287A (en) | 1998-12-03 | 2000-06-07 | Ferring Bv | Controlled release pharmaceutical formulation |
| DE19908041A1 (de) | 1999-02-24 | 2000-08-31 | Hoecker Hartwig | Kovalent verbrückte Insulindimere |
| WO2000058360A2 (en) | 1999-03-29 | 2000-10-05 | Uutech Limited | Analogs of gastric inhibitory peptide and their use for treatment of diabetes |
| US6746853B1 (en) | 1999-05-19 | 2004-06-08 | Xencor, Inc. | Proteins with insulin-like activity useful in the treatment of diabetes |
| AUPQ661800A0 (en) | 2000-03-31 | 2000-05-04 | Metabolic Pharmaceuticals Limited | Insulin-potentiating compounds |
| JP2004509079A (ja) | 2000-08-02 | 2004-03-25 | セラテクノロジーズ・インコーポレーテッド | 効力が増大した修飾生体ペプチド |
| AU2001284697A1 (en) | 2000-08-04 | 2002-02-18 | Dmi Biosciences, Inc. | Method of synthesizing diketopiperazines |
| US7052686B2 (en) | 2000-09-29 | 2006-05-30 | Schering Corporation | Pegylated interleukin-10 |
| KR100449454B1 (ko) | 2000-10-02 | 2004-09-21 | 이현철 | 단일사슬 인슐린 유도체의 유전자를 포함하는 당뇨병치료용 벡터 |
| KR101229995B1 (ko) | 2000-12-11 | 2013-02-06 | 씨제이 주식회사 | 생체내 에리스로포이에틴 활성이 증진된 융합단백질 |
| EP1243276A1 (en) | 2001-03-23 | 2002-09-25 | Franciscus Marinus Hendrikus De Groot | Elongated and multiple spacers containing activatible prodrugs |
| MXPA03009566A (es) | 2001-04-19 | 2004-12-06 | Scripps Research Inst | Metodos y composicion para la produccion de pares trna-aminoaciltrna sintetasa ortogonales. |
| BR0215029A (pt) | 2001-12-20 | 2005-12-20 | Lilly Co Eli | Molécula de insulina, uso da mesma, composição, uso desta, microcristal, processo para prepará-lo, uso deste, e, métodos para preparar uma molécula de insulina, para tratar hiperglicemia, e para tratar diabetes mellitus |
| FR2842209B1 (fr) | 2002-07-09 | 2007-11-23 | Nouvelle protease aspartique dite saspase et son utilisation dans le domaine cosmetique et therapeutique | |
| ATE458534T1 (de) | 2002-10-04 | 2010-03-15 | Microchips Inc | Medizinische vorrichtung zur gesteuerten arzneimittelverabreichung sowie herzüberwachung und/oder herzstimulation |
| WO2004067548A2 (en) | 2003-01-31 | 2004-08-12 | Theratechnologies Inc. | Chemically modified metabolites of regulatory peptides and methods of producing and using same |
| EP1626981A4 (en) | 2003-03-04 | 2006-11-22 | Biorexis Pharmaceutical Corp | PROTEINS PROTECTED AGAINST DIPEPTIDYLPEPTIDASE |
| PL1605897T3 (pl) | 2003-03-19 | 2012-12-31 | Lilly Co Eli | Związki będące połączeniem GLP-1 z poli(glikolem etylenowym) |
| EP1620118B1 (en) | 2003-04-08 | 2014-06-18 | Yeda Research And Development Co., Ltd. | Reversible pegylated drugs |
| WO2005027978A2 (en) | 2003-09-19 | 2005-03-31 | Novo Nordisk A/S | Albumin-binding derivatives of therapeutic peptides |
| WO2005035003A2 (en) | 2003-09-22 | 2005-04-21 | Dihedron Corporation | Compositions and methods for increasing drug efficiency |
| PL2332968T3 (pl) | 2003-11-05 | 2017-08-31 | Dana-Farber Cancer Institute, Inc. | Stabilizowane alfa-helikalne peptydy i ich zastosowania |
| EP1692168B1 (en) | 2003-12-03 | 2011-07-20 | Novo Nordisk A/S | Single-chain insulin |
| EP1812082B1 (en) | 2004-10-21 | 2013-08-14 | IGF Oncology, LLC | Toxins and radionuclides coupled to IGF-1 receptor ligands for the treatment of cancer |
| WO2006097521A1 (en) | 2005-03-18 | 2006-09-21 | Novo Nordisk A/S | Pegylated single-chain insulin |
| US7521211B2 (en) * | 2005-04-05 | 2009-04-21 | Regeneron Pharmaceuticals, Inc | IGF-1 and IGF-2 chimeric polypeptides and therapeutic uses thereof |
| WO2006113452A2 (en) | 2005-04-13 | 2006-10-26 | University Of Medicine And Dentistry Of New Jersey | Glycoprotein hormone analogs |
| GB2427360A (en) * | 2005-06-22 | 2006-12-27 | Complex Biosystems Gmbh | Aliphatic prodrug linker |
| US8304386B2 (en) | 2006-02-03 | 2012-11-06 | Prolor Biotech, Inc. | Long-acting growth hormone and methods of producing same |
| JP2009527526A (ja) | 2006-02-21 | 2009-07-30 | ノボ・ノルデイスク・エー/エス | 単鎖インスリンのアナログとその製薬的製剤 |
| EP1996224B1 (en) | 2006-03-15 | 2012-11-07 | Novo Nordisk A/S | Mixtures of amylin and insulin |
| US9505823B2 (en) | 2006-08-07 | 2016-11-29 | TEV A Biopharmaceuticals USA, Inc. | Albumin-insulin fusion proteins |
| CA2660835A1 (en) | 2006-08-17 | 2008-02-21 | Amylin Pharmaceuticals, Inc. | Dpp-iv resistant gip hybrid polypeptides with selectable propperties |
| CL2007002502A1 (es) | 2006-08-31 | 2008-05-30 | Hoffmann La Roche | Variantes del factor de crecimiento similar a insulina-1 humano (igf-1) pegilados en lisina; metodo de produccion; proteina de fusion que la comprende; y su uso para tratar la enfermedad de alzheimer. |
| CA2663083A1 (en) | 2006-09-08 | 2008-03-13 | Ambrx, Inc. | Modified human plasma polypeptide or fc scaffolds and their uses |
| US20090098130A1 (en) * | 2007-01-05 | 2009-04-16 | Bradshaw Curt W | Glucagon-like protein-1 receptor (glp-1r) agonist compounds |
| CA2683698C (en) | 2007-04-19 | 2013-09-10 | Hyun Hee Kwak | A biodegradable microsphere composition suitable for the controlled release of glucose controlling peptide and formulation thereof |
| EP2036923A1 (en) | 2007-09-11 | 2009-03-18 | Novo Nordisk A/S | Improved derivates of amylin |
| EP2036539A1 (en) | 2007-09-11 | 2009-03-18 | Novo Nordisk A/S | Stable formulations of amylin and its analogues |
| CN101157725B (zh) | 2007-10-24 | 2012-07-25 | 中国药科大学 | 人胰岛素类似物的制备方法及用途 |
| MX338336B (es) | 2007-11-20 | 2016-04-07 | Ambrx Inc | Polipeptidos de insulina modificados y sus usos. |
| AR063987A1 (es) | 2007-11-27 | 2009-03-04 | Segundo Mariano | Aposito utilizable como cobertura temporal para el tratamiento de heridas y procesos para su fabricacion |
| WO2009099763A1 (en) | 2008-01-30 | 2009-08-13 | Indiana University Research And Technology Corporation | Ester-based peptide prodrugs |
| JP5588354B2 (ja) | 2008-02-01 | 2014-09-10 | アセンディス ファーマ エー/エス | 自己切断可能なリンカーを含むプロドラッグ |
| EP2356139A4 (en) | 2008-07-23 | 2013-01-09 | Harvard College | LIGURE COMBINED POLYPEPTIDES |
| WO2010071807A1 (en) | 2008-12-19 | 2010-06-24 | Indiana University Research And Technology Corporation | Amide based glucagon superfamily peptide prodrugs |
| JP5789515B2 (ja) | 2008-12-19 | 2015-10-07 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションIndiana University Research And Technology Corporation | インスリン類似体 |
| CN102300580A (zh) | 2008-12-19 | 2011-12-28 | 印第安纳大学研究及科技有限公司 | 二肽连接的药剂 |
| CA2744558A1 (en) * | 2008-12-19 | 2010-07-15 | Indiana University Research And Technology Corporation | Amide-based insulin prodrugs |
| EP2408470A4 (en) | 2009-03-20 | 2012-08-29 | Smartcells Inc | SOLUBLE NONDEPOT INSULIN CONJUGATE AND ITS USE |
| MA33467B1 (fr) | 2009-07-31 | 2012-07-03 | Sanofi Aventis Deutschland | Promédicaments comprenant un conjugué insuline-lieur |
| 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 |
| CN103068842B (zh) * | 2010-06-16 | 2016-10-19 | 印第安纳大学研究及科技有限公司 | 对胰岛素受体具有高活性的单链胰岛素激动剂 |
| WO2011163462A2 (en) | 2010-06-24 | 2011-12-29 | Indiana University Research And Technology Corporation | Amide-based insulin prodrugs |
| US8778872B2 (en) | 2010-06-24 | 2014-07-15 | Indiana University Research And Technology Corporation | Amide based glucagon superfamily peptide prodrugs |
| WO2011163460A1 (en) | 2010-06-24 | 2011-12-29 | Indiana University Research And Technology Corporation | Yl-based insulin-like growth factors exhibiting high activity at the insulin receptor |
-
2013
- 2013-09-25 WO PCT/US2013/061676 patent/WO2014052451A2/en not_active Ceased
- 2013-09-25 JP JP2015534623A patent/JP6387008B2/ja not_active Expired - Fee Related
- 2013-09-25 EP EP13841334.9A patent/EP2900255B1/en not_active Not-in-force
- 2013-09-25 US US14/431,040 patent/US9593156B2/en not_active Expired - Fee Related
- 2013-09-25 CN CN201810145984.0A patent/CN108383902A/zh active Pending
- 2013-09-25 CA CA2886228A patent/CA2886228A1/en not_active Abandoned
- 2013-09-25 CN CN201380061231.7A patent/CN104981251B/zh not_active Expired - Fee Related
- 2013-09-25 AU AU2013323669A patent/AU2013323669B2/en not_active Ceased
- 2013-09-25 EP EP18174352.7A patent/EP3395358B1/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| US9593156B2 (en) | 2017-03-14 |
| CN108383902A (zh) | 2018-08-10 |
| AU2013323669B2 (en) | 2018-03-01 |
| EP3395358B1 (en) | 2019-11-06 |
| CN104981251A (zh) | 2015-10-14 |
| JP6387008B2 (ja) | 2018-09-05 |
| US20150274802A1 (en) | 2015-10-01 |
| EP2900255B1 (en) | 2019-01-30 |
| WO2014052451A2 (en) | 2014-04-03 |
| AU2013323669A1 (en) | 2015-03-26 |
| CN104981251B (zh) | 2018-03-20 |
| EP2900255A4 (en) | 2016-06-22 |
| JP2015532283A (ja) | 2015-11-09 |
| WO2014052451A3 (en) | 2014-06-19 |
| EP2900255A2 (en) | 2015-08-05 |
| EP3395358A1 (en) | 2018-10-31 |
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