ES2209885T3 - Peptidos insulinotropicos de larga duracion. - Google Patents
Peptidos insulinotropicos de larga duracion.Info
- Publication number
- ES2209885T3 ES2209885T3 ES00930796T ES00930796T ES2209885T3 ES 2209885 T3 ES2209885 T3 ES 2209885T3 ES 00930796 T ES00930796 T ES 00930796T ES 00930796 T ES00930796 T ES 00930796T ES 2209885 T3 ES2209885 T3 ES 2209885T3
- Authority
- ES
- Spain
- Prior art keywords
- fmoc
- lys
- baselineskip
- peptide
- glp
- 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.)
- Expired - Lifetime
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 200
- 230000002473 insulinotropic effect Effects 0.000 title claims abstract description 89
- 102000004196 processed proteins & peptides Human genes 0.000 title description 75
- 230000007774 longterm Effects 0.000 title 1
- 239000012634 fragment Substances 0.000 claims abstract description 44
- 239000012503 blood component Substances 0.000 claims abstract description 29
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 17
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 69
- 210000004369 blood Anatomy 0.000 claims description 54
- 239000008280 blood Substances 0.000 claims description 53
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 30
- 238000001727 in vivo Methods 0.000 claims description 29
- 229940125396 insulin Drugs 0.000 claims description 27
- 102000004877 Insulin Human genes 0.000 claims description 25
- 108090001061 Insulin Proteins 0.000 claims description 25
- 239000000306 component Substances 0.000 claims description 24
- NGJOFQZEYQGZMB-KTKZVXAJSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical group C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NGJOFQZEYQGZMB-KTKZVXAJSA-N 0.000 claims description 23
- 102000009027 Albumins Human genes 0.000 claims description 23
- 108010088751 Albumins Proteins 0.000 claims description 23
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 claims description 23
- 206010012601 diabetes mellitus Diseases 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- 108010071390 Serum Albumin Proteins 0.000 claims description 14
- 102000007562 Serum Albumin Human genes 0.000 claims description 14
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 108091005601 modified peptides Proteins 0.000 claims description 11
- 102000004506 Blood Proteins Human genes 0.000 claims description 10
- 108010017384 Blood Proteins Proteins 0.000 claims description 10
- HXMVNCMPQGPRLN-UHFFFAOYSA-N 2-hydroxyputrescine Chemical compound NCCC(O)CN HXMVNCMPQGPRLN-UHFFFAOYSA-N 0.000 claims description 8
- 230000014509 gene expression Effects 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 5
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 3
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 claims 4
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 147
- -1 carboxy, phosphoryl Chemical group 0.000 description 129
- 229920005989 resin Polymers 0.000 description 70
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- 235000001014 amino acid Nutrition 0.000 description 63
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- 229940024606 amino acid Drugs 0.000 description 60
- 150000001413 amino acids Chemical class 0.000 description 60
- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-N 0.000 description 57
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Classifications
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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
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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- A61P25/08—Antiepileptics; Anticonvulsants
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- 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
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- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- 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
- C07K14/605—Glucagons
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Neurosurgery (AREA)
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- Biomedical Technology (AREA)
- Diabetes (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Hematology (AREA)
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- Psychiatry (AREA)
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- Virology (AREA)
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- Pain & Pain Management (AREA)
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- Surgery (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Child & Adolescent Psychology (AREA)
- Anesthesiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13440699P | 1999-05-17 | 1999-05-17 | |
| US134406P | 1999-05-17 | ||
| US15978399P | 1999-10-15 | 1999-10-15 | |
| US159783P | 1999-10-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2209885T3 true ES2209885T3 (es) | 2004-07-01 |
Family
ID=26832298
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES00930796T Expired - Lifetime ES2209885T3 (es) | 1999-05-17 | 2000-05-17 | Peptidos insulinotropicos de larga duracion. |
Country Status (16)
| Country | Link |
|---|---|
| US (4) | US6329336B1 (enExample) |
| EP (1) | EP1180121B9 (enExample) |
| JP (5) | JP4115671B2 (enExample) |
| CN (1) | CN1191273C (enExample) |
| AT (1) | ATE252601T1 (enExample) |
| AU (1) | AU754770B2 (enExample) |
| BR (1) | BR0010750A (enExample) |
| CA (2) | CA2501421A1 (enExample) |
| DE (1) | DE60006100T2 (enExample) |
| DK (1) | DK1180121T3 (enExample) |
| EA (1) | EA003922B1 (enExample) |
| ES (1) | ES2209885T3 (enExample) |
| NO (1) | NO20015584L (enExample) |
| PT (1) | PT1180121E (enExample) |
| SI (1) | SI1180121T1 (enExample) |
| WO (1) | WO2000069911A1 (enExample) |
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| FR2686899B1 (fr) | 1992-01-31 | 1995-09-01 | Rhone Poulenc Rorer Sa | Nouveaux polypeptides biologiquement actifs, leur preparation et compositions pharmaceutiques les contenant. |
| US6605648B1 (en) * | 1999-04-06 | 2003-08-12 | Phillips Plastics Corporation | Sinterable structures and method |
| US6849714B1 (en) * | 1999-05-17 | 2005-02-01 | Conjuchem, Inc. | Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components |
| US20090175821A1 (en) * | 1999-05-17 | 2009-07-09 | Bridon Dominique P | Modified therapeutic peptides with extended half-lives in vivo |
| ATE252601T1 (de) * | 1999-05-17 | 2003-11-15 | Conjuchem Inc | Lang wirkende insulinotrope peptide |
| US6887470B1 (en) * | 1999-09-10 | 2005-05-03 | Conjuchem, Inc. | Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components |
| US6514500B1 (en) * | 1999-10-15 | 2003-02-04 | Conjuchem, Inc. | Long lasting synthetic glucagon like peptide {GLP-!} |
| US20040266673A1 (en) * | 2002-07-31 | 2004-12-30 | Peter Bakis | Long lasting natriuretic peptide derivatives |
| US7601691B2 (en) | 1999-05-17 | 2009-10-13 | Conjuchem Biotechnologies Inc. | Anti-obesity agents |
| US7087411B2 (en) | 1999-06-08 | 2006-08-08 | Regeneron Pharmaceuticals, Inc. | Fusion protein capable of binding VEGF |
| US6447772B1 (en) * | 1999-10-01 | 2002-09-10 | Klaire Laboratories, Inc. | Compositions and methods relating to reduction of symptoms of autism |
| ES2529300T3 (es) | 2000-04-12 | 2015-02-18 | Novozymes Biopharma Dk A/S | Proteínas de fusión de albúmina |
| SK288342B6 (en) * | 2000-12-07 | 2016-03-01 | Lilly Co Eli | GLP-1 fusion proteins |
| CN101696240A (zh) | 2001-02-02 | 2010-04-21 | 康久化学生物技术公司 | 长效生长激素释放因子衍生物 |
| DE60226702D1 (de) * | 2001-02-16 | 2008-07-03 | Conjuchem Biotechnologies Inc | Lang wirkendes glucagon-ähnliches peptid-2 für die behandlung von gastrointestinalen krankheiten und störungen |
| CN1162446C (zh) | 2001-05-10 | 2004-08-18 | 上海华谊生物技术有限公司 | 促胰岛素分泌肽衍生物 |
| CA2448891A1 (en) | 2001-05-31 | 2002-12-05 | Conjuchem Inc. | Long lasting fusion peptide inhibitors for hiv infection |
| AU2002317599B2 (en) | 2001-07-31 | 2008-04-03 | The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services | GLP-1 exendin-4 peptide analogs and uses thereof |
| US6642003B2 (en) | 2001-08-02 | 2003-11-04 | Cedars-Sinai Medical Center | Human glucose-dependent insulin-secreting cell line |
| US20030226155A1 (en) * | 2001-08-30 | 2003-12-04 | Biorexis Pharmaceutical Corporation | Modified transferrin-antibody fusion proteins |
| US7176278B2 (en) * | 2001-08-30 | 2007-02-13 | Biorexis Technology, Inc. | Modified transferrin fusion proteins |
| US8129504B2 (en) | 2001-08-30 | 2012-03-06 | Biorexis Technology, Inc. | Oral delivery of modified transferrin fusion proteins |
| US20070031440A1 (en) * | 2001-08-30 | 2007-02-08 | Prior Christopher P | Modified transferin-antibody fusion proteins |
| AU2002323501C1 (en) * | 2001-08-30 | 2010-04-29 | Biorexis Technology, Inc | Modified transferrin fusion proteins |
| JP2005514337A (ja) * | 2001-10-18 | 2005-05-19 | ブリストル−マイヤーズ スクイブ カンパニー | ヒトグルカゴン様ペプチド−１模倣体、並びに糖尿病および関連疾患の処置におけるその使用 |
| EP1463752A4 (en) * | 2001-12-21 | 2005-07-13 | Human Genome Sciences Inc | ALBUMIN FUSION PROTEINS |
| WO2005077042A2 (en) | 2004-02-09 | 2005-08-25 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| WO2003060071A2 (en) | 2001-12-21 | 2003-07-24 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| WO2005003296A2 (en) | 2003-01-22 | 2005-01-13 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| US20030166512A1 (en) * | 2002-02-13 | 2003-09-04 | Medbridge, Inc. | Protein carrier system for therapeutic oligonucleotides |
| NZ534125A (en) * | 2002-02-20 | 2006-11-30 | Emisphere Tech Inc | A formulation comprising a GLP-1 compound and a delivery agent |
| US7141240B2 (en) * | 2002-03-12 | 2006-11-28 | Cedars-Sinai Medical Center | Glucose-dependent insulin-secreting cells transfected with a nucleotide sequence encoding GLP-1 |
| EP1575490A4 (en) * | 2002-06-04 | 2007-08-08 | Lilly Co Eli | MODIFIED ANALOGUES OF GLUCAGON-LIKE PEPTIDE-1 (GLP-1) |
| EP1837031B1 (en) * | 2002-06-07 | 2009-10-14 | Waratah Pharmaceuticals, Inc. | Compositions and methods for treating diabetes |
| EP1525219B1 (en) | 2002-07-04 | 2009-05-27 | Zealand Pharma A/S | Glp-1 and methods for treating diabetes |
| DE60333306D1 (de) * | 2002-08-30 | 2010-08-19 | Biorexis Pharmaceutical Corp | Modifizierte transferrin-fusionsproteine mit doppelten transferrin-amino- oder carboxy-terminalen domänen |
| US7575750B2 (en) * | 2002-09-24 | 2009-08-18 | Frontiers Biotechnologies Col, Ltd. | Human immunodeficiency virus (HIV) gp41 peptide derivatives with enhanced solubility and antiviral activity |
| AU2003268621B2 (en) | 2002-10-02 | 2009-01-15 | Zealand Pharma A/S | Stabilized exendin-4 compounds |
| US20040229810A1 (en) * | 2002-10-22 | 2004-11-18 | Antonio Cruz | Gastrin compositions and formulations, and methods of use and preparation |
| US7790681B2 (en) * | 2002-12-17 | 2010-09-07 | Amylin Pharmaceuticals, Inc. | Treatment of cardiac arrhythmias with GLP-1 receptor ligands |
| US20040209803A1 (en) * | 2002-12-19 | 2004-10-21 | Alain Baron | Compositions for the treatment and prevention of nephropathy |
| US7731947B2 (en) | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
| US7655618B2 (en) | 2002-12-27 | 2010-02-02 | Diobex, Inc. | Compositions and methods for the prevention and control of insulin-induced hypoglycemia |
| NZ541365A (en) * | 2002-12-27 | 2009-09-25 | Diobex Inc | Compositions and methods for the prevention and control of insulin-induced hypoglycemia |
| US20070060512A1 (en) * | 2003-03-04 | 2007-03-15 | Homayoun Sadeghi | Dipeptidyl-peptidase protected protein |
| US20040242566A1 (en) * | 2003-03-25 | 2004-12-02 | Syrrx, Inc. | Dipeptidyl peptidase inhibitors |
| KR101198346B1 (ko) * | 2003-04-08 | 2012-11-06 | 노보 노르디스크 에이/에스 | 크로마토그래피 고정상의 재생 |
| WO2004089985A1 (en) * | 2003-04-11 | 2004-10-21 | Novo Nordisk A/S | Stable pharmaceutical compositions |
| CA2820537C (en) | 2003-04-23 | 2015-10-20 | Valeritas, Inc. | Hydraulically actuated pump for fluid administration |
| CN1812983A (zh) | 2003-05-30 | 2006-08-02 | 兰贝克赛实验室有限公司 | 取代的吡咯衍生物及其作为hmg－co抑制剂的用途 |
| DK1641823T3 (da) | 2003-06-12 | 2011-12-12 | Lilly Co Eli | GLP-1-analog fusionsproteiner |
| CA2526957C (en) * | 2003-07-25 | 2011-07-12 | Conjuchem Inc. | Long lasting insulin derivatives and methods thereof |
| CN1964989B (zh) * | 2003-07-25 | 2012-02-01 | 康久化学生物技术公司 | 长效胰岛素衍生物及其方法 |
| AU2004265341A1 (en) | 2003-08-13 | 2005-02-24 | Takeda Pharmaceutical Company Limited | 4-pyrimidone derivatives and their use as peptidyl peptidase inhibitors |
| US20060205037A1 (en) * | 2003-08-28 | 2006-09-14 | Homayoun Sadeghi | Modified transferrin fusion proteins |
| US20070275871A1 (en) * | 2003-08-28 | 2007-11-29 | Biorexis Technology, Inc. | Epo Mimetic Peptides and Fusion Proteins |
| WO2005021026A2 (en) * | 2003-08-29 | 2005-03-10 | Amylin Pharmaceuticals, Inc. | Methods for treating or ameliorating ghrelin-associated diseases and disorders |
| WO2005026148A1 (en) * | 2003-09-08 | 2005-03-24 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
| US7214190B1 (en) | 2003-09-09 | 2007-05-08 | Kitchener Clark Wilson | Apparatus and method for noninvasive monitoring of analytes in body fluids |
| KR20060109940A (ko) * | 2003-12-18 | 2006-10-23 | 노보 노르디스크 에이/에스 | 알부민-유사제에 연결된 신규 ｇｌｐ-1 유사체 |
| US20060286129A1 (en) * | 2003-12-19 | 2006-12-21 | Emisphere Technologies, Inc. | Oral GLP-1 formulations |
| CA2554458A1 (en) * | 2004-01-30 | 2005-08-11 | Waratah Pharmaceuticals, Inc. | The combined use of glp-1 agonists and gastrin for regulating blood glucose levels |
| US8076288B2 (en) * | 2004-02-11 | 2011-12-13 | Amylin Pharmaceuticals, Inc. | Hybrid polypeptides having glucose lowering activity |
| WO2005095381A1 (en) * | 2004-03-15 | 2005-10-13 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| MXPA06012260A (es) * | 2004-04-23 | 2006-12-15 | Conjuchem Biotechnologies Inc | Metodo para la purificacion de conjugados de albumina. |
| CN1318587C (zh) * | 2004-04-30 | 2007-05-30 | 成都芝田生物工程有限公司 | 酰胺化Exendin－4多肽的重组制备方法 |
| WO2006014425A1 (en) | 2004-07-02 | 2006-02-09 | Biovalve Technologies, Inc. | Methods and devices for delivering glp-1 and uses thereof |
| DE102004043153B4 (de) * | 2004-09-03 | 2013-11-21 | Philipps-Universität Marburg | Erfindung betreffend GLP-1 und Exendin |
| AU2012202855B2 (en) * | 2004-09-03 | 2015-02-26 | Philipps-Universitat Marburg | GLP-1 and exendin related invention |
| EP2330126B1 (en) | 2004-10-07 | 2015-12-23 | Novo Nordisk A/S | Protracted exendin-4 compounds |
| US7893017B2 (en) | 2004-10-07 | 2011-02-22 | Novo Nordisk A/S | Protracted GLP-1 compounds |
| US20080125361A1 (en) * | 2004-11-12 | 2008-05-29 | Novo Nordisk A/S | Stable Formulations Of Peptides |
| JP2008524331A (ja) * | 2004-12-21 | 2008-07-10 | 武田薬品工業株式会社 | ジペプチジルペプチダーゼ阻害剤 |
| US8716221B2 (en) * | 2005-01-14 | 2014-05-06 | Wuxi Grandchamp Pharmaceutical Technology Co., Ltd. | Modified exendins and uses thereof |
| TWI376234B (en) * | 2005-02-01 | 2012-11-11 | Msd Oss Bv | Conjugates of a polypeptide and an oligosaccharide |
| WO2006083761A2 (en) | 2005-02-03 | 2006-08-10 | Alza Corporation | Solvent/polymer solutions as suspension vehicles |
| US11246913B2 (en) | 2005-02-03 | 2022-02-15 | Intarcia Therapeutics, Inc. | Suspension formulation comprising an insulinotropic peptide |
| TWI372629B (en) | 2005-03-18 | 2012-09-21 | Novo Nordisk As | Acylated glp-1 compounds |
| JP5755398B2 (ja) | 2005-03-18 | 2015-07-29 | ノヴォ ノルディスク アー／エス | 伸長されたｇｌｐ−１化合物 |
| EP2330124B1 (en) * | 2005-08-11 | 2015-02-25 | Amylin Pharmaceuticals, LLC | Hybrid polypeptides with selectable properties |
| PL1942898T5 (pl) | 2005-09-14 | 2014-10-31 | Takeda Pharmaceuticals Co | Inhibitory peptydazy dipeptydylowej do leczenia cukrzycy |
| US20070060529A1 (en) * | 2005-09-14 | 2007-03-15 | Christopher Ronald J | Administration of dipeptidyl peptidase inhibitors |
| CN102908351B (zh) * | 2005-09-14 | 2014-07-23 | 武田药品工业株式会社 | 用于治疗糖尿病的二肽基肽酶抑制剂 |
| TW200745080A (en) * | 2005-09-16 | 2007-12-16 | Takeda Pharmaceuticals Co | Polymorphs of tartrate salt of 2-[2-(3-(R)-amino-piperidin-1-yl)-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile and methods of use therefor |
| TW200745079A (en) * | 2005-09-16 | 2007-12-16 | Takeda Pharmaceuticals Co | Polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor |
| CN102675221A (zh) * | 2005-09-16 | 2012-09-19 | 武田药品工业株式会社 | 用于制备嘧啶二酮衍生物的方法中的中间体 |
| WO2007051987A1 (en) * | 2005-11-01 | 2007-05-10 | Activotec Spp Limited | Insulinotropic compounds and uses thereof |
| BRPI0618379A2 (pt) | 2005-11-08 | 2011-08-30 | Ranbaxy Lab Ltd | processo para preparação do hemi-sal de cálcio do ácido (3r,5r) -7-[2-(4-fluorofenil)-5-isopropil-3-fenil-4-[(4-hidroxime tilfenilamino) carbonil]-pirrol-1-il] -3, 5-diidroxi heptanóico |
| US8039432B2 (en) | 2005-11-09 | 2011-10-18 | Conjuchem, Llc | Method of treatment of diabetes and/or obesity with reduced nausea side effect |
| US20080280328A1 (en) * | 2005-11-18 | 2008-11-13 | Novozymes A/S | Glucoamylase Variants |
| CA2634495A1 (en) * | 2005-12-22 | 2007-06-28 | Conjuchem Biotechnologies Inc. | Process for the production of preformed conjugates of albumin and a therapeutic agent |
| EP1816201A1 (en) | 2006-02-06 | 2007-08-08 | CSL Behring GmbH | Modified coagulation factor VIIa with extended half-life |
| DK1987052T3 (da) * | 2006-02-08 | 2011-08-15 | Lonza Ag | Syntese af glucagonlignende peptider |
| JP2009531456A (ja) * | 2006-03-28 | 2009-09-03 | 武田薬品工業株式会社 | （ｒ）−３−アミノピペリジン二塩酸塩の調製 |
| JP2009532117A (ja) | 2006-03-30 | 2009-09-10 | ヴァレリタス，エルエルシー | マルチカートリッジ式流体投与装置 |
| ATE481963T1 (de) | 2006-05-30 | 2010-10-15 | Intarcia Therapeutics Inc | Zweiteiliger flussmodulator mit einem internen kanal für ein osmotisches ausgabesystem |
| KR100886783B1 (ko) | 2006-06-12 | 2009-03-04 | 성균관대학교산학협력단 | N-말단이 수식된 peg-trail 결합체, 이의 제조방법 및 이의 용도 |
| AR061930A1 (es) | 2006-07-18 | 2008-10-01 | Centocor Inc | Mimeticuerpos de glp-1 humanos, composiciones, metodos y usos |
| CN101511868B (zh) * | 2006-07-24 | 2013-03-06 | 比奥雷克西斯制药公司 | 毒蜥外泌肽融合蛋白 |
| PL2359808T3 (pl) | 2006-08-09 | 2013-10-31 | Intarcia Therapeutics Inc | Osmotyczne systemy dostawcze i zespoły tłokowe |
| CL2007002634A1 (es) * | 2006-09-13 | 2008-05-16 | Smithkline Beecham Corp | Uso de una composicion que comprende al menos un polipeptido que tiene actividad de peptido-1 semejante a glucagon (glp-1) como agente hipoglucemiante de larga duracion. |
| DK2073810T3 (da) * | 2006-09-13 | 2011-10-31 | Takeda Pharmaceutical | Anvendelse af 2-6-(3-aminio-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl-4-fluor-benzonitril til behandling af diabetes, cancer, autoimmune sygdomme og HIV infektion |
| US8324383B2 (en) | 2006-09-13 | 2012-12-04 | Takeda Pharmaceutical Company Limited | Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile |
| TW200838536A (en) * | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| US20090098130A1 (en) * | 2007-01-05 | 2009-04-16 | Bradshaw Curt W | Glucagon-like protein-1 receptor (glp-1r) agonist compounds |
| AU2011254001B2 (en) * | 2007-01-05 | 2012-08-02 | Covx Technologies Ireland Limited | Glucagon-like protein-1 receptor (GLP-1R) agonist compounds |
| US20090099074A1 (en) * | 2007-01-10 | 2009-04-16 | Conjuchem Biotechnologies Inc. | Modulating food intake |
| GEP20135944B (en) | 2007-02-15 | 2013-10-25 | Indiana Unversity Research And Tech Corporation | Glucagon/glp-1 receptor co-agonists |
| US8093236B2 (en) | 2007-03-13 | 2012-01-10 | Takeda Pharmaceuticals Company Limited | Weekly administration of dipeptidyl peptidase inhibitors |
| JP5351884B2 (ja) | 2007-04-23 | 2013-11-27 | インターシア セラピューティクス，インコーポレイティド | インスリン分泌促進性ペプチドの懸濁製剤及び使用 |
| EP2171080A4 (en) | 2007-06-12 | 2010-10-27 | Glaxosmithkline Llc | PROCESS FOR DETECTING PROTEIN IN PLASMA |
| US20090054332A1 (en) * | 2007-06-21 | 2009-02-26 | Conjuchem Biotechnologies, Inc. | Thombopoietin peptide conjugates |
| US7960336B2 (en) * | 2007-08-03 | 2011-06-14 | Pharmain Corporation | Composition for long-acting peptide analogs |
| EP2190460B1 (en) | 2007-09-05 | 2014-12-17 | Novo Nordisk A/S | Peptides derivatized with a-b-c-d- and their therapeutical use |
| WO2009030774A1 (en) | 2007-09-05 | 2009-03-12 | Novo Nordisk A/S | Truncated glp-1 derivatives and their therapeutical use |
| JP5476304B2 (ja) | 2007-09-05 | 2014-04-23 | ノボ・ノルデイスク・エー／エス | グルカゴン様ペプチド−１誘導体及びそれらの医薬用途 |
| EP2205624B1 (en) * | 2007-10-27 | 2016-09-07 | Corden Pharma Colorado, Inc. | Insulinotropic peptide synthesis using solid and solution phase combination techniques |
| CN102026666B (zh) * | 2007-12-11 | 2013-10-16 | 常山凯捷健生物药物研发（河北）有限公司 | 促胰岛素肽缀合物制剂 |
| CA2726861C (en) | 2008-02-13 | 2014-05-27 | Intarcia Therapeutics, Inc. | Devices, formulations, and methods for delivery of multiple beneficial agents |
| EP2303313B1 (en) | 2008-05-21 | 2015-10-28 | Amylin Pharmaceuticals, LLC | Exendins to lower cholestrol and triglycerides |
| MX337038B (es) | 2008-06-17 | 2016-02-10 | Univ Indiana Res & Tech Corp | Co-antagonistas de receptor de glucagon/glp-1. |
| BRPI0915282A2 (pt) | 2008-06-17 | 2017-02-07 | Univ Indiana Res & Tech Corp | agonistas mistos baseados no gip para o tratamento de distúrbios metabólicos e obesidade |
| CA2726894A1 (en) | 2008-06-27 | 2009-12-30 | Duke University | Therapeutic agents comprising elastin-like peptides |
| AU2009279090A1 (en) | 2008-08-06 | 2010-02-11 | Novo Nordisk Health Care Ag | Conjugated proteins with prolonged in vivo efficacy |
| TW201012829A (en) * | 2008-09-22 | 2010-04-01 | Ipsen Mfg Ireland Ltd | Process for the synthesis of (Aib8,35)hGLP-1(7-36)-NH2 |
| MX2011004017A (es) | 2008-10-15 | 2011-06-24 | Angiochem Inc | Conjugados de agonistas glp-1 y usos de los mismos. |
| BRPI0920881B1 (pt) | 2008-10-17 | 2021-09-21 | Sanofi-Aventis Deutschland Gmbh | Composição farmacêutica, seu uso e método de preparação da mesma, kit e dispositivo |
| BRPI0922689A2 (pt) | 2008-12-05 | 2018-11-06 | Angiochem Inc. | conjugados de neurotensina ou análogos de neurotensina e usos dos mesmos |
| LT2373681T (lt) | 2008-12-10 | 2017-04-10 | Glaxosmithkline Llc | Albiglutido farmacinės kompozicijos |
| KR20110122100A (ko) | 2009-01-22 | 2011-11-09 | 노보 노르디스크 헬스 케어 악티엔게젤샤프트 | 안정한 성장 호르몬 화합물 |
| AU2010218139B2 (en) | 2009-02-25 | 2012-11-01 | Merck Sharp & Dohme Corp. | Metabolic engineering of a galactose assimilation pathway in the glycoengineered yeast Pichia pastoris |
| EP2416797A4 (en) | 2009-04-10 | 2013-04-24 | Amylin Pharmaceuticals Llc | AMYLINAGONIST COMPOUNDS FOR OXYGEN ANIMAL MICE |
| MX2011013625A (es) | 2009-06-16 | 2012-01-20 | Univ Indiana Res & Tech Corp | Compuestos glucagon activo de receptor de gip. |
| CA2766537A1 (en) * | 2009-07-02 | 2011-01-06 | Angiochem Inc. | Multimeric peptide conjugates and uses thereof |
| CN101987868B (zh) * | 2009-07-30 | 2013-09-04 | 江苏豪森医药集团有限公司 | Glp-1类似物的衍生物或其可药用盐和用途 |
| CN102612376A (zh) | 2009-08-06 | 2012-07-25 | 诺沃-诺迪斯克保健股份有限公司 | 具有延长的体内功效的生长激素 |
| RU2547990C2 (ru) | 2009-09-28 | 2015-04-10 | Интарсия Терапьютикс, Инк. | Быстрое достижение и/или прекращение существенной стабильной доставки лекарственного средства |
| KR101525473B1 (ko) * | 2009-09-30 | 2015-06-03 | 고쿠리츠 다이가쿠 호진 교토 다이가쿠 | 췌도 이미징용 분자 프로브 및 그 사용 |
| WO2011048614A2 (en) | 2009-10-22 | 2011-04-28 | Cadila Healthcare Limited | Short chain peptidomimetics based orally active glp-1 agonist and glucagon receptor antagonist |
| DK2498802T3 (en) | 2009-11-13 | 2015-04-13 | Sanofi Aventis Deutschland | Pharmaceutical composition comprising a GLP-1 agonist, insulin and a methionine |
| NZ599847A (en) | 2009-11-13 | 2013-09-27 | Sanofi Aventis Deutschland | Pharmaceutical composition comprising a glp-1 agonist and methionine |
| EP2504021A4 (en) | 2009-11-23 | 2013-05-15 | Amylin Pharmaceuticals Llc | Polypeptide conjugate |
| MX345736B (es) | 2010-01-22 | 2017-02-14 | Novo Nordisk Healthcare Ag | Hormonas de crecimiento con eficacia in vivo prolongada. |
| EP2525833A2 (en) | 2010-01-22 | 2012-11-28 | Novo Nordisk Health Care AG | Stable growth hormone compounds |
| JP2013518115A (ja) | 2010-01-27 | 2013-05-20 | 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 | 代謝疾患及び肥満の治療のためのグルカゴンアンタゴニスト‐ｇｉｐアゴニスト複合体及び組成物 |
| BR112012020882A2 (pt) | 2010-02-24 | 2015-11-03 | Merck Sharp & Dohme | métodos para produzir uma glicoproteína heteróloga e para produzir uma composição de glicoproteína, célula hospedeira, composição de glicoproteína, e, uso da pichia pastoris recombinante. |
| CA2792663A1 (en) * | 2010-03-26 | 2011-09-29 | Novo Nordisk A/S | Novel glucagon analogues |
| WO2011123943A1 (en) | 2010-04-09 | 2011-10-13 | Mount Sinai Hospital | Methods for treating disorders of the gastrointestinal tract using a glp-1 agonist |
| PH12012502121A1 (en) | 2010-04-27 | 2019-07-10 | Zealand Pharma As | Peptide conjugates of glp-1 receptor agonists and gastrin and their use |
| JP2013525491A (ja) | 2010-05-04 | 2013-06-20 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | 心血管障害を治療または予防し心血管保護を提供する方法 |
| RU2604067C2 (ru) | 2010-05-13 | 2016-12-10 | Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн | Пептиды глюкагонового суперсемейства, обладающие активностью относительно ядерных гормональных рецепторов |
| WO2011143208A1 (en) | 2010-05-13 | 2011-11-17 | Indiana University Research And Technology Corporation | Glucagon superfamily peptides exhibiting g protein-coupled receptor activity |
| MX339614B (es) | 2010-08-30 | 2016-06-02 | Sanofi - Aventis Deutschland GmbH | Uso de ave0010 para la fabricacion de un medicamento para el tratamiento de la diabetes mellitus tipo 2. |
| AU2011343190B2 (en) | 2010-12-16 | 2016-12-08 | Novo Nordisk A/S | Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid |
| EP2654773B1 (en) | 2010-12-22 | 2018-10-03 | Indiana University Research and Technology Corporation | Glucagon analogs exhibiting gip receptor activity |
| US20120208755A1 (en) | 2011-02-16 | 2012-08-16 | Intarcia Therapeutics, Inc. | Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers |
| WO2012122025A2 (en) * | 2011-03-04 | 2012-09-13 | Intrexon Corporation | Vectors conditionally expressing protein |
| EP3225631B1 (en) | 2011-04-12 | 2019-01-09 | Novo Nordisk A/S | Double-acylated glp-1 derivatives |
| US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
| RU2014101697A (ru) | 2011-06-22 | 2015-07-27 | Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн | Коагонисты рецепторов глюкагона/glp-1 |
| RS56173B1 (sr) | 2011-06-22 | 2017-11-30 | Univ Indiana Res & Tech Corp | Koagonisti receptora za glukagon/glp-1 receptora |
| KR101357117B1 (ko) * | 2011-06-28 | 2014-02-06 | 비앤엘델리팜 주식회사 | 폴리에틸렌글라이콜 또는 이의 유도체로 페길화된 엑센딘-4 유사체, 이의 제조방법 및 이를 유효성분으로 함유하는 당뇨병 예방 또는 치료용 약학적 조성물 |
| CN108079281A (zh) | 2011-08-29 | 2018-05-29 | 赛诺菲-安万特德国有限公司 | 用于2型糖尿病患者中的血糖控制的药物组合 |
| AR087744A1 (es) | 2011-09-01 | 2014-04-16 | Sanofi Aventis Deutschland | Composicion farmaceutica para uso en el tratamiento de una enfermedad neurodegenerativa |
| CN103189389B (zh) * | 2011-09-03 | 2017-08-11 | 深圳市健元医药科技有限公司 | 新的glp‑ⅰ类似物及其制备方法和用途 |
| CN102286092B (zh) * | 2011-09-14 | 2014-01-01 | 深圳翰宇药业股份有限公司 | 利拉鲁肽的固相合成方法 |
| US8541368B2 (en) | 2011-09-23 | 2013-09-24 | Novo Nordisk A/S | Glucagon analogues |
| AU2012331053A1 (en) | 2011-11-03 | 2014-05-29 | Zealand Pharma A/S | GLP-1 receptor agonist peptide gastrin conjugates |
| US9499587B2 (en) | 2012-01-23 | 2016-11-22 | University Of South Florida | Gamma-AApeptides with potent and broad-spectrum antimicrobial activity |
| ES2715308T3 (es) | 2012-03-22 | 2019-06-03 | Novo Nordisk As | Composiciones que comprenden un agente de suministro y su preparación |
| EP2827885B1 (en) | 2012-03-22 | 2018-08-15 | Novo Nordisk A/S | Compositions of glp-1 peptides and preparation thereof |
| WO2013163162A1 (en) * | 2012-04-24 | 2013-10-31 | Amylin Pharmaceuticals, Llc | Site-specific enzymatic modification of exendins and analogs thereof |
| US9289507B2 (en) | 2012-05-17 | 2016-03-22 | Extend Biosciences, Inc. | Carriers for improved drug delivery |
| JP6517690B2 (ja) | 2012-06-20 | 2019-05-22 | ノヴォ ノルディスク アー／エス | ペプチド及び送達剤を含む錠剤製剤 |
| US9340600B2 (en) | 2012-06-21 | 2016-05-17 | Indiana University Research And Technology Corporation | Glucagon analogs exhibiting GIP receptor activity |
| EP2863954A1 (en) | 2012-06-21 | 2015-04-29 | Indiana University Research and Technology Corporation | Incretin receptor ligand polypeptide fc-region fusion polypeptides and conjugates with altered fc-effector function |
| UA117103C2 (uk) | 2012-07-23 | 2018-06-25 | Зіленд Фарма А/С | Сполука, яка має активність агоніста глюкагону |
| TWI608013B (zh) | 2012-09-17 | 2017-12-11 | 西蘭製藥公司 | 升糖素類似物 |
| UA116217C2 (uk) | 2012-10-09 | 2018-02-26 | Санофі | Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону |
| JP6408998B2 (ja) | 2012-12-21 | 2018-10-17 | サノフイＳａｎｏｆｉ | 二重ｇｌｐ１／ｇｉｐまたは三方ｇｌｐ１／ｇｉｐ／グルカゴンアゴニスト |
| TWI780236B (zh) | 2013-02-04 | 2022-10-11 | 法商賽諾菲公司 | 胰島素類似物及/或胰島素衍生物之穩定化醫藥調配物 |
| HUE048687T2 (hu) | 2013-02-18 | 2020-08-28 | Vegenics Pty Ltd | Ligandum kötõ molekulák és alkalmazásaik |
| CN105324397B (zh) | 2013-03-14 | 2020-01-14 | 印第安纳大学研究及科技有限公司 | 胰岛素-肠促胰岛素缀合物 |
| CN104592380A (zh) * | 2013-03-15 | 2015-05-06 | 深圳君圣泰生物技术有限公司 | 一种多肽、多肽衍生物、多肽的可药用盐、药物组合物及其应用 |
| CN104650212A (zh) * | 2013-03-15 | 2015-05-27 | 深圳君圣泰生物技术有限公司 | 一种多肽、多肽衍生物、多肽的可药用盐、药物组合物及其应用 |
| WO2014161835A1 (en) * | 2013-04-03 | 2014-10-09 | Sanofi | Modified blood glucose regulating proteins with altered pharmacological activity profile and preparation thereof |
| ES2841123T3 (es) | 2013-04-05 | 2021-07-07 | Formulacion Del Compuesto De La Hormona De Crecimiento | Formulación del compuesto de la hormona de crecimiento |
| AU2014255608B2 (en) | 2013-04-18 | 2018-01-25 | Novo Nordisk A/S | Stable, protracted GLP-1/glucagon receptor co-agonists for medical use |
| MY172578A (en) | 2013-05-02 | 2019-12-03 | Novo Nordisk As | Oral dosing of glp-1 compounds |
| US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
| BR112016008115B1 (pt) | 2013-10-17 | 2024-03-12 | Boehringer Ingelheim International Gmbh | Análogos de glucagon acilados |
| CA2929459C (en) | 2013-11-06 | 2022-05-03 | Zealand Pharma A/S | Gip-glp-1 dual agonist compounds and methods |
| WO2015067716A1 (en) | 2013-11-06 | 2015-05-14 | Zealand Pharma A/S | Glucagon-glp-1-gip triple agonist compounds |
| WO2015086728A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Exendin-4 peptide analogues as dual glp-1/gip receptor agonists |
| EP3080149A1 (en) | 2013-12-13 | 2016-10-19 | Sanofi | Dual glp-1/glucagon receptor agonists |
| WO2015086730A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Non-acylated exendin-4 peptide analogues |
| TW201609799A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 雙重ｇｌｐ－１／ｇｉｐ受體促效劑 |
| CN106029087A (zh) | 2013-12-20 | 2016-10-12 | 印第安纳大学研究及科技有限公司 | 脂质化肠降血糖素受体配体人免疫球蛋白fc区融合多肽 |
| SG11201604708VA (en) | 2014-01-09 | 2016-07-28 | Sanofi Sa | Stabilized glycerol free pharmaceutical formulations of insulin analogues and/or insulin derivatives |
| CN112957455A (zh) | 2014-01-09 | 2021-06-15 | 赛诺菲 | 胰岛素类似物和/或胰岛素衍生物的稳定化药物制剂 |
| EP3091964A1 (en) | 2014-01-09 | 2016-11-16 | Sanofi | Stabilized pharmaceutical formulations of insulin aspart |
| WO2015138638A1 (en) | 2014-03-11 | 2015-09-17 | Theraly Pharmaceuticals, Inc. | Long acting trail receptor agonists for treatment of autoimmune diseases |
| TW201625669A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑 |
| TW201625668A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物 |
| TW201625670A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑 |
| JP2017525656A (ja) | 2014-06-04 | 2017-09-07 | ノヴォ ノルディスク アー／エス | 医療用のｇｌｐ−１／グルカゴン受容体コアゴニスト |
| US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
| GB201415598D0 (en) | 2014-09-03 | 2014-10-15 | Univ Birmingham | Elavated Itercranial Pressure Treatment |
| EP3206710B1 (en) | 2014-09-24 | 2020-05-06 | Indiana University Research & Technology Corporation | Incretin-insulin conjugates |
| US9889085B1 (en) | 2014-09-30 | 2018-02-13 | Intarcia Therapeutics, Inc. | Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c |
| WO2016065042A1 (en) | 2014-10-22 | 2016-04-28 | Extend Biosciences, Inc. | Therapeutic vitamin d conjugates |
| WO2016065052A1 (en) | 2014-10-22 | 2016-04-28 | Extend Biosciences, Inc. | Insulin vitamin d conjugates |
| US9789197B2 (en) | 2014-10-22 | 2017-10-17 | Extend Biosciences, Inc. | RNAi vitamin D conjugates |
| US10253078B2 (en) | 2014-10-29 | 2019-04-09 | Zealand Pharma A/S | GIP agonist compounds and methods |
| BR112017012406A2 (pt) | 2014-12-12 | 2018-07-31 | Sanofi Aventis Deutschland | formulação com relação fixa de insulina glargina/lixisenatida |
| TWI748945B (zh) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | 第２型糖尿病病患治療 |
| TW201705975A (zh) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | 第２型糖尿病病患之治療 |
| ES2763329T3 (es) | 2015-04-16 | 2020-05-28 | Zealand Pharma As | Análogo de glucagón acilado |
| AU2016270984B2 (en) | 2015-06-03 | 2021-02-25 | Intarcia Therapeutics, Inc. | Implant placement and removal systems |
| AR105319A1 (es) | 2015-06-05 | 2017-09-27 | Sanofi Sa | Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico |
| CN107921143B (zh) | 2015-06-15 | 2021-11-19 | 安吉奥开米公司 | 用于治疗软脑膜癌病的方法 |
| TW201706291A (zh) | 2015-07-10 | 2017-02-16 | 賽諾菲公司 | 作為選擇性肽雙重ｇｌｐ－１／升糖素受體促效劑之新毒蜥外泌肽（ｅｘｅｎｄｉｎ－４）衍生物 |
| ES3013312T3 (en) | 2015-12-17 | 2025-04-11 | Univ Johns Hopkins | Ameliorating systemic sclerosis with death receptor agonists |
| LT3393496T (lt) | 2015-12-23 | 2023-12-11 | The Johns Hopkins University | Ilgo veikimo glp-1r agonistas, kaip neurologinių ir neurodegeneracinių būklių terapija |
| US11084879B2 (en) | 2016-04-07 | 2021-08-10 | The Johns Hopkins University | Compositions and methods for treating pancreatitis and pain with death receptor agonists |
| SG11201810102SA (en) | 2016-05-16 | 2018-12-28 | Intarcia Therapeutics Inc | Glucagon-receptor selective polypeptides and methods of use thereof |
| USD840030S1 (en) | 2016-06-02 | 2019-02-05 | Intarcia Therapeutics, Inc. | Implant placement guide |
| USD860451S1 (en) | 2016-06-02 | 2019-09-17 | Intarcia Therapeutics, Inc. | Implant removal tool |
| CN108070030B (zh) * | 2016-11-17 | 2023-06-23 | 江苏豪森药业集团有限公司 | 洛塞那肽及其类似物的制备方法 |
| ES2979184T3 (es) | 2016-12-09 | 2024-09-24 | Zealand Pharma As | Agonistas duales de glp-1/glp-2 acilados |
| IL267736B2 (en) | 2017-01-03 | 2024-03-01 | Intarcia Therapeutics Inc | Methods comprising continuous administration of a glp-1 receptor agonist and co-adminstration of a drug |
| JOP20180028A1 (ar) | 2017-03-31 | 2019-01-30 | Takeda Pharmaceuticals Co | مركب ببتيد |
| CN109503700A (zh) * | 2017-09-14 | 2019-03-22 | 南京安吉生物科技有限公司 | 马来酰亚胺基团修饰的血管生成抑制剂hm-1及其应用 |
| US10905750B2 (en) | 2017-11-10 | 2021-02-02 | Donald J. Davidson | GRP78 antagonist that block binding of receptor tyrosine kinase orphan receptors as immunotherapy anticancer agents |
| AR114353A1 (es) | 2018-02-02 | 2020-08-26 | Novo Nordisk As | Composiciones sólidas que comprenden un agonista del glp-1 y una sal del ácido n-(8-(2-hidroxibenzoil)amino)caprílico |
| WO2019200594A1 (zh) | 2018-04-19 | 2019-10-24 | 杭州先为达生物科技有限公司 | 酰化的glp-1衍生物 |
| IL320142A (en) | 2018-10-11 | 2025-06-01 | Intarcia Therapeutics Inc | Human amylin analog polypeptides and methods of use |
| CN109400695B (zh) | 2018-10-31 | 2020-06-30 | 中南大学湘雅医院 | 一种多肽的修饰方法及应用 |
| CN110183531A (zh) * | 2019-05-17 | 2019-08-30 | 河北常山生化药业股份有限公司 | 一种艾本那肽前体的制备方法 |
| CN111333714A (zh) * | 2020-03-05 | 2020-06-26 | 成都奥达生物科技有限公司 | 一种长效glp-1化合物 |
| US20230158165A1 (en) * | 2020-03-27 | 2023-05-25 | Epivax, Inc. | Tregitope constructs useful in the prevention and treatment of type 1 diabetes |
| US12233115B2 (en) | 2022-09-30 | 2025-02-25 | Extend Biosciences, Inc. | Long-acting parathyroid hormone |
| CN115819493A (zh) * | 2022-11-16 | 2023-03-21 | 河北常山生化药业股份有限公司 | 一种多肽固相合成方法 |
| WO2024123812A1 (en) | 2022-12-05 | 2024-06-13 | Shattuck Labs, Inc. | Fusion proteins for the treatment of cardiometabolic diseases |
| WO2025069009A1 (en) | 2023-09-29 | 2025-04-03 | Graviton Bioscience Bv | Rock2 inhibitors in the treatment of obesity |
Family Cites Families (86)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4206199A (en) * | 1977-07-22 | 1980-06-03 | Takeda Chemical Industries, Ltd. | Novel glucagon fragment and its derivatives |
| US4423034A (en) * | 1980-10-16 | 1983-12-27 | Toyo Jozo Kabushiki Kaisha | Process for the preparation of antibodies |
| US4462941A (en) * | 1982-06-10 | 1984-07-31 | The Regents Of The University Of California | Dynorphin amide analogs |
| US5614492A (en) | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
| US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
| US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
| DK608589D0 (da) | 1989-12-01 | 1989-12-01 | Holm Arne | Kemisk fremgangsmaade |
| US5116944A (en) * | 1989-12-29 | 1992-05-26 | Neorx Corporation | Conjugates having improved characteristics for in vivo administration |
| US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
| WO1991011457A1 (en) | 1990-01-24 | 1991-08-08 | Buckley Douglas I | Glp-1 analogs useful for diabetes treatment |
| US5843440A (en) * | 1990-10-03 | 1998-12-01 | Redcell Canada, Inc. | Cellular and serum protein anchors for modulating pharmacokinetics |
| US5612034A (en) | 1990-10-03 | 1997-03-18 | Redcell, Inc. | Super-globuling for in vivo extended lifetimes |
| JPH06509551A (ja) | 1991-04-05 | 1994-10-27 | ジェネンテク，インコーポレイテッド | Ｇｐ ＩＩ↓ｂＩＩＩ↓ａに対する高い特異性を有する血小板凝集阻害剤 |
| CZ315594A3 (en) | 1992-06-15 | 1995-07-12 | Pfizer | Peptide of glucagon type, insulinotropic derivatives, process of their preparation, pharmaceutical composition containing such compounds and use |
| EP0602290B1 (en) | 1992-12-04 | 1999-08-25 | ConjuChem, Inc. | Antibody-conjugated Hepatitis B surface antigen and use thereof |
| US5424286A (en) * | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
| US5614487A (en) * | 1993-05-28 | 1997-03-25 | Genentech, Inc. | Sustained release pharmaceutical composition |
| US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
| US5580853A (en) * | 1994-03-22 | 1996-12-03 | New England Deaconess Hospital | Modified polypeptides with increased biological activity |
| US5837682A (en) * | 1996-03-08 | 1998-11-17 | The Children's Medical Center Corporation | Angiostatin fragments and method of use |
| NZ285501A (en) * | 1994-04-26 | 1998-02-26 | Childrens Medical Center | Plasminogen analogs (angiostatin), endothelial inhibitors, assays and kits |
| US5639725A (en) * | 1994-04-26 | 1997-06-17 | Children's Hospital Medical Center Corp. | Angiostatin protein |
| US5945403A (en) | 1997-05-30 | 1999-08-31 | The Children's Medical Center Corporation | Angiostatin fragments and method of use |
| US5574008A (en) | 1994-08-30 | 1996-11-12 | Eli Lilly And Company | Biologically active fragments of glucagon-like insulinotropic peptide |
| US5654276A (en) * | 1995-06-07 | 1997-08-05 | Affymax Technologies N.V. | Peptides and compounds that bind to the IL-5 receptor |
| US5854221A (en) * | 1996-12-12 | 1998-12-29 | The Children's Medical Center Corporation | Endothelial cell proliferation inhibitor and method of use |
| CZ298612B6 (cs) | 1995-12-13 | 2007-11-21 | The Children's Medical Center Corporation | Inhibitor proliferace endothelových bunek a jeho použití |
| WO1997025074A2 (en) | 1996-01-12 | 1997-07-17 | Redcell Canada, Inc. | Cellular and serum protein anchors for diagnostic imaging |
| US6277583B1 (en) * | 1996-02-07 | 2001-08-21 | Conjuchem, Inc. | Affinity labeling libraries and applications thereof |
| ID17252A (id) | 1996-04-29 | 1997-12-11 | Akzo Nobel Nv | Proses pembuatan obyek yang terbuat dari selulosa |
| BR9708911A (pt) | 1996-05-03 | 1999-08-03 | Abbott Lab | Composto fragmento de peptídeo processo par tratar uma doença em um paciente em necessidade de terapia antioangiogênese composição polinucleotídeo único ou de duplo-filamento isolado vetor e processo para produzir um fragmento de peptídeo de kringle 5 ou proteína de fusão de kringle 5 solúvel |
| US5801146A (en) * | 1996-05-03 | 1998-09-01 | Abbott Laboratories | Compound and method for inhibiting angiogenesis |
| TR199802789T2 (xx) | 1996-06-05 | 1999-03-22 | Boehringer Mannheim Gmbh | Eksendin analoglar� bunlar�n �retimi i�in y�ntemler ve bunlar� i�eren farmas�tik m�stahzarlar. |
| US5840733A (en) | 1996-07-01 | 1998-11-24 | Redcell, Canada, Inc. | Methods and compositions for producing novel conjugates of thrombin inhibitors and endogenous carriers resulting in anti-thrombins with extended lifetimes |
| CA2262647C (en) | 1996-08-08 | 2007-12-04 | Amylin Pharmaceuticals, Inc. | Methods for regulating gastrointestinal motility |
| US6277819B1 (en) | 1996-08-30 | 2001-08-21 | Eli Lilly And Company | Use of GLP-1 or analogs in treatment of myocardial infarction |
| DK0944648T3 (da) | 1996-08-30 | 2007-07-02 | Novo Nordisk As | GLP-1 derivater |
| US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
| AU4351897A (en) * | 1996-09-16 | 1998-04-02 | Conjuchem, Inc. | Affinity labeling libraries with tagged leaving groups |
| 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 |
| US5864372A (en) * | 1996-12-10 | 1999-01-26 | United Microelectronics Corporation | Apparatus for implementing a block matching algorithm for motion estimation in video image processing |
| US6723530B1 (en) * | 1997-02-05 | 2004-04-20 | Amylin Pharmaceuticals, Inc. | Polynucleotides encoding proexendin, and methods and uses thereof |
| JP2002510193A (ja) | 1997-03-31 | 2002-04-02 | イーライ・リリー・アンド・カンパニー | グルカゴン様ペプチド−１類似体 |
| WO1998043658A1 (en) | 1997-03-31 | 1998-10-08 | Eli Lilly And Company | Glucagon-like peptide-1 analogs |
| EP1001985A1 (en) | 1997-06-26 | 2000-05-24 | Karolinska Innovations AB | Kringle domains 1-5 of plasminogen, capable of modulating angiogenesis in vivo |
| ES2293688T5 (es) | 1997-08-08 | 2011-05-04 | Amylin Pharmaceuticals, Inc. | Nuevos compuestos análogos de la exendina. |
| EP1056474B1 (en) * | 1997-11-07 | 2002-06-12 | ConjuChem, Inc. | Affinity markers for human serum albumin |
| ATE216402T1 (de) * | 1997-11-07 | 2002-05-15 | Conjuchem Inc | Opioid-konjugate mit endogenen trägerproteinen |
| US6437092B1 (en) * | 1998-11-06 | 2002-08-20 | Conjuchem, Inc. | Conjugates of opioids and endogenous carriers |
| WO1999024015A1 (en) | 1997-11-12 | 1999-05-20 | Alza Corporation | Buffered drug formulations for transdermal electrotransport delivery |
| JP2003522721A (ja) | 1997-11-14 | 2003-07-29 | アミリン・ファーマシューティカルズ，インコーポレイテッド | 新規なエキセンジンアゴニスト化合物 |
| BR9814189A (pt) | 1997-11-14 | 2000-10-03 | Amylin Pharmaceuticals Inc | "compostos agonistas da exendina" |
| CA2312190A1 (en) | 1997-12-05 | 1999-06-17 | Eli Lilly And Company | Glp-1 formulations |
| EP1062229A1 (en) | 1998-03-09 | 2000-12-27 | Zealand Pharmaceuticals A/S | Pharmacologically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
| US6107489A (en) * | 1998-03-17 | 2000-08-22 | Conjuchem, Inc. | Extended lifetimes in vivo renin inhibitors |
| CA2291066A1 (en) * | 1998-03-23 | 1999-09-30 | Conjuchem, Inc. | Local delivery of long lasting therapeutic agents |
| US20030170250A1 (en) * | 1998-03-23 | 2003-09-11 | Ezrin Alan M. | Local delivery of long lasting therapeutic agents |
| GB9815505D0 (en) | 1998-07-16 | 1998-09-16 | Adprotech Plc | Polypeptide derivatives |
| CA2343207A1 (en) | 1998-09-09 | 2000-03-16 | U.S. Army Institute Of Surgical Research | Nasopharyngeal airway with reflectance pulse oximeter sensor |
| US6284725B1 (en) * | 1998-10-08 | 2001-09-04 | Bionebraska, Inc. | Metabolic intervention with GLP-1 to improve the function of ischemic and reperfused tissue |
| US6440417B1 (en) * | 1998-11-06 | 2002-08-27 | Conjuchem, Inc. | Antibodies to argatroban derivatives and their use in therapeutic and diagnostic treatments |
| EP1153125B1 (en) | 1999-02-10 | 2007-04-18 | The Children's Medical Center Corporation | Deglycosylated kringle 1-5 region fragments of plasminogen and methods of use |
| US6465424B1 (en) | 1999-02-17 | 2002-10-15 | Bristol-Myers Squibb Company | Anti-angiogenic agent and method for inhibiting angiogenesis |
| US6451974B1 (en) * | 1999-03-17 | 2002-09-17 | Novo Nordisk A/S | Method of acylating peptides and novel acylating agents |
| AU771755B2 (en) | 1999-03-18 | 2004-04-01 | Children's Medical Center Corporation | Novel antiangiogenic peptides |
| WO2000061179A1 (en) | 1999-04-14 | 2000-10-19 | Karolinska Innovations Ab | Kringle domains of plasminogen, capable of modulating angiogenesis in vivo |
| ATE226593T1 (de) * | 1999-05-17 | 2002-11-15 | Conjuchem Inc | Lang wirkende peptidinhibitoren der virusfusion mit körperzellen bei viralen infektionen |
| SI1105409T1 (sl) | 1999-05-17 | 2006-06-30 | Conjuchem Inc | Zascita endogenih peptidov pred peptidazno ucinkovitostjo s konjugacijo na krvne komponente |
| US7601691B2 (en) * | 1999-05-17 | 2009-10-13 | Conjuchem Biotechnologies Inc. | Anti-obesity agents |
| US7144854B1 (en) * | 1999-09-10 | 2006-12-05 | Conjuchem, Inc. | Long lasting anti-angiogenic peptides |
| US20040266673A1 (en) * | 2002-07-31 | 2004-12-30 | Peter Bakis | Long lasting natriuretic peptide derivatives |
| US6514500B1 (en) * | 1999-10-15 | 2003-02-04 | Conjuchem, Inc. | Long lasting synthetic glucagon like peptide {GLP-!} |
| US6887470B1 (en) * | 1999-09-10 | 2005-05-03 | Conjuchem, Inc. | Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components |
| US6849714B1 (en) * | 1999-05-17 | 2005-02-01 | Conjuchem, Inc. | Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components |
| ATE252601T1 (de) * | 1999-05-17 | 2003-11-15 | Conjuchem Inc | Lang wirkende insulinotrope peptide |
| DE19926154A1 (de) | 1999-06-09 | 2000-12-14 | Ktb Tumorforschungs Gmbh | Verfahren zur Herstellung einer injizierbaren Arzneimittelzubereitung |
| DE19926475A1 (de) | 1999-06-10 | 2000-12-14 | Ktb Tumorforschungs Gmbh | Träger-Pharmaka-Konjugate |
| US6706892B1 (en) * | 1999-09-07 | 2004-03-16 | Conjuchem, Inc. | Pulmonary delivery for bioconjugation |
| US7090851B1 (en) * | 1999-09-10 | 2006-08-15 | Conjuchem Inc. | Long lasting fusion peptide inhibitors of viral infection |
| CN101696240A (zh) * | 2001-02-02 | 2010-04-21 | 康久化学生物技术公司 | 长效生长激素释放因子衍生物 |
| DE60226702D1 (de) * | 2001-02-16 | 2008-07-03 | Conjuchem Biotechnologies Inc | Lang wirkendes glucagon-ähnliches peptid-2 für die behandlung von gastrointestinalen krankheiten und störungen |
| CA2448891A1 (en) * | 2001-05-31 | 2002-12-05 | Conjuchem Inc. | Long lasting fusion peptide inhibitors for hiv infection |
| CA2526957C (en) * | 2003-07-25 | 2011-07-12 | Conjuchem Inc. | Long lasting insulin derivatives and methods thereof |
| MXPA06012260A (es) * | 2004-04-23 | 2006-12-15 | Conjuchem Biotechnologies Inc | Metodo para la purificacion de conjugados de albumina. |
| US8039432B2 (en) * | 2005-11-09 | 2011-10-18 | Conjuchem, Llc | Method of treatment of diabetes and/or obesity with reduced nausea side effect |
| CA2634495A1 (en) * | 2005-12-22 | 2007-06-28 | Conjuchem Biotechnologies Inc. | Process for the production of preformed conjugates of albumin and a therapeutic agent |
-
2000
- 2000-05-17 AT AT00930796T patent/ATE252601T1/de active
- 2000-05-17 SI SI200030286T patent/SI1180121T1/xx unknown
- 2000-05-17 AU AU48555/00A patent/AU754770B2/en not_active Ceased
- 2000-05-17 CN CNB008065489A patent/CN1191273C/zh not_active Expired - Lifetime
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- 2000-05-17 EP EP00930796A patent/EP1180121B9/en not_active Expired - Lifetime
- 2000-05-17 BR BR0010750-6A patent/BR0010750A/pt not_active Application Discontinuation
- 2000-05-17 EA EA200100939A patent/EA003922B1/ru not_active IP Right Cessation
- 2000-05-17 CA CA002501421A patent/CA2501421A1/en not_active Abandoned
- 2000-05-17 WO PCT/US2000/013563 patent/WO2000069911A1/en not_active Ceased
- 2000-05-17 US US09/623,618 patent/US6329336B1/en not_active Expired - Fee Related
- 2000-05-17 DK DK00930796T patent/DK1180121T3/da active
- 2000-05-17 JP JP2000618327A patent/JP4115671B2/ja not_active Expired - Fee Related
- 2000-05-17 ES ES00930796T patent/ES2209885T3/es not_active Expired - Lifetime
- 2000-05-17 PT PT00930796T patent/PT1180121E/pt unknown
- 2000-05-17 CA CA2363712A patent/CA2363712C/en not_active Expired - Fee Related
-
2001
- 2001-06-06 US US09/876,388 patent/US6593295B2/en not_active Expired - Fee Related
- 2001-11-15 NO NO20015584A patent/NO20015584L/no not_active Application Discontinuation
-
2005
- 2005-05-24 JP JP2005151458A patent/JP4116016B2/ja not_active Expired - Fee Related
- 2005-12-14 JP JP2005361126A patent/JP2006151986A/ja not_active Withdrawn
-
2006
- 2006-02-08 US US11/350,703 patent/US7741286B2/en not_active Expired - Fee Related
-
2008
- 2008-07-18 JP JP2008187967A patent/JP2009001583A/ja active Pending
- 2008-07-18 JP JP2008187966A patent/JP2009007371A/ja active Pending
-
2010
- 2010-04-13 US US12/759,153 patent/US20110071082A1/en not_active Abandoned
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