EA036415B1 - Устойчивые к действию протеазы липидированные аналоги glp-1 - Google Patents
Устойчивые к действию протеазы липидированные аналоги glp-1 Download PDFInfo
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- EA036415B1 EA036415B1 EA201792640A EA201792640A EA036415B1 EA 036415 B1 EA036415 B1 EA 036415B1 EA 201792640 A EA201792640 A EA 201792640A EA 201792640 A EA201792640 A EA 201792640A EA 036415 B1 EA036415 B1 EA 036415B1
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| CA3025592A1 (en) * | 2016-06-09 | 2017-12-14 | Medimmune Limited | Protease-resistant mono-lipidated peptides |
| MA50047A (fr) * | 2017-10-31 | 2020-07-08 | Medimmune Ltd | Administration orale d'analogues peptidiques de glp-1 |
| SMT202200352T1 (it) | 2018-04-05 | 2022-09-14 | Sun Pharmaceutical Ind Ltd | Analoghi del glp-1 innovativi |
| KR20240118914A (ko) | 2021-01-20 | 2024-08-05 | 바이킹 테라퓨틱스 인코포레이티드 | 대사 및 간 질환 치료를 위한 조성물 및 방법 |
| CA3231953A1 (en) | 2021-09-15 | 2023-03-23 | Brian Lian | Compositions and methods for the treatment of metabolic and liver disorders |
| TW202346323A (zh) * | 2022-02-07 | 2023-12-01 | 英商梅迪繆思有限公司 | 具有改善的生物穩定性的ｇｌｐ—１及升糖素雙重激動肽 |
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| WO2014088631A1 (en) * | 2012-12-06 | 2014-06-12 | Stealth Peptides International, Inc. | Peptide therapeutics and methods for using same |
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| CN101010339B (zh) * | 2004-07-02 | 2011-11-09 | 布里斯托尔-迈尔斯斯奎布公司 | 人类胰高血糖素样肽-1调节剂及它们在治疗糖尿病及相关病况中的用途 |
| CA2621699A1 (en) * | 2005-09-08 | 2007-03-15 | Trustees Of Tufts College | Stabilized glp-1 analogs |
| EP1854455B1 (en) * | 2006-05-10 | 2009-10-07 | Biocompatibles UK Limited | Spherical microcapsules comprising GLP-1 peptides, their production and use |
| EP2021014A1 (en) | 2006-05-26 | 2009-02-11 | Brystol-Myers Squibb Company | Sustained release glp-1 receptor modulators |
| US20090318353A1 (en) | 2006-08-25 | 2009-12-24 | Novo Nordisk A/S | Acylated Exendin-4 Compounds |
| US8563521B2 (en) | 2007-06-21 | 2013-10-22 | Technische Universitat Munchen | Biological active proteins having increased in vivo and/or in vitro stability |
| KR101277560B1 (ko) | 2007-12-11 | 2013-06-25 | 카딜라 핼쓰캐어 리미티드 | 글루카곤 안타고니스트 활성 및 ｇｌｐ-1 아고니스트 활성의 펩티드 유사체 |
| CN102307897B (zh) * | 2008-12-05 | 2016-01-20 | 葛兰素集团有限公司 | 选出蛋白酶抗性多肽的方法 |
| WO2010148089A1 (en) | 2009-06-16 | 2010-12-23 | Indiana University Research And Technology Corporation | Gip receptor-active glucagon compounds |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014049610A2 (en) * | 2012-09-26 | 2014-04-03 | Cadila Healthcare Limited | Peptides as gip, glp-1 and glucagon receptors triple-agonist |
| WO2014088631A1 (en) * | 2012-12-06 | 2014-06-12 | Stealth Peptides International, Inc. | Peptide therapeutics and methods for using same |
Non-Patent Citations (4)
| Title |
|---|
| GREEN B D, ET AL.: "DEGRADATION, RECEPTOR BINDING, INSULIN SECRETING AND ANTIHYPERGLYCAEMIC ACTIONS OF PALMITATE-DERIVATISED NATIVE AND ALA8-SUBSTITUTED GLP-1 ANALOGUES", BIOLOGICAL CHEMISTRY, WALTER DE GRUYTER GMBH & CO., BERLIN, DE, vol. 385, no. 02, 1 February 2004 (2004-02-01), BERLIN, DE, pages 169 - 177, XP009067701, ISSN: 1431-6730, DOI: 10.1515/BC.2004.035 * |
| HUI HONGXIANG , ZHAO XIAONING, PERFETTI RICCARDO: "Structure and function studies of glucagon-like peptide-1 (GLP-1): the designing of a novel pharmacological agent for the treatment of diabetes.", DIABETES/METABOLISM RESEARCH AND REVIEWS, WILEY, LONDON,, GB, vol. 21, no. 4, 1 July 2005 (2005-07-01), GB, pages 313 - 331, XP002559636, ISSN: 1520-7552, DOI: 10.1002/dmrr.553 * |
| KIM, S. ; WAN KIM, S. ; BAE, Y.H.: "Synthesis, bioactivity and specificity of glucagon-like peptide-1 (7-37)/polymer conjugate to isolated rat islets", BIOMATERIALS, ELSEVIER, AMSTERDAM, NL, vol. 26, no. 17, 1 June 2005 (2005-06-01), AMSTERDAM, NL, pages 3597 - 3606, XP027767990, ISSN: 0142-9612 * |
| YOUN, Y.S. CHAE, S.Y. LEE, S. JEON, J.E. SHIN, H.G. LEE, K.C.: "Evaluation of therapeutic potentials of site-specific PEGylated glucagon-like peptide-1 isomers as a type 2 anti-diabetic treatment: Insulinotropic activity, glucose-stabilizing capability, and proteolytic stability", BIOCHEMICAL PHARMACOLOGY, ELSEVIER, US, vol. 73, no. 1, 6 December 2006 (2006-12-06), US, pages 84 - 93, XP005794625, ISSN: 0006-2952, DOI: 10.1016/j.bcp.2006.09.013 * |
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