AU2006220187B2 - Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof - Google Patents
Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof Download PDFInfo
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- AU2006220187B2 AU2006220187B2 AU2006220187A AU2006220187A AU2006220187B2 AU 2006220187 B2 AU2006220187 B2 AU 2006220187B2 AU 2006220187 A AU2006220187 A AU 2006220187A AU 2006220187 A AU2006220187 A AU 2006220187A AU 2006220187 B2 AU2006220187 B2 AU 2006220187B2
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- thiazoline
- glucopyranoso
- dideoxy
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- thiazole
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- C07—ORGANIC CHEMISTRY
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- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Hospice & Palliative Care (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| AU2013200241A AU2013200241A1 (en) | 2005-03-01 | 2013-01-17 | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof |
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| US65687805P | 2005-03-01 | 2005-03-01 | |
| US60/656,878 | 2005-03-01 | ||
| PCT/CA2006/000300 WO2006092049A1 (en) | 2005-03-01 | 2006-03-01 | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof |
Related Child Applications (1)
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| AU2013200241A Division AU2013200241A1 (en) | 2005-03-01 | 2013-01-17 | Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof |
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| AU2006220187A1 AU2006220187A1 (en) | 2006-09-08 |
| AU2006220187B2 true AU2006220187B2 (en) | 2012-11-08 |
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| EP (2) | EP1869060B1 (https=) |
| JP (1) | JP5154954B2 (https=) |
| CN (1) | CN101208352B (https=) |
| AU (1) | AU2006220187B2 (https=) |
| CA (2) | CA2599843C (https=) |
| WO (1) | WO2006092049A1 (https=) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006016904A2 (en) * | 2004-04-14 | 2006-02-16 | Uab Research Foundation | Activators of hexosamine biosynthesis as inhibitors of injury induced by ischemia or hemorrhagic shock |
| CN107253970A (zh) * | 2006-08-31 | 2017-10-17 | 西蒙·弗雷瑟大学 | 选择性糖苷酶抑制剂及其用途 |
| AU2007291870B2 (en) | 2006-08-31 | 2012-12-06 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| GB0622702D0 (en) * | 2006-11-15 | 2006-12-27 | Univ Dundee | Selective glycosidase inhibitors |
| US8518903B2 (en) | 2007-04-19 | 2013-08-27 | University of Pittsburgh—of the Commonwealth System of Higher Education | Use of toll-like receptor-9 agonists |
| EP2321289A4 (en) * | 2008-08-01 | 2011-11-16 | Univ Fraser Simon | SELECTIVE GLYCOSIDASE HEMMER AND ITS USE |
| CA2732335A1 (en) | 2008-08-01 | 2010-02-04 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| CA2737267A1 (en) * | 2008-09-16 | 2010-04-08 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| WO2011140640A1 (en) * | 2010-05-11 | 2011-11-17 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| US10668092B2 (en) | 2010-09-24 | 2020-06-02 | The John Hopkins University | Compositions and methods for treatment of inflammatory disorders |
| US9072760B2 (en) | 2010-09-24 | 2015-07-07 | University of Pittsburgh—of the Commonwealth System of Higher Education | TLR4 inhibitors for the treatment of human infectious and inflammatory disorders |
| WO2012040719A2 (en) * | 2010-09-24 | 2012-03-29 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Novel tlr4 inhibitors for the treatment of human infectious and inflammatory disorders |
| US8933040B2 (en) | 2010-11-08 | 2015-01-13 | Craig A. Coburn | Selective glycosidase inhibitors and uses thereof |
| US8901087B2 (en) * | 2010-11-08 | 2014-12-02 | Merck Sharp & Dohme Corp. | Selective glycosidase inhibitors and uses thereof |
| TW201249848A (en) | 2010-11-08 | 2012-12-16 | Merck Sharp & Dohme | Selective glycosidase inhibitors and uses thereof |
| WO2012061972A1 (en) * | 2010-11-08 | 2012-05-18 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| WO2012088425A2 (en) | 2010-12-22 | 2012-06-28 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Gap junction-enhancing agents for treatment of necrotizing enterocolitis and inflammatory bowel disease |
| RU2609210C2 (ru) * | 2010-12-23 | 2017-01-31 | Алектос Терапьютикс Инк. | Селективные ингибиторы гликозидазы и их применение |
| EP2688899B1 (en) | 2011-03-24 | 2017-02-22 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| EP2691407B1 (en) | 2011-03-31 | 2017-02-22 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| WO2012129802A1 (en) * | 2011-03-31 | 2012-10-04 | Alectos Therapeutics Inc. | Pyrano[3,2-d]thiazol derivatives and uses as selective glycosidase inhibitors thereof |
| US9701693B2 (en) | 2011-06-27 | 2017-07-11 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| EP2726468B1 (en) * | 2011-06-27 | 2017-04-12 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| BR112013033098B8 (pt) | 2011-06-27 | 2021-03-23 | Alectos Therapeutics Inc | inibidores de glicosidade seletivos e usos dos mesmos |
| US9126957B2 (en) | 2011-08-18 | 2015-09-08 | Merck Sharp & Dohme Corp. | Selective glycosidase inhibitors and uses thereof |
| ES2568603T3 (es) * | 2011-08-25 | 2016-05-03 | Merck Patent Gmbh | Pirano[3,2-d][1,3]tiazol como inhibidores de glicosidasas |
| EP2847199B1 (en) | 2012-05-08 | 2017-10-25 | Merck Sharp & Dohme Corp. | Permeable glycosidase inhibitors and uses thereof |
| EP2890675A4 (en) | 2012-08-31 | 2016-01-13 | Alectos Therapeutics Inc | GLYCOSIDASE INHIBITORS AND USES THEREOF |
| EP2890676B1 (en) | 2012-08-31 | 2018-12-05 | Alectos Therapeutics Inc. | Glycosidase inhibitors and uses thereof |
| WO2014052453A1 (en) | 2012-09-25 | 2014-04-03 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Oral therapy of necrotizing enterocolitis |
| KR20150079711A (ko) * | 2012-10-31 | 2015-07-08 | 알렉토스 테라퓨틱스 인크. | 글리코시다아제 저해제 및 이의 용도 |
| WO2014100934A1 (en) * | 2012-12-24 | 2014-07-03 | Merck Sharp & Dohme Corp. | Glycosidase inhibitors and uses thereof |
| WO2014171206A1 (ja) * | 2013-04-17 | 2014-10-23 | Yuasa Tomoyuki | 糖尿病治療薬の新規なスクリーニング方法 |
| KR102043337B1 (ko) | 2014-08-28 | 2019-11-11 | 아셰뉴론 에스아 | 글리코시다제 저해제 |
| US11261183B2 (en) | 2016-02-25 | 2022-03-01 | Asceneuron Sa | Sulfoximine glycosidase inhibitors |
| CA3014572C (en) | 2016-02-25 | 2023-10-03 | Asceneuron S.A. | Acid addition salts of piperazine derivatives |
| KR20180132629A (ko) | 2016-02-25 | 2018-12-12 | 아셰뉴론 에스아 | 글리코시다제 저해제 |
| AU2017222964B2 (en) | 2016-02-25 | 2020-01-02 | Asceneuron S. A. | Glycosidase inhibitors |
| US11213525B2 (en) | 2017-08-24 | 2022-01-04 | Asceneuron Sa | Linear glycosidase inhibitors |
| WO2020039027A1 (en) | 2018-08-22 | 2020-02-27 | Asceneuron S. A. | Pyrrolidine glycosidase inhibitors |
| JP7407171B2 (ja) | 2018-08-22 | 2023-12-28 | エースニューロン・ソシエテ・アノニム | グリコシダーゼ阻害剤として有用なピペラジン誘導体のコハク酸付加塩及びフマル酸付加塩 |
| WO2020039029A1 (en) | 2018-08-22 | 2020-02-27 | Asceneuron S. A. | Spiro compounds as glycosidase inhibitors |
| WO2020039028A1 (en) | 2018-08-22 | 2020-02-27 | Asceneuron S. A. | Tetrahydro-benzoazepine glycosidase inhibitors |
| CN114524854B (zh) * | 2022-02-25 | 2023-05-26 | 中国农业大学 | 一种糖基芳香环碳苷衍生物及其制备方法与应用 |
| WO2024083820A1 (en) | 2022-10-18 | 2024-04-25 | Institut National de la Santé et de la Recherche Médicale | Method and composition for determining the level of o-glcnacylation in horses |
| CN116376875B (zh) * | 2023-03-03 | 2024-02-23 | 云南师范大学 | 耐热性提高的n-乙酰氨基葡萄糖苷酶突变体及其应用 |
| CN116555229B (zh) * | 2023-05-25 | 2024-09-20 | 云南师范大学 | N-乙酰氨基葡萄糖苷酶突变体、重组表达载体及菌和应用 |
| CN118086249B (zh) * | 2024-01-24 | 2024-12-06 | 云南师范大学 | 一种协同提高酶活和热稳定性的n-乙酰氨基葡萄糖苷酶突变体及其制备与应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002072860A1 (en) * | 2001-03-14 | 2002-09-19 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing hyaluronic acid or its derivative |
| WO2004103368A1 (en) * | 2003-05-22 | 2004-12-02 | The Hospital For Sick Children | Treatment of tay sachs or sandhoff diseases by enhancing hexosaminidase activity |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9818732D0 (en) * | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collection of compounds |
| US6774140B1 (en) * | 1999-05-11 | 2004-08-10 | The Scripps Research Institute | Iminocyclitol inhibitors of hexoaminidase and glycosidase |
| AU2007291870B2 (en) * | 2006-08-31 | 2012-12-06 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| CA2732335A1 (en) * | 2008-08-01 | 2010-02-04 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| EP2321289A4 (en) * | 2008-08-01 | 2011-11-16 | Univ Fraser Simon | SELECTIVE GLYCOSIDASE HEMMER AND ITS USE |
| CA2737267A1 (en) * | 2008-09-16 | 2010-04-08 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| WO2011140640A1 (en) * | 2010-05-11 | 2011-11-17 | Simon Fraser University | Selective glycosidase inhibitors and uses thereof |
| US8933040B2 (en) * | 2010-11-08 | 2015-01-13 | Craig A. Coburn | Selective glycosidase inhibitors and uses thereof |
| RU2609210C2 (ru) * | 2010-12-23 | 2017-01-31 | Алектос Терапьютикс Инк. | Селективные ингибиторы гликозидазы и их применение |
| EP2688899B1 (en) * | 2011-03-24 | 2017-02-22 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
| EP2691407B1 (en) * | 2011-03-31 | 2017-02-22 | Alectos Therapeutics Inc. | Selective glycosidase inhibitors and uses thereof |
-
2006
- 2006-03-01 CA CA2599843A patent/CA2599843C/en not_active Expired - Fee Related
- 2006-03-01 AU AU2006220187A patent/AU2006220187B2/en not_active Ceased
- 2006-03-01 WO PCT/CA2006/000300 patent/WO2006092049A1/en not_active Ceased
- 2006-03-01 EP EP06705254A patent/EP1869060B1/en not_active Expired - Lifetime
- 2006-03-01 CA CA2819464A patent/CA2819464A1/en not_active Abandoned
- 2006-03-01 CN CN2006800149950A patent/CN101208352B/zh not_active Expired - Fee Related
- 2006-03-01 JP JP2007557300A patent/JP5154954B2/ja not_active Expired - Fee Related
- 2006-03-01 US US11/817,465 patent/US20080287375A1/en not_active Abandoned
- 2006-03-01 EP EP11184538A patent/EP2436687A1/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002072860A1 (en) * | 2001-03-14 | 2002-09-19 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing hyaluronic acid or its derivative |
| WO2004103368A1 (en) * | 2003-05-22 | 2004-12-02 | The Hospital For Sick Children | Treatment of tay sachs or sandhoff diseases by enhancing hexosaminidase activity |
Non-Patent Citations (2)
| Title |
|---|
| Hanover, J. A. et al., Archives of Biochemistry and Biophysics, 1999, Vol. 362, No. 1, pages 38-45. * |
| Liu, K. et al., Journal of neurochemistry, 2004, Vol. 89, No. 4, pages 1044-1055. * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2436687A1 (en) | 2012-04-04 |
| CA2819464A1 (en) | 2006-09-08 |
| EP1869060A4 (en) | 2009-08-12 |
| US20080287375A1 (en) | 2008-11-20 |
| WO2006092049A1 (en) | 2006-09-08 |
| AU2006220187A1 (en) | 2006-09-08 |
| CA2599843C (en) | 2013-08-27 |
| JP5154954B2 (ja) | 2013-02-27 |
| CN101208352B (zh) | 2013-08-07 |
| CA2599843A1 (en) | 2006-09-08 |
| EP1869060A1 (en) | 2007-12-26 |
| CN101208352A (zh) | 2008-06-25 |
| JP2008531604A (ja) | 2008-08-14 |
| EP1869060B1 (en) | 2012-08-15 |
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