JP7104627B2 - ラパグルチン(rapaglutins)、glutの新規阻害剤及びその使用 - Google Patents
ラパグルチン(rapaglutins)、glutの新規阻害剤及びその使用 Download PDFInfo
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- JP7104627B2 JP7104627B2 JP2018540115A JP2018540115A JP7104627B2 JP 7104627 B2 JP7104627 B2 JP 7104627B2 JP 2018540115 A JP2018540115 A JP 2018540115A JP 2018540115 A JP2018540115 A JP 2018540115A JP 7104627 B2 JP7104627 B2 JP 7104627B2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
- C07K5/126—Tetrapeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662291453P | 2016-02-04 | 2016-02-04 | |
| US62/291,453 | 2016-02-04 | ||
| PCT/US2017/016516 WO2017136731A1 (en) | 2016-02-04 | 2017-02-03 | Rapaglutins, novel inhibitors of glut and use thereof |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2019504087A JP2019504087A (ja) | 2019-02-14 |
| JP2019504087A5 JP2019504087A5 (enExample) | 2020-02-13 |
| JP7104627B2 true JP7104627B2 (ja) | 2022-07-21 |
Family
ID=59500972
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2018540115A Active JP7104627B2 (ja) | 2016-02-04 | 2017-02-03 | ラパグルチン(rapaglutins)、glutの新規阻害剤及びその使用 |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US11708391B2 (enExample) |
| EP (1) | EP3411046B1 (enExample) |
| JP (1) | JP7104627B2 (enExample) |
| CN (1) | CN108697729B (enExample) |
| AU (1) | AU2017213630B2 (enExample) |
| CA (1) | CA3013783A1 (enExample) |
| MX (1) | MX2018009408A (enExample) |
| WO (1) | WO2017136731A1 (enExample) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX380313B (es) | 2016-02-04 | 2025-03-12 | Univ Johns Hopkins | Rapadocinas, inhibidores de transportador 1 de nucleósido equilibrador y usos de los mismos. |
| US11066416B2 (en) | 2016-02-04 | 2021-07-20 | The Johns Hopkins University | Rapafucin derivative compounds and methods of use thereof |
| MX2018009408A (es) | 2016-02-04 | 2018-11-09 | Univ Johns Hopkins | Rapaglutinas, nuevos inhibidores de transportadores de glucosa (glut) y uso de los mismos. |
| TW202126323A (zh) * | 2019-10-01 | 2021-07-16 | 約翰斯赫普金斯大學 | 雷帕弗辛(Rapafucin)衍生化合物及其使用方法 |
| WO2021067405A1 (en) * | 2019-10-01 | 2021-04-08 | The Johns Hopkins University | Neuroprotective compounds and methods of use thereof |
| CN112294792B (zh) * | 2020-09-22 | 2021-10-22 | 厦门市中医院 | 化合物wzb117在制备治疗和/或预防肝损伤药物中的用途 |
| CN115364224B (zh) * | 2022-08-25 | 2024-02-02 | 杭州天玑济世生物科技有限公司 | Glut1抑制剂作为线粒体自噬诱导剂的用途 |
| CN120271673A (zh) * | 2024-01-08 | 2025-07-08 | 重庆医科大学 | 一种化合物、包含其的药物组合物及其用途 |
| CN120617307B (zh) * | 2025-06-16 | 2025-12-09 | 烟台大学 | 一种wzb117纳米制剂及其制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010520289A (ja) | 2007-03-07 | 2010-06-10 | アブラクシス バイオサイエンス, エルエルシー | 抗癌剤としてラパマイシンおよびアルブミンを含むナノ粒子 |
| US20140073581A1 (en) | 2010-11-30 | 2014-03-13 | The Johns Hopkins University | Hybrid Cyclic Libraries and Screens Thereof |
Family Cites Families (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5100899A (en) | 1989-06-06 | 1992-03-31 | Roy Calne | Methods of inhibiting transplant rejection in mammals using rapamycin and derivatives and prodrugs thereof |
| US5457194A (en) | 1993-03-17 | 1995-10-10 | Abbott Laboratories | Substituted aliphatic amine-containing macrocyclic immunomodulators |
| US5798355A (en) | 1995-06-07 | 1998-08-25 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity |
| US5527907A (en) | 1993-11-19 | 1996-06-18 | Abbott Laboratories | Macrolide immunomodulators |
| US7056935B2 (en) | 1995-06-07 | 2006-06-06 | Gpi Nil Holdings, Inc. | Rotamase enzyme activity inhibitors |
| US5696135A (en) | 1995-06-07 | 1997-12-09 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity effective at stimulating neuronal growth |
| US6984635B1 (en) | 1998-02-13 | 2006-01-10 | Board Of Trustees Of The Leland Stanford Jr. University | Dimerizing agents, their production and use |
| EP1352910A1 (en) | 2002-04-10 | 2003-10-15 | Grünenthal GmbH | New analogs of nitrobenzylthioinosine |
| EP2143727B1 (en) | 2003-04-18 | 2015-01-21 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors |
| WO2005117562A2 (en) | 2004-06-04 | 2005-12-15 | Xenoport, Inc. | Ent1 transporters expressed in cancer cells |
| GB0417852D0 (en) | 2004-08-11 | 2004-09-15 | Biotica Tech Ltd | Production of polyketides and other natural products |
| CA2626325A1 (en) | 2005-10-28 | 2007-05-10 | Praecis Pharmaceuticals Incorporated | Methods for identifying compounds of interest using encoded libraries |
| US20080306098A1 (en) | 2006-11-06 | 2008-12-11 | Mutz Mitchell W | Pharmacokinetics of protease inhibitors and other drugs |
| CA2688240A1 (en) | 2007-05-24 | 2008-12-04 | The United States Government As Represented By The Department Of Veterans Affairs | Intranuclear protein transduction through a nucleoside salvage pathway |
| JP2011524413A (ja) | 2008-06-17 | 2011-09-01 | バイオチカ テクノロジー リミテッド | 新規化合物、及びこれらの製造のための方法 |
| US20140206624A1 (en) * | 2011-02-04 | 2014-07-24 | The Brigham And Women's Hospital, Inc. | Treatment of leukemia |
| EP2607352A1 (en) | 2011-12-22 | 2013-06-26 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Pipecolate-diketoamides for treatment of psychiatric disorders |
| KR101733736B1 (ko) | 2012-01-06 | 2017-05-10 | 삼성에스디아이 주식회사 | 리튬 이차 전지용 음극 활물질, 그 제조 방법 및 이를 포함하는 리튬 이차 전지 |
| WO2014008636A1 (en) | 2012-07-11 | 2014-01-16 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as hiv integrase inhibitors |
| US10167259B2 (en) | 2013-06-14 | 2019-01-01 | The Board Of Regents Of The University Of Texas System | Allosteric inhibitors of proteasome and methods of use thereof |
| WO2016112295A1 (en) | 2015-01-09 | 2016-07-14 | Warp Drive Bio, Inc. | Compounds that participate in cooperative binding and uses thereof |
| EP3355930A4 (en) | 2015-10-01 | 2019-03-06 | Warp Drive Bio, Inc. | METHOD AND REAGENTS FOR THE ANALYSIS OF PROTEIN-PROTEIN INTERFACES |
| US11066416B2 (en) | 2016-02-04 | 2021-07-20 | The Johns Hopkins University | Rapafucin derivative compounds and methods of use thereof |
| US10662220B2 (en) * | 2016-02-04 | 2020-05-26 | The Johns Hopkins University | Synthesis and composition of rapafucin libraries |
| MX380313B (es) * | 2016-02-04 | 2025-03-12 | Univ Johns Hopkins | Rapadocinas, inhibidores de transportador 1 de nucleósido equilibrador y usos de los mismos. |
| MX2018009408A (es) | 2016-02-04 | 2018-11-09 | Univ Johns Hopkins | Rapaglutinas, nuevos inhibidores de transportadores de glucosa (glut) y uso de los mismos. |
| MX386103B (es) | 2016-04-22 | 2025-03-18 | Astrazeneca Ab | Inhibidores de mcl-1 y metodos de uso de los mismos. |
| CA3035757A1 (en) | 2016-09-02 | 2018-03-08 | The Johns Hopkins University | Mif inhibitors and methods of use thereof |
| UY37900A (es) | 2017-09-26 | 2019-04-30 | Novartis Ag | Nuevos derivados de rapamicina |
-
2017
- 2017-02-03 MX MX2018009408A patent/MX2018009408A/es unknown
- 2017-02-03 EP EP17748278.3A patent/EP3411046B1/en active Active
- 2017-02-03 JP JP2018540115A patent/JP7104627B2/ja active Active
- 2017-02-03 AU AU2017213630A patent/AU2017213630B2/en active Active
- 2017-02-03 CA CA3013783A patent/CA3013783A1/en not_active Abandoned
- 2017-02-03 WO PCT/US2017/016516 patent/WO2017136731A1/en not_active Ceased
- 2017-02-03 CN CN201780010180.3A patent/CN108697729B/zh active Active
- 2017-02-03 US US16/074,300 patent/US11708391B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010520289A (ja) | 2007-03-07 | 2010-06-10 | アブラクシス バイオサイエンス, エルエルシー | 抗癌剤としてラパマイシンおよびアルブミンを含むナノ粒子 |
| US20140073581A1 (en) | 2010-11-30 | 2014-03-13 | The Johns Hopkins University | Hybrid Cyclic Libraries and Screens Thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| US11708391B2 (en) | 2023-07-25 |
| JP2019504087A (ja) | 2019-02-14 |
| WO2017136731A1 (en) | 2017-08-10 |
| CN108697729B (zh) | 2023-05-09 |
| CN108697729A (zh) | 2018-10-23 |
| US20210214390A1 (en) | 2021-07-15 |
| EP3411046B1 (en) | 2025-07-16 |
| MX2018009408A (es) | 2018-11-09 |
| WO2017136731A8 (en) | 2018-08-23 |
| EP3411046A4 (en) | 2019-11-27 |
| EP3411046A1 (en) | 2018-12-12 |
| AU2017213630A1 (en) | 2018-08-16 |
| AU2017213630B2 (en) | 2022-05-12 |
| CA3013783A1 (en) | 2017-08-10 |
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