CN104411713A - Par4激动剂肽 - Google Patents
Par4激动剂肽 Download PDFInfo
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- CN104411713A CN104411713A CN201380034451.0A CN201380034451A CN104411713A CN 104411713 A CN104411713 A CN 104411713A CN 201380034451 A CN201380034451 A CN 201380034451A CN 104411713 A CN104411713 A CN 104411713A
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- peptide
- par4
- minutes
- mmol
- phe
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Cell Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Immunology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261638577P | 2012-04-26 | 2012-04-26 | |
| US61/638577 | 2012-04-26 | ||
| US201361781538P | 2013-03-14 | 2013-03-14 | |
| US61/781538 | 2013-03-14 | ||
| PCT/US2013/037897 WO2013163248A1 (en) | 2012-04-26 | 2013-04-24 | Par4 agonist peptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104411713A true CN104411713A (zh) | 2015-03-11 |
Family
ID=48289680
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380034451.0A Pending CN104411713A (zh) | 2012-04-26 | 2013-04-24 | Par4激动剂肽 |
Country Status (9)
| Country | Link |
|---|---|
| US (3) | US8927688B2 (https=) |
| EP (1) | EP2841448A1 (https=) |
| JP (1) | JP2015516983A (https=) |
| CN (1) | CN104411713A (https=) |
| BR (1) | BR112014026644A2 (https=) |
| CA (1) | CA2871640A1 (https=) |
| EA (1) | EA201491959A1 (https=) |
| MX (1) | MX2014012803A (https=) |
| WO (1) | WO2013163248A1 (https=) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110218218A (zh) * | 2018-03-01 | 2019-09-10 | 江苏恒瑞医药股份有限公司 | 苯并呋喃类衍生物、其制备方法及其在医药上的应用 |
| CN110627817A (zh) * | 2018-06-25 | 2019-12-31 | 中国药科大学 | 咪唑并环类par4拮抗剂及其医药用途 |
| CN111094300A (zh) * | 2018-01-31 | 2020-05-01 | 江苏恒瑞医药股份有限公司 | 苯并杂芳基类衍生物、其制备方法及其在医药上的应用 |
| CN111349105A (zh) * | 2018-12-24 | 2020-06-30 | 江苏恒瑞医药股份有限公司 | 苯并呋喃类衍生物、其制备方法及其在医药上的应用 |
| CN111362970A (zh) * | 2018-12-25 | 2020-07-03 | 天津药物研究院有限公司 | 苯并呋喃类衍生物及其制备方法和用途 |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI2841437T1 (sl) * | 2012-04-26 | 2017-09-29 | Bristol-Myers Squibb Company | Derivati imidazotiadiazola in imidazopirazina kot proteazno aktivirani receptor 4 (PAR4) inhibitorji za zdravljenje agregacije trombocitov |
| US20160274108A1 (en) * | 2013-10-25 | 2016-09-22 | Bristol-Myers Squibb Company | Diagnostic methods for par4 antagonist therapy |
| WO2016134450A1 (en) * | 2015-02-26 | 2016-09-01 | Université de Montréal | Imidazopyridazine and imidazothiadiazole compounds |
| US9789087B2 (en) | 2015-08-03 | 2017-10-17 | Thomas Jefferson University | PAR4 inhibitor therapy for patients with PAR4 polymorphism |
| US9963466B2 (en) | 2016-03-07 | 2018-05-08 | Vanderbilt University | Substituted 5-membered heterocyclic analogs as protease activated receptor 4 (PAR-4) antagonists |
| WO2017184520A1 (en) * | 2016-04-18 | 2017-10-26 | Vanderbilt University | Substituted and fused 6-membered protease activated receptor 4 (par-4) antagonists |
| US12077607B2 (en) | 2021-09-23 | 2024-09-03 | University Of Utah Research Foundation | Functional and therapeutic effects of PAR4 cleavage by cathepsin G |
| CN117285527A (zh) * | 2023-09-25 | 2023-12-26 | 中国药科大学 | 一种噌啉类par4拮抗剂及其医药应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001058930A1 (en) * | 2000-02-09 | 2001-08-16 | Zymogenetics, Inc. | Par4 peptides and polypeptides |
| WO2001094411A1 (en) * | 2000-06-05 | 2001-12-13 | The Regents Of The University Of California | Peptides modulating protease activated receptors and methods of using same |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2928079B2 (ja) * | 1994-02-14 | 1999-07-28 | 永信薬品工業股▲ふん▼有限公司 | １−（置換ベンジル）−３−（置換アリール）縮合ピラゾール類、その製造法及びその用途 |
| US6387942B2 (en) * | 2000-06-19 | 2002-05-14 | Yung Shin Pharmaceutical Ind. Co. Ltd | Method of treating disorders related to protease-activated receptors-induced cell activation |
| WO2003033515A1 (en) * | 2001-10-15 | 2003-04-24 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of acne vulgaris |
| JP2007527416A (ja) | 2003-10-31 | 2007-09-27 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ペルオキシソーム増殖因子活性化受容体（ｐｐａｒ）二重作動薬として有用なフェノキシ酢酸誘導体 |
-
2013
- 2013-04-24 CA CA2871640A patent/CA2871640A1/en not_active Abandoned
- 2013-04-24 MX MX2014012803A patent/MX2014012803A/es unknown
- 2013-04-24 BR BR112014026644A patent/BR112014026644A2/pt not_active IP Right Cessation
- 2013-04-24 WO PCT/US2013/037897 patent/WO2013163248A1/en not_active Ceased
- 2013-04-24 EA EA201491959A patent/EA201491959A1/ru unknown
- 2013-04-24 CN CN201380034451.0A patent/CN104411713A/zh active Pending
- 2013-04-24 JP JP2015509095A patent/JP2015516983A/ja active Pending
- 2013-04-24 US US13/869,093 patent/US8927688B2/en active Active
- 2013-04-24 EP EP13720698.3A patent/EP2841448A1/en not_active Withdrawn
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2014
- 2014-11-26 US US14/554,387 patent/US9303065B2/en active Active
-
2016
- 2016-02-23 US US15/051,067 patent/US9605024B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001058930A1 (en) * | 2000-02-09 | 2001-08-16 | Zymogenetics, Inc. | Par4 peptides and polypeptides |
| WO2001094411A1 (en) * | 2000-06-05 | 2001-12-13 | The Regents Of The University Of California | Peptides modulating protease activated receptors and methods of using same |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111094300A (zh) * | 2018-01-31 | 2020-05-01 | 江苏恒瑞医药股份有限公司 | 苯并杂芳基类衍生物、其制备方法及其在医药上的应用 |
| CN111094300B (zh) * | 2018-01-31 | 2022-09-16 | 江苏恒瑞医药股份有限公司 | 苯并杂芳基类衍生物、其制备方法及其在医药上的应用 |
| CN110218218A (zh) * | 2018-03-01 | 2019-09-10 | 江苏恒瑞医药股份有限公司 | 苯并呋喃类衍生物、其制备方法及其在医药上的应用 |
| CN110218218B (zh) * | 2018-03-01 | 2022-04-08 | 江苏恒瑞医药股份有限公司 | 苯并呋喃类衍生物、其制备方法及其在医药上的应用 |
| CN110627817A (zh) * | 2018-06-25 | 2019-12-31 | 中国药科大学 | 咪唑并环类par4拮抗剂及其医药用途 |
| CN110627817B (zh) * | 2018-06-25 | 2022-03-29 | 中国药科大学 | 咪唑并环类par4拮抗剂及其医药用途 |
| CN111349105A (zh) * | 2018-12-24 | 2020-06-30 | 江苏恒瑞医药股份有限公司 | 苯并呋喃类衍生物、其制备方法及其在医药上的应用 |
| CN111349105B (zh) * | 2018-12-24 | 2023-04-07 | 江苏恒瑞医药股份有限公司 | 苯并呋喃类衍生物、其制备方法及其在医药上的应用 |
| CN111362970A (zh) * | 2018-12-25 | 2020-07-03 | 天津药物研究院有限公司 | 苯并呋喃类衍生物及其制备方法和用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2015516983A (ja) | 2015-06-18 |
| US9303065B2 (en) | 2016-04-05 |
| MX2014012803A (es) | 2015-01-15 |
| US8927688B2 (en) | 2015-01-06 |
| US20160304560A1 (en) | 2016-10-20 |
| US20150158910A1 (en) | 2015-06-11 |
| BR112014026644A2 (pt) | 2017-06-27 |
| EA201491959A1 (ru) | 2016-05-31 |
| EP2841448A1 (en) | 2015-03-04 |
| US20130289238A1 (en) | 2013-10-31 |
| CA2871640A1 (en) | 2013-10-31 |
| WO2013163248A1 (en) | 2013-10-31 |
| US9605024B2 (en) | 2017-03-28 |
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