CA2871640A1 - Par4 agonist peptides - Google Patents
Par4 agonist peptides Download PDFInfo
- Publication number
- CA2871640A1 CA2871640A1 CA2871640A CA2871640A CA2871640A1 CA 2871640 A1 CA2871640 A1 CA 2871640A1 CA 2871640 A CA2871640 A CA 2871640A CA 2871640 A CA2871640 A CA 2871640A CA 2871640 A1 CA2871640 A1 CA 2871640A1
- Authority
- CA
- Canada
- Prior art keywords
- mmol
- peptide
- par4
- amino acid
- mhz
- 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.)
- Abandoned
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 240
- 239000000556 agonist Substances 0.000 title claims abstract description 136
- 102000004196 processed proteins & peptides Human genes 0.000 title abstract description 56
- 101150101745 F2rl3 gene Proteins 0.000 title 1
- 101150114311 PAWR gene Proteins 0.000 title 1
- 102100040853 PRKC apoptosis WT1 regulator protein Human genes 0.000 title 1
- 238000003556 assay Methods 0.000 claims abstract description 62
- 102100023710 Proteinase-activated receptor 4 Human genes 0.000 claims abstract description 21
- 101001113471 Homo sapiens Proteinase-activated receptor 4 Proteins 0.000 claims abstract 20
- 101000613565 Homo sapiens PRKC apoptosis WT1 regulator protein Proteins 0.000 claims abstract 13
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 44
- 150000001413 amino acids Chemical group 0.000 claims description 38
- 230000000694 effects Effects 0.000 claims description 35
- 230000004913 activation Effects 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 claims description 14
- JPNRPAJITHRXRH-BQBZGAKWSA-N Lys-Asn Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CC(N)=O JPNRPAJITHRXRH-BQBZGAKWSA-N 0.000 claims description 8
- HQVDJTYKCMIWJP-YUMQZZPRSA-N Lys-Asn-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O HQVDJTYKCMIWJP-YUMQZZPRSA-N 0.000 claims description 8
- KAFHLONDOVSENM-HNNXBMFYSA-N O-Benzyl-L-tyrosine Chemical compound C1=CC(C[C@H](N)C(O)=O)=CC=C1OCC1=CC=CC=C1 KAFHLONDOVSENM-HNNXBMFYSA-N 0.000 claims 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 261
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- 229910052740 iodine Inorganic materials 0.000 description 24
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- 125000001424 substituent group Chemical group 0.000 description 24
- 125000003545 alkoxy group Chemical group 0.000 description 23
- 125000003118 aryl group Chemical group 0.000 description 23
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 22
- 230000008878 coupling Effects 0.000 description 22
- 238000010168 coupling process Methods 0.000 description 22
- 238000005859 coupling reaction Methods 0.000 description 22
- UVNXNSUKKOLFBM-UHFFFAOYSA-N imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=CSC2=NC=CN21 UVNXNSUKKOLFBM-UHFFFAOYSA-N 0.000 description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 22
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- 238000011282 treatment Methods 0.000 description 22
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- 229940002612 prodrug Drugs 0.000 description 21
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- 239000012453 solvate Chemical class 0.000 description 20
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- 125000001246 bromo group Chemical group Br* 0.000 description 15
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- 238000010926 purge Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000004728 pyruvic acid derivatives Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
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- 125000006413 ring segment Chemical group 0.000 description 1
- 229960001148 rivaroxaban Drugs 0.000 description 1
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- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical class OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
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- 238000013341 scale-up Methods 0.000 description 1
- 238000003572 second messenger assay Methods 0.000 description 1
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Natural products [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 description 1
- 229940055619 selenocysteine Drugs 0.000 description 1
- 235000016491 selenocysteine Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
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- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000005403 thiohaloalkoxy group Chemical group 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 239000003856 thrombin receptor antagonist Substances 0.000 description 1
- 150000003595 thromboxanes Chemical class 0.000 description 1
- 208000005057 thyrotoxicosis Diseases 0.000 description 1
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 1
- 229960002528 ticagrelor Drugs 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
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- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
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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 | |
| US61/638,577 | 2012-04-26 | ||
| US201361781538P | 2013-03-14 | 2013-03-14 | |
| US61/781,538 | 2013-03-14 | ||
| PCT/US2013/037897 WO2013163248A1 (en) | 2012-04-26 | 2013-04-24 | Par4 agonist peptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2871640A1 true CA2871640A1 (en) | 2013-10-31 |
Family
ID=48289680
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2871640A Abandoned CA2871640A1 (en) | 2012-04-26 | 2013-04-24 | Par4 agonist peptides |
Country Status (9)
| Country | Link |
|---|---|
| US (3) | US8927688B2 (enExample) |
| EP (1) | EP2841448A1 (enExample) |
| JP (1) | JP2015516983A (enExample) |
| CN (1) | CN104411713A (enExample) |
| BR (1) | BR112014026644A2 (enExample) |
| CA (1) | CA2871640A1 (enExample) |
| EA (1) | EA201491959A1 (enExample) |
| MX (1) | MX2014012803A (enExample) |
| WO (1) | WO2013163248A1 (enExample) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6073464B2 (ja) * | 2012-04-26 | 2017-02-01 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 血小板凝集を治療するためのプロテアーゼ活性化受容体４（ｐａｒ４）阻害剤としてのイミダゾチアジアゾールおよびイミダゾピラジン誘導体 |
| EP3060233A4 (en) * | 2013-10-25 | 2017-04-12 | Bristol-Myers Squibb Company | Diagnostic methods for par4 antagonist therapy |
| EP3262053B1 (en) | 2015-02-26 | 2022-10-05 | Université de Montréal | Imidazothiadiazole compounds as par4-inhibitors |
| 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 |
| US20190119300A1 (en) * | 2016-04-18 | 2019-04-25 | Vanderbilt University | Substituted and fused 6-membered protease activated receptor 4 (par-4) antagonists |
| WO2019149205A1 (zh) * | 2018-01-31 | 2019-08-08 | 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 |
| 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 |
| 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 |
| 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 |
| 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 |
Family Cites Families (6)
| 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 |
| 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 |
| 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 |
| AU2004285530A1 (en) | 2003-10-31 | 2005-05-12 | Janssen Pharmaceutica N.V. | Phenoxyacetic acids derivatives useful as peroxisome proliferator-activated receptor (PPAR) dual agonists |
-
2013
- 2013-04-24 JP JP2015509095A patent/JP2015516983A/ja active Pending
- 2013-04-24 MX MX2014012803A patent/MX2014012803A/es unknown
- 2013-04-24 EP EP13720698.3A patent/EP2841448A1/en not_active Withdrawn
- 2013-04-24 CA CA2871640A patent/CA2871640A1/en not_active Abandoned
- 2013-04-24 EA EA201491959A patent/EA201491959A1/ru unknown
- 2013-04-24 CN CN201380034451.0A patent/CN104411713A/zh active Pending
- 2013-04-24 BR BR112014026644A patent/BR112014026644A2/pt not_active IP Right Cessation
- 2013-04-24 US US13/869,093 patent/US8927688B2/en active Active
- 2013-04-24 WO PCT/US2013/037897 patent/WO2013163248A1/en not_active Ceased
-
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
Also Published As
| Publication number | Publication date |
|---|---|
| BR112014026644A2 (pt) | 2017-06-27 |
| US8927688B2 (en) | 2015-01-06 |
| US20150158910A1 (en) | 2015-06-11 |
| US20130289238A1 (en) | 2013-10-31 |
| US20160304560A1 (en) | 2016-10-20 |
| US9605024B2 (en) | 2017-03-28 |
| EA201491959A1 (ru) | 2016-05-31 |
| CN104411713A (zh) | 2015-03-11 |
| WO2013163248A1 (en) | 2013-10-31 |
| JP2015516983A (ja) | 2015-06-18 |
| US9303065B2 (en) | 2016-04-05 |
| MX2014012803A (es) | 2015-01-15 |
| EP2841448A1 (en) | 2015-03-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20190424 |