Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis
PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low μM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48, possessing a 2 nM IC50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
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| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 5 vom: 14. März, Seite 3571-3589 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Xiaojun [VerfasserIn] |
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| Links: |
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| Themen: |
EC 3.4.21.5 |
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| Anmerkungen: |
Date Completed 15.03.2024 Date Revised 15.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c01986 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368752739 |
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| 100 | 1 | |a Zhang, Xiaojun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis |
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| 500 | |a Date Completed 15.03.2024 | ||
| 500 | |a Date Revised 15.03.2024 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low μM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48, possessing a 2 nM IC50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a Fibrinolytic Agents |2 NLM | |
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| 700 | 1 | |a Jiang, Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Richter, Jeremy M |e verfasserin |4 aut | |
| 700 | 1 | |a Bates, J Alex |e verfasserin |4 aut | |
| 700 | 1 | |a Reznik, Samuel K |e verfasserin |4 aut | |
| 700 | 1 | |a Stachura, Sylwia |e verfasserin |4 aut | |
| 700 | 1 | |a Rampulla, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Doddalingappa, Dyamanna |e verfasserin |4 aut | |
| 700 | 1 | |a Ulaganathan, Sankar |e verfasserin |4 aut | |
| 700 | 1 | |a Hua, Ji |e verfasserin |4 aut | |
| 700 | 1 | |a Bostwick, Jeffrey S |e verfasserin |4 aut | |
| 700 | 1 | |a Sum, Chi |e verfasserin |4 aut | |
| 700 | 1 | |a Posy, Shana |e verfasserin |4 aut | |
| 700 | 1 | |a Malmstrom, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Dickey, Joyce |e verfasserin |4 aut | |
| 700 | 1 | |a Harden, David |e verfasserin |4 aut | |
| 700 | 1 | |a Lawrence, R Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Guarino, Victor R |e verfasserin |4 aut | |
| 700 | 1 | |a Schumacher, William A |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Pancras |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Gordon, David A |e verfasserin |4 aut | |
| 700 | 1 | |a Wexler, Ruth R |e verfasserin |4 aut | |
| 700 | 1 | |a Priestley, E Scott |e verfasserin |4 aut | |
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