Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors
Copyright © 2019 American Chemical Society..
Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
ACS medicinal chemistry letters - 10(2019), 11 vom: 14. Nov., Seite 1518-1523 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Haffner, Curt D [VerfasserIn] |
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| Anmerkungen: |
Date Revised 14.11.2020 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1021/acsmedchemlett.9b00141 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM303526645 |
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| 245 | 1 | 0 | |a Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors |
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| 520 | |a Copyright © 2019 American Chemical Society. | ||
| 520 | |a Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Charnley, Adam K |e verfasserin |4 aut | |
| 700 | 1 | |a Aquino, Christopher J |e verfasserin |4 aut | |
| 700 | 1 | |a Casillas, Linda |e verfasserin |4 aut | |
| 700 | 1 | |a Convery, Máire A |e verfasserin |4 aut | |
| 700 | 1 | |a Cox, Julie A |e verfasserin |4 aut | |
| 700 | 1 | |a Elban, Mark A |e verfasserin |4 aut | |
| 700 | 1 | |a Goodwin, Nicole C |e verfasserin |4 aut | |
| 700 | 1 | |a Gough, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Haile, Pamela A |e verfasserin |4 aut | |
| 700 | 1 | |a Hughes, Terry V |e verfasserin |4 aut | |
| 700 | 1 | |a Knapp-Reed, Beth |e verfasserin |4 aut | |
| 700 | 1 | |a Kreatsoulas, Constantine |e verfasserin |4 aut | |
| 700 | 1 | |a Lakdawala, Ami S |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Huijie |e verfasserin |4 aut | |
| 700 | 1 | |a Lian, Yiqian |e verfasserin |4 aut | |
| 700 | 1 | |a Lipshutz, David |e verfasserin |4 aut | |
| 700 | 1 | |a Mehlmann, John F |e verfasserin |4 aut | |
| 700 | 1 | |a Ouellette, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Romano, Joseph |e verfasserin |4 aut | |
| 700 | 1 | |a Shewchuk, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Shu, Arthur |e verfasserin |4 aut | |
| 700 | 1 | |a Votta, Bartholomew J |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Huiqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Bertin, John |e verfasserin |4 aut | |
| 700 | 1 | |a Marquis, Robert W |e verfasserin |4 aut | |
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