The Discovery of 7-Isopropoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-N-(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,2-a]pyrimidine-6-carboxamide (BIO-7488), a Potent, Selective, and CNS-Penetrant IRAK4 Inhibitor for the Treatment of Ischemic Stroke
Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of damage-associated molecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation. Lead compounds from the series were evaluated in CNS PK/PD models of inflammation, as well as a mouse model of ischemic stroke. The SAR optimization detailed within culminates in the discovery of BIO-7488, a highly selective and potent IRAK4 inhibitor that is CNS penetrant and has excellent ADME properties.
| 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), 6 vom: 28. März, Seite 4676-4690 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Evans, Ryan [VerfasserIn] |
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| Links: |
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| Themen: |
Cytokines |
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| Anmerkungen: |
Date Completed 29.03.2024 Date Revised 29.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c02226 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 4 | |a The Discovery of 7-Isopropoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-N-(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,2-a]pyrimidine-6-carboxamide (BIO-7488), a Potent, Selective, and CNS-Penetrant IRAK4 Inhibitor for the Treatment of Ischemic Stroke |
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| 520 | |a Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of damage-associated molecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation. Lead compounds from the series were evaluated in CNS PK/PD models of inflammation, as well as a mouse model of ischemic stroke. The SAR optimization detailed within culminates in the discovery of BIO-7488, a highly selective and potent IRAK4 inhibitor that is CNS penetrant and has excellent ADME properties | ||
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| 700 | 1 | |a Bolduc, Philippe N |e verfasserin |4 aut | |
| 700 | 1 | |a Pfaffenbach, Magnus |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Fang |e verfasserin |4 aut | |
| 700 | 1 | |a May-Dracka, Tricia |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Terry |e verfasserin |4 aut | |
| 700 | 1 | |a Hopkins, Brian T |e verfasserin |4 aut | |
| 700 | 1 | |a Chodaparambil, Jayanth V |e verfasserin |4 aut | |
| 700 | 1 | |a Henry, Kate L |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Pei |e verfasserin |4 aut | |
| 700 | 1 | |a Metrick, Claire |e verfasserin |4 aut | |
| 700 | 1 | |a Nelson, Ashley |e verfasserin |4 aut | |
| 700 | 1 | |a Trapa, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Thomas, Ankur |e verfasserin |4 aut | |
| 700 | 1 | |a Burkly, Linda |e verfasserin |4 aut | |
| 700 | 1 | |a Peterson, Emily A |e verfasserin |4 aut | |
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