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.
J Med Chem
; 67(6): 4676-4690, 2024 Mar 28.
Article
in En
| MEDLINE
| ID: mdl-38467640
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interleukin-1 Receptor-Associated Kinases
/
Ischemic Stroke
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
United States