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 amage-ssociated olecular 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.

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.3c02226DOI Listing

Publication Analysis

Top Keywords

discovery bio-7488
8
potent selective
8
selective cns-penetrant
8
cns-penetrant irak4
8
irak4 inhibitor
8
ischemic stroke
8
irak4
5
bio-7488 potent
4
inhibitor treatment
4
treatment ischemic
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!