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

• Published in: Journal of medicinal chemistry Vol. 67; no. 6; pp. 4676 - 4690
• Main Authors: Evans, Ryan, Bolduc, Philippe N., Pfaffenbach, Magnus, Gao, Fang, May-Dracka, Tricia, Fang, Terry, Hopkins, Brian T., Chodaparambil, Jayanth V, Henry, Kate L., Li, Pei, Metrick, Claire, Nelson, Ashley, Trapa, Patrick, Thomas, Ankur, Burkly, Linda, Peterson, Emily A.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.03.2024; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Cytokines; Humans; Interleukin-1 Receptor-Associated Kinases; Ischemic Stroke; Life Sciences & Biomedicine; Mice; Pharmacology & Pharmacy; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Science & Technology; Signal Transduction; INTERLEUKIN-1
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c02226

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.