Author: Gao, Fang ; Silbereis, John ; Xin, Zhili ; Evans, Ryan ; Mccarl, Christie-Ann ; Li, Pei ; Mathieu, Steven ; Fang, Terry ; Bolduc, Philippe N. ; Gu, Rong-Fang ; Peterson, Emily A. ; Chodaparambil, Jayanth V. ; Vera Rebollar, Jorge A. ; Metrick, Claire ; Henry, Kate L. ; Pfaffenbach, Magnus

Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.

28 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Gao, Fang ; Li, Pei ; Trapa, Patrick ; Metrick, Claire ; Bolduc, Philippe N ; Nelson, Ashley ; Peterson, Emily A ; Burkly, Linda ; Thomas, Ankur ; Hopkins, Brian T ; Pfaffenbach, Magnus ; Henry, Kate L ; Chodaparambil, Jayanth V ; Fang, Terry ; Evans, Ryan ; May-Dracka, Tricia

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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Indication	Highest Phase	Country/Location	Organization	Date
Ischemic stroke	Discovery	US	Biogen, Inc.	11 Mar 2024

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