Discovery of BIO-8169A Highly Potent, Selective, and Brain-Penetrant IRAK4 Inhibitor for the Treatment of Neuroinflammation

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.