Discovery of GLPG4471, a potent and selective IRAK4 inhibitor for the treatment of inflammatory and autoimmune diseases.

Interleukin-1 receptor associated kinase 4 (IRAK4) is a key mediator of the secretion of cytokines and interferons via Toll-like receptor and interleukin-1 receptor signaling pathways. Modulation of IRAK4 activity has been investigated for the treatment of inflammatory and autoimmune diseases and of malignancies. Here, new IRAK4 inhibitors were identified from a high throughput screening campaign. Initial structure-activity relationship efforts aimed at improving potency and lipophilic efficiency on IRAK4. Then, structural modifications were made to increase stability towards amide cleavage upon incubation in hepatocytes, and to decrease human ether-a-go-go related gene (hERG) inhibition. Optimization of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties led to compound 21 (GLPG4471), a potent IRAK4 inhibitor that showed excellent selectivity when tested against a panel of 369 kinases. Compound 21 exhibited potent inhibition of cytokine secretion in cellular and whole blood phenotypic assays. Compound 21 displayed dose-dependent activity in vivo in a mouse model of collagen-induced arthritis.