Discovery of Edecesertib (GS-5718): A Potent, Selective Inhibitor of IRAK4

Interleukin-1 receptor-associated kinase 4 (IRAK4) activity
mediates
pro-inflammatory signaling and cytokine production downstream of toll-like
and interleukin-1 receptors (TLR, IL-1R). Selective IRAK4 inhibitors
have generated interest as potential treatments for inflammatory diseases.
Herein, we report the discovery of GS-5718 (edecesertib), a potent,
selective, orally bioavailable IRAK4 inhibitor. Key to this endeavor
were efforts undertaken to improve the chemical series’ profile
after a significant hERG liability was encountered for an early compound.
GS-5718 was safe and well-tolerated in IND-enabling preclinical animal
toxicity studies, demonstrated efficacy in a mouse NZB lupus model,
and additionally demonstrated human pharmacokinetic properties suitable
for once-daily administration. Edecesertib is currently under clinical
evaluation for the treatment of lupus.