Discovery of Orally Efficacious Phosphoinositide 3-Kinase delta Inhibitors with Improved Metabolic Stability

Aberrant signaling of phosphoinositide 3-kinase delta (PI3K delta) has been implicated in numerous pathologies including hematological malignancies and rheumatoid arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3K delta inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3K delta which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of rheumatoid arthritis.