Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3‑Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)

The lipid kinase phosphoinositide
3-kinase γ (PI3Kγ) has attracted attention as a potential
target to treat a variety of autoimmune disorders, including multiple
sclerosis, due to its role in immune modulation and microglial activation.
By minimizing the number of hydrogen bond donors while targeting a
previously uncovered selectivity pocket adjacent to the ATP binding
site of PI3Kγ, we discovered a series of azaisoindolinones as
selective, brain penetrant inhibitors of PI3Kγ.
This ultimately led to the discovery of 16, an orally
bioavailable compound that showed efficacy in murine experimental
autoimmune encephalomyelitis (EAE), a preclinical model of multiple
sclerosis.