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 gamma (PI3K gamma) 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 PI3K gamma, we discovered a series of aza-isoindolinones as selective, brain penetrant inhibitors of PI3K gamma. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.