Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3-Kinase γ

A series of high,affinity second-generation thiazolopiperidine inhibitors of PI3K gamma were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher level of PI3K gamma selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.