Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3‑Kinase (PI3K)‑γ Inhibitors

In
this paper, we describe the discovery and optimization of a
new chemotype of isoform selective PI3Kγ inhibitors. Starting
from an HTS hit, potency and physicochemical properties could be improved
to give compounds such as 15, which is a potent and remarkably
selective PI3Kγ inhibitor with ADME properties suitable for
oral administration. Compound 15 was advanced into in
vivo studies showing dose-dependent inhibition of LPS-induced airway
neutrophilia
in rats when administered orally.