Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.
Perry MWD, Björhall K, Bold P, Brűlls M, Börjesson U, Carlsson J, Chang HA, Chen Y, Eriksson A, Fihn BM, Fransson R, Fredlund L, Ge H, Huang H, Karabelas K, Lamm Bergström E, Lever S, Lindmark H, Mogemark M, Nikitidis A, Palmgren AP, Pemberton N, Petersen J, Rodrigo Blomqvist M, Smith RW, Thomas MJ, Ullah V, Tyrchan C, Wennberg T, Westin Eriksson A, Yang W, Zhao S, Öster L.
Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.