Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.
Matthew W D PerryKarin BjörhallPeter BoldMikael BrűllsUlf BörjessonJohan CarlssonHui-Fang Amy ChangYunhua ChenAnders ErikssonBritt-Marie FihnRebecca FranssonLinda FredlundHongbin GeHaijuan HuangKostas KarabelasEva Lamm BergströmSarah LeverHelena LindmarkMickael MogemarkAntonios NikitidisAnna-Pia PalmgrenNils PembertonJens PetersenMio Rodrigo BlomqvistReed W SmithMatthew J ThomasVictoria UllahChristian TyrchanTiiu WennbergAnnika Westin ErikssonWenzhen YangShuchun ZhaoLinda ÖsterPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- lung function
- allergic rhinitis
- end stage renal disease
- chronic obstructive pulmonary disease
- small molecule
- chronic kidney disease
- ejection fraction
- induced apoptosis
- newly diagnosed
- high throughput
- peritoneal dialysis
- prognostic factors
- cell cycle arrest
- patient reported outcomes
- signaling pathway
- cystic fibrosis
- endoplasmic reticulum stress
- combination therapy
- smoking cessation