Discovery and Toxicological Profiling of Aminopyridines as Orally Bioavailable Selective Inhibitors of PI3-Kinase γ

Using a novel physiologically relevant
in vitro human whole blood
neutrophil shape change assay, an aminopyrazine series of selective
PI3Kγ inhibitors was identified and prioritized for further
optimization. Severe solubility limitations associated with the series
leading to low oral bioavailability and poor exposures, especially
at higher doses, were overcome by moving to an aminopyridine core.
Compound 33, with the optimal balance of on-target activity,
selectivity, and pharmacokinetic parameters, progressed into in vivo
studies and demonstrated good efficacy (10 mg/kg) in a rat model of
airway inflammation. Sufficient exposures were achieved at high doses
to support toxicological studies, where unexpected inflammatory cell
infiltrates in cardiovascular tissue prevented further compound development.