Down, K; Jones, KL; Jones, P; Keeling, SE; Le, J; Livia, S; Lucas, F; Lunniss, CJ; Parr, NJ; Robinson, Ed; Rowland, P; Amour, A; Smith, S; Thomas, DA; Vitulli, G; Washio, Y; Hamblin, JN; Baldwin, I; Cooper, AWJ; Deakin, AM; Felton, LM; Guntrip, SB; Hardy, C; Harrison, Z; ,
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3K delta potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (G5K2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3K delta over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.