文摘
Optimization of lead compound <b>1b>, through extensive use of structure-based design and a focus on PI3K未 potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates <b>2b> (GSK2269557) and <b>3b> (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds <b>2b> and <b>3b> are both highly selective for PI3K未 over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.